DE4324014A1 - Process for the production of a composition which can be reconstituted in water - Google Patents

Process for the production of a composition which can be reconstituted in water

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Publication number
DE4324014A1
DE4324014A1 DE4324014A DE4324014A DE4324014A1 DE 4324014 A1 DE4324014 A1 DE 4324014A1 DE 4324014 A DE4324014 A DE 4324014A DE 4324014 A DE4324014 A DE 4324014A DE 4324014 A1 DE4324014 A1 DE 4324014A1
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DE
Germany
Prior art keywords
temperature
sodium sesquihydrate
pantoprazole sodium
sucrose
lyophilisate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
DE4324014A
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German (de)
Other versions
DE4324014C2 (en
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Priority to DE4324014A priority Critical patent/DE4324014C2/en
Priority to PCT/EP1994/004093 priority patent/WO1996017607A1/en
Publication of DE4324014A1 publication Critical patent/DE4324014A1/en
Application granted granted Critical
Publication of DE4324014C2 publication Critical patent/DE4324014C2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A process for the production of a lyophilisate of pantoprazole sodium sesquihydrate is characterised in that aqueous solutions of pantaprazole sodium sesquihydrate are lyophilised in the presence of sucrose as aid at a temperature of -25 DEG C to -30 DEG C. The lyophilisate is distinguished by being easy to reconstitute and having satisfactory storability.

Description

Technisches GebietTechnical field

Die Erfindung bezieht sich auf ein Verfahren zur Herstellung einer in physiologisch verträglichen Flüssigkeiten rekonstituierbaren festen Zube­ reitung für den Wirkstoff Pantoprazol.The invention relates to a method for producing an in physiologically compatible liquids reconstitutable solid accessories riding for the active ingredient pantoprazole.

Stand der TechnikState of the art

Aus EP-B-0166287 ist der Wirkstoff 5-Difluormethoxy-2-[(3,4-dimethyl- 2-pyridyl)methylsulfinyl]-1H-benzimidazol bekannt. Dieser Wirkstoff, der unter dem International Nonproprietory Name (INN) Pantoprazol bekannt ist, eignet sich insbesondere bei parenteraler Verabreichung in hervorragender Weise zur Behandlung akuter blutender Magen-Ulzera. Zur intravenösen Verabreichung wird vorteilhaft das Sesquihydrat des Natriumsalzes von Pantoprazol eingesetzt. Dieses ist jedoch in wäßrigen Lösungen für eine Lagerhaltung auch bei Kühlung nicht stabil genug. Auch die Einarbeitung des Wirkstoffes in nichtphysiologische Lösungsmittel, wie z. B. Polyethylen­ glykol führt nicht zu Lösungen, die bei Raumtemperatur gelagert werden können. Diese Lösungen müssen bei 4°C bis 8°C gelagert werden. Weiterhin nachteilig ist hierbei die bei diesen Temperaturen hohe Viskosität, die ein dosiergenaues Entnehmen und Verdünnen mit Wasser für Injektionszwecke sehr erschwert.From EP-B-0166287 the active ingredient 5-difluoromethoxy-2 - [(3,4-dimethyl- 2-pyridyl) methylsulfinyl] -1H-benzimidazole known. This active ingredient, the known under the International Nonproprietory Name (INN) pantoprazole, is particularly suitable for parenteral administration Way to treat acute bleeding gastric ulcers. For intravenous Administration will advantageously the sesquihydrate of the sodium salt of Pantoprazole used. However, this is in aqueous solutions for one Storage not stable enough even with cooling. The incorporation of the Active ingredient in non-physiological solvents, such as. B. polyethylene glycol does not result in solutions that are stored at room temperature can. These solutions must be stored at 4 ° C to 8 ° C. Farther the disadvantage here is the high viscosity at these temperatures, the one very precise dosing and dilution with water for injections difficult.

Es besteht daher ein Bedarf an einer für parenterale Zwecke geeigneten festen Formulierung für Pantoprazol-Natrium-Sesquihydrat, die eine ausreichende Lagerstabilität bei Raumtemperatur über mindestens 18 Monate besitzt und einfach auf die zu verabreichende Dosis in flüssiger Form rekonstituierbar ist.There is therefore a need for one that is suitable for parenteral purposes solid formulation for pantoprazole sodium sesquihydrate, which is a adequate storage stability at room temperature for at least 18 months owns and simply on the dose to be administered in liquid form is reconstitutable.

Zahlreiche Versuche, den Wirkstoff mit und ohne Hilfsstoffe zu lyophilisieren, führten nicht zu brauchbaren Lyophilisaten. Aus den Erfahrungen bei der Herstellung von Pantoprazol-Tabletten war zu erwarten, daß der für Lyophilisierungen gebräuchliche Hilfsstoff Mannit geeignet sein könnte. Jedoch führte das Lyophilisieren des Wirkstoffs in Gegenwart von Mannit als Hilfsstoff nicht zu einer befriedigenden physikalischen Stabi­ lität.Numerous attempts to add the active ingredient with and without excipients lyophilization did not lead to usable lyophilisates. From the Experience in the manufacture of pantoprazole tablets was expected  that the auxiliary used for lyophilization mannite may be suitable could. However, lyophilizing the drug in the presence of Mannitol as an additive does not lead to a satisfactory physical stabilization lity.

Beschreibung der ErfindungDescription of the invention

Überraschenderweise wurde nun gefunden, daß es möglich ist, unter be­ stimmten Bedingungen Pantoprazol-Natrium-Sesquihydrat mit Saccharose als Hilfsstoff zu einem Produkt mit den gewünschten Eigenschaften zu lyophili­ sieren. Dies ist deshalb als überaus überraschend anzusehen, weil sich Saccharose bei der Entwicklung von Pantoprazol-Tabletten als inkompatibel mit dem Wirkstoff erwiesen hatte. Es wurde gefunden, daß diese Inkompati­ bilität durch eine schnelle und effiziente Trocknung bei einer Produkt­ temperatur von -25°C bis -30°C, vorzugsweise bei -27°C, während des Lyophilisationsprozesses überwunden werden kann.Surprisingly, it has now been found that it is possible to be under agreed conditions pantoprazole sodium sesquihydrate with sucrose as Excipient to a product with the desired properties to lyophili sieren. This is to be regarded as extremely surprising because Sucrose in the development of pantoprazole tablets as incompatible with the active ingredient. It was found that this incompatibility stability through quick and efficient drying of a product temperature from -25 ° C to -30 ° C, preferably at -27 ° C, during the Lyophilization process can be overcome.

Gegenstand der Erfindung ist daher ein Verfahren zur Herstellung eines Lyophilisats von Pantoprazol-Natrium-Sesquihydrat, das dadurch gekenn­ zeichnet ist, daß man Pantoprazol-Natrium-Sesquihydrat in Gegenwart von Saccharose als Hilfsstoff bei einer Produkttemperatur von -25°C bis -30°C, vorzugsweise bei einer Temperatur von -27°C, lyophilisiert.The invention therefore relates to a method for producing a Lyophilisate of pantoprazole sodium sesquihydrate, characterized thereby is that you can pantoprazole sodium sesquihydrate in the presence of Sucrose as an auxiliary at a product temperature of -25 ° C to -30 ° C, preferably lyophilized at a temperature of -27 ° C.

Ein weiterer Gegenstand der Erfindung ist ein Saccharose als Hilfsstoff enthaltendes Lyophilisat von Pantoprazol-Natrium-Sesquihydrat, hergestellt nach dem erfindungsgemäßen Verfahren.Another object of the invention is a sucrose as an adjuvant containing lyophilisate of pantoprazole sodium sesquihydrate by the method according to the invention.

Weitere Gegenstände ergeben sich aus den Patentansprüchen.Further subjects emerge from the patent claims.

HerstellungsbeispielManufacturing example

Zur Herstellung von 700 Einzeldosen wird eine Lösung von 31,57 g Panto­ prazol-Natrium-Sesquihydrat und 25,31 g Saccharose in 1208,72 g Wasser für Injektionszwecke hergestellt. 700 Vials werden mit je 1,8 ml dieser Lösung befüllt.A solution of 31.57 g of Panto is used to produce 700 single cans prazol sodium sesquihydrate and 25.31 g sucrose in 1208.72 g water for Injection manufactured. 700 vials are each with 1.8 ml of this solution filled.

Die Lyophilisierung wird wie folgt durchgeführt:The lyophilization is carried out as follows:

Der Kondensator wird auf -70°C vorgekühlt. Die Stellfläche wird mit den Vials mit aufgesetztem Stopfen beladen und auf -32°C gekühlt. Nach Abkühlen des Vialinhalts auf -27°C wird ein Vakuum von weniger als 0,58 mbar angelegt. In einer ersten Trocknungsphase wird unter Nachregelung der Temperatur der Stellfläche der Vialinhalt für acht Stunden auf -27°C gehalten. In einer zweiten Trocknungsphase wird das Vakuum auf einen möglichst kleinen Wert gebracht und danach die Temperatur um 5°C pro Stunde erhöht bis 35°C erreicht sind. Bei dieser Temperatur wird das Lyophilisat zwei Stunden lang getempert. Nach Fluten der Lyophilisationskammer mit Stickstoff werden die Vials mit Stopfen verschlossen und nach Entnahme aus der Lyophilisationskammer verbördelt.The condenser is pre-cooled to -70 ° C. The footprint is with the Load the vials with the stopper and cool to -32 ° C. After cooling the vial contents to -27 ° C becomes a vacuum of less than 0.58 mbar created. In a first drying phase, the Temperature of the surface of the vial contents for eight hours at -27 ° C held. In a second drying phase, the vacuum is reduced to one brought the smallest possible value and then the temperature by 5 ° C per hour increased until 35 ° C are reached. At this temperature the lyophilisate annealed for two hours. After flooding the lyophilization chamber with The vials are sealed with nitrogen and plugged out after removal the lyophilization chamber crimped.

Pro Vial sind 45,1 mg Pantoprazol-Natrium-Sesquihydrat enthalten. Zur Verabreichung werden die Vialinhalte mit 10 ml physiologischer Kochsalz­ lösung rekonstituiert und als klare Lösung injiziert.Each vial contains 45.1 mg pantoprazole sodium sesquihydrate. For The vial contents are administered with 10 ml of physiological common salt reconstituted solution and injected as a clear solution.

Claims (10)

1. Verfahren zur Herstellung eines Lyophilisats von Pantoprazol-Natrium- Sesquihydrat, dadurch gekennzeichnet, daß man wäßrige Lösungen von Panto­ prazol-Natrium-Sesquihydrat in Gegenwart von Saccharose als Hilfsstoff bei einer Produkttemperatur von -25°C bis -30°C lyophilisiert.1. A process for the preparation of a lyophilizate of pantoprazole sodium sesquihydrate, characterized in that lyophilized aqueous solutions of panto prazol sodium sesquihydrate in the presence of sucrose as an auxiliary at a product temperature of -25 ° C to -30 ° C. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man bei einer Temperatur von -27°C lyophilisiert.2. The method according to claim 1, characterized in that one Temperature of -27 ° C lyophilized. 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man über 6 bis 8 Stunden lyophilisiert.3. The method according to claim 1, characterized in that one over 6 to 8th Hours lyophilized. 4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man in einem zweiten Trocknungsschritt die Temperatur des Lyophilisats um 4°C bis 6°C pro Stunde erhöht, bis eine Temperatur von 30°C bis 40°C erreicht ist.4. The method according to claim 1, characterized in that one second drying step the temperature of the lyophilizate by 4 ° C to 6 ° C increased per hour until a temperature of 30 ° C to 40 ° C is reached. 5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß man anschließend das Lyophilisat bei einer Temperatur von 30°C bis 40°C ein bis drei Stunden tempert.5. The method according to claim 4, characterized in that one then the lyophilisate at a temperature of 30 ° C to 40 ° C for one to three hours tempered. 6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß man bei einer Temperatur von 35°C zwei Stunden tempert.6. The method according to claim 5, characterized in that one Temperature of 35 ° C anneals for two hours. 7. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Lyophilisation in Vials, enthaltend 40 bis 50 mg Pantoprazol-Natrium- Sesquihydrat und 30 bis 40 mg Saccharose gelöst in 1,5 bis 2 ml Wasser, durchführt.7. The method according to claim 1, characterized in that the Lyophilization in vials containing 40 to 50 mg pantoprazole sodium Sesquihydrate and 30 to 40 mg sucrose dissolved in 1.5 to 2 ml water, carries out. 8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, daß in den Vials 45,1 mg Pantoprazol-Natrium-Sesquihydrat und 36,16 mg Saccharose in 1,8 ml Wasser enthalten sind.8. The method according to claim 7, characterized in that in the vials 45.1 mg pantoprazole sodium sesquihydrate and 36.16 mg sucrose in 1.8 ml Water are included. 9. Lyophilisate von Pantoprazol-Natrium-Sesquihydrat erhältlich nach den Verfahren der Ansprüche 1 bis 8. 9. Lyophilisate of pantoprazole sodium sesquihydrate available according to the Method of claims 1 to 8.   10. Lyophilisate von Pantoprazol-Natrium-Sesquihydrat enthaltend pro 45,1 mg Pantoprazol-Natrium-Sesquihydrat 30 bis 40 mg Saccharose.10. Lyophilisate of pantoprazole sodium sesquihydrate containing pro 45.1 mg pantoprazole sodium sesquihydrate 30 to 40 mg sucrose.
DE4324014A 1993-07-17 1993-07-17 Process for the preparation of a preparation reconstitutable in water Expired - Fee Related DE4324014C2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE4324014A DE4324014C2 (en) 1993-07-17 1993-07-17 Process for the preparation of a preparation reconstitutable in water
PCT/EP1994/004093 WO1996017607A1 (en) 1993-07-17 1994-12-09 Method of producing a pantoprazol lyophilisate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4324014A DE4324014C2 (en) 1993-07-17 1993-07-17 Process for the preparation of a preparation reconstitutable in water
PCT/EP1994/004093 WO1996017607A1 (en) 1993-07-17 1994-12-09 Method of producing a pantoprazol lyophilisate

Publications (2)

Publication Number Publication Date
DE4324014A1 true DE4324014A1 (en) 1995-01-19
DE4324014C2 DE4324014C2 (en) 1995-06-08

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WO (1) WO1996017607A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996017607A1 (en) * 1993-07-17 1996-06-13 Byk Gulden Lomberg Chemische Fabrik Gmbh Method of producing a pantoprazol lyophilisate
WO2002041919A1 (en) * 2000-11-22 2002-05-30 Altana Pharma Ag Freeze-dried pantoprazole preparation and pantoprazole injection
GB2404856A (en) * 2003-08-18 2005-02-16 Cadila Pharm Ltd Stable pharmaceutical composition of rabeprazole
WO2005077936A1 (en) * 2004-02-11 2005-08-25 Ulkar Kimya Sanayii Ve Ticaret A.S. Pyridine benzimidazole sulfoxides with high purity
AU2006235847B2 (en) * 2000-11-22 2007-06-07 Takeda Gmbh Lyophilized pantoprazole preparation

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0858272B1 (en) * 1995-10-17 2004-04-21 Checkmate International Pty Ltd Shelving system
US7683177B2 (en) 2003-06-10 2010-03-23 Teva Pharmaceutical Industries Ltd Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole
CN102512418B (en) * 2010-12-06 2014-11-26 山东绿叶制药有限公司 Pantoprazole sodium drug composition and preparation method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4219390A1 (en) * 1991-06-17 1992-12-24 Byk Gulden Lomberg Chem Fab ORAL PHARMACEUTICAL FORMULAS FOR SAEURELABILE ACTIVE SUBSTANCES

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG52479A1 (en) * 1992-07-28 1998-09-28 Astra Ab Injection and injection kit containing omeprazole and its analogs
DE4324014C2 (en) * 1993-07-17 1995-06-08 Byk Gulden Lomberg Chem Fab Process for the preparation of a preparation reconstitutable in water

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4219390A1 (en) * 1991-06-17 1992-12-24 Byk Gulden Lomberg Chem Fab ORAL PHARMACEUTICAL FORMULAS FOR SAEURELABILE ACTIVE SUBSTANCES

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996017607A1 (en) * 1993-07-17 1996-06-13 Byk Gulden Lomberg Chemische Fabrik Gmbh Method of producing a pantoprazol lyophilisate
AU2006235847C1 (en) * 2000-11-22 2008-02-21 Takeda Gmbh Lyophilized pantoprazole preparation
HRP20030410B1 (en) * 2000-11-22 2011-02-28 Nycomed Gmbh Freeze dried pantoprazole preparation and pantoprazole injection
US8754108B2 (en) 2000-11-22 2014-06-17 Takeda, GmbH Freeze-dried pantoprazole preparation and pantoprazole injection
EP1762249A3 (en) * 2000-11-22 2014-05-14 Takeda GmbH Freeze-dried pantoprazole preparation and pantoprazole injection
AU2002216042B2 (en) * 2000-11-22 2006-08-03 Takeda Gmbh Freeze-dried pantoprazole preparation and pantoprazole injection
EA007602B1 (en) * 2000-11-22 2006-12-29 Алтана Фарма Аг Pantoprazole preparation obtained by freeze drying and solution for injections based thereon
AU2006235847B2 (en) * 2000-11-22 2007-06-07 Takeda Gmbh Lyophilized pantoprazole preparation
CZ304348B6 (en) * 2000-11-22 2014-03-19 Takeda Gmbh Process for preparing lyophilized preparation
WO2002041919A1 (en) * 2000-11-22 2002-05-30 Altana Pharma Ag Freeze-dried pantoprazole preparation and pantoprazole injection
US7351723B2 (en) 2000-11-22 2008-04-01 Nycomed Gmbh Freeze-dried pantoprazole preparation and pantoprazole injection
US6780881B2 (en) 2000-11-22 2004-08-24 Altana Pharma Ag Freeze-dried pantoprazole preparation and pantoprazole injection
GB2404856B (en) * 2003-08-18 2007-10-10 Cadila Pharm Ltd Stable pharmaceutical composition of rabeprazole
GB2404856A (en) * 2003-08-18 2005-02-16 Cadila Pharm Ltd Stable pharmaceutical composition of rabeprazole
WO2005077936A1 (en) * 2004-02-11 2005-08-25 Ulkar Kimya Sanayii Ve Ticaret A.S. Pyridine benzimidazole sulfoxides with high purity

Also Published As

Publication number Publication date
DE4324014C2 (en) 1995-06-08
WO1996017607A1 (en) 1996-06-13

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