WO2001039741A2 - Mitomycin c solution - Google Patents
Mitomycin c solution Download PDFInfo
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- WO2001039741A2 WO2001039741A2 PCT/EP2000/011903 EP0011903W WO0139741A2 WO 2001039741 A2 WO2001039741 A2 WO 2001039741A2 EP 0011903 W EP0011903 W EP 0011903W WO 0139741 A2 WO0139741 A2 WO 0139741A2
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K47/02—Inorganic compounds
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- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
Definitions
- the invention relates to a stable aqueous solution of the cytostatic mitomycin C and in particular a drug containing mitomycin C.
- Mitomycin C (Antibiot. Chemother. 8 (1958) 228) isolated in 1958 is an antibiotic isolated from Streptomyces caespei tosus, which has excellent antitumor activity and is used in particular in the treatment of bladder tumors.
- Mito ⁇ vycin dry substance is usually sold, from which a solution is prepared immediately before use.
- the shelf life of the solution is usually limited to one day, with other therapeutic requirements (e.g. continuous infusion) to a maximum of 5 days and due to the breakdown of mitomycin C, there is a loss of activity of up to 10% during this time.
- BESTATIGUNGSKOPIE It is therefore an object of the present invention to provide a sufficiently stable, preferably long-term stable mitomycin solution which contains mitomycin C in sufficient concentration and suitable composition for clinical use.
- a drug is to be provided in the form of an instillation solution which is suitable for the treatment of bladder tumors.
- the object is achieved by a buffered aqueous, dextrose-free mitomycin C solution which is adjusted to a pH in the range from 6.0 to 9.0 and contains 0.1 to 0.45 mg / ml mitomycin C and in which the The ratio of mitomycin C concentration to the ionic strength of the buffer substances is approximately 0.005 to 0.2, ie the ionic strength is in the range of about 7.5 to 60 mmol / 1.
- aqueous mitomycin C solutions is maintained with an essentially unchanged concentration of active substance, ie essentially unchanged activity, if a buffer of low ionic strength, preferably in the range, is used to prepare the solution prepared from 7.5 to 60 mmol / 1.
- the mitomycin C concentrations suitable for therapeutic use are usually in the range from about 0.1 to 0.45 mg / ml mitomycin C, corresponding to about 0.30 to 1.35 mmol / 1.
- mitomycin C solutions with more than 0.45 mg / ml mitomycin C have the disadvantage that long-term storage of the solutions in the refrigerator leads to crystallization of the active substance.
- a mitomycin C concentration of less than 0.1 mg / ml should also be of subordinate practical importance, since, for example, when instilling the urinary bladder for the treatment of bladder tumors, the patient had to be instilled or infused with large amounts of liquid in order to obtain a corresponding one To apply the amount of active ingredient. It has been shown according to the invention that mitomycin C solutions which contain 0.1 to 0.45 mg / ml of active ingredient and in which the ratio of mitomycin C concentration to the ionic strength of the buffer substances is in the range from about 0.005 to 0.2, have a very high storage stability when stored in a refrigerator (approx. 5 ° C) and the loss of active ingredient (loss of activity) after less than a year of storage is less than 10%. When using buffers with very low ionic strength, preferably> 30 mmol / 1 or> 15 mmol / 1, the loss of activity can be reduced to less than 5% after one year of storage.
- the mitomycin C solutions are adjusted to a range from 6 to 9, preferably 7 to 8. Solutions with a pH of 7.75 are particularly preferred.
- a phosphate buffer has proven to be particularly advantageous in which disodium phosphate (Na z HP0 4 "12 H 2 0) and sodium dihydrogen phosphate (NaH z P0 4 -2 H 2 0) in a molar ratio of about 6: 1.
- disodium phosphate Na z HP0 4 "12 H 2 0
- sodium dihydrogen phosphate NaH z P0 4 -2 H 2 0
- a phosphate buffer with an ionic strength of about 30 is used, which is obtained by using 3.350 g / 1 disodium hydrogen phosphate and 264 mg / ml sodium dihydrogen phosphate. It has also been shown that halving the phosphate concentrations again (i.e. 1.675 g / 1 disodium hydrogen phosphate and 132 mg / ml sodium dihydrogen phosphate; ionic strength about 15 mmol / 1) leads to a further increase in the storage stability of the mitomycin C solutions.
- mitomycin C solutions are made using the above Phosphate buffers are provided that contain 0.4 mg / ml (corresponding to approximately 1.2 mmol / 1) mitomycin C.
- the invention thus further relates to a mitomycin C-containing medicament which comprises a solution described above, which is in a form suitable for infusion or instillation, and additional pharmaceutically acceptable auxiliaries, such as e.g. Contains sodium chloride or mannitol.
- the medicament is preferably a pharmaceutical preparation for the treatment of bladder tumors, the medicament being in a form suitable for instillation into the bladder.
- mitomycin was dissolved in phosphate buffer, sterile filtered and e.g. for analytical tests filled into 5 ml sample tubes, which were kept in the refrigerator.
- Solution 2 205.55 mg in 500.00 ml PPIII buffer + 7.5 g NaCl / 1 buffer
- the mitomycin C content of the solutions prepared was determined using high performance liquid chromatography (HPLC) under the following conditions: 1) Analytical system
- HPLC pump type Knauer HPLC pump type 364.00
- Integrator type / evaluation system Jasco / Borwin
- Injector loop volume 20 ⁇ l stationary phase: Molnar, EnCa Pharm 100 RP 18
- the method used fulfills the requirement for precise measurement results.
- the HPLC measurements were made approximately weekly over a period of more than 1 year.
- the values shown in FIG. 1 were obtained for the solution of mitomycin C in the phosphate buffer of Example 1. It is clearly shown that when the phosphate buffer with an ionic strength of approximately 30 mmol / l is used, a very high storage stability is achieved, the loss of activity after storage for more than 1 year being less than 5%.
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Abstract
Description
Mitomycin C- ösunα Mitomycin C-ösunα
Die Erfindung betrifft eine stabile wäßrige Lösung des Zytostatikums Mitomycin C und insbesondere ein Mitomycin C-enthalten- des Arzneimittel .The invention relates to a stable aqueous solution of the cytostatic mitomycin C and in particular a drug containing mitomycin C.
Das 1958 isolierte Mitomycin C (Antibiot. Chemother. 8 (1958) 228) ist ein aus Streptomyces caespei tosus isoliertes Antibiotikum, das ausgezeichnete Antitumor-Wirkung besitzt und insbesondere bei der Behandlung von Blasentumoren eingesetzt wird.Mitomycin C (Antibiot. Chemother. 8 (1958) 228) isolated in 1958 is an antibiotic isolated from Streptomyces caespei tosus, which has excellent antitumor activity and is used in particular in the treatment of bladder tumors.
Nachteilig im Hinblick auf die klinische Anwendung von Mitomycin C ist die geringe Stabilität von Mitomycin-Infusionslösungen und die damit einhergehende begrenzte Lagerfähigkeit. Aus diesem Grund wird üblicherweise Mitoπvycin-Trockensubstanz vertrieben, aus der unmittelbar vor Anwendung eine Lösung zubereitet wird. Die Haltbarkeit der Lösung ist in der Regel auf einen Tag, bei anderen therapeutischen Erfordernissen (z.B. Dauerinfusion) auf höchstens 5 Tage begrenzt und aufgrund des Abbaus von Mitomycin C mit einem Wirkverlust in dieser Zeit von bis zu 10 % verbunden.A disadvantage with regard to the clinical use of mitomycin C is the low stability of mitomycin infusion solutions and the associated limited shelf life. For this reason, Mitoπvycin dry substance is usually sold, from which a solution is prepared immediately before use. The shelf life of the solution is usually limited to one day, with other therapeutic requirements (e.g. continuous infusion) to a maximum of 5 days and due to the breakdown of mitomycin C, there is a loss of activity of up to 10% during this time.
BESTATIGUNGSKOPIE Aufgabe der vorliegenden Erfindung ist es daher, eine hinreichend stabile, vorzugsweise langzeitstabile Mitomycin-Lösung zur Verfügung zu stellen, die Mitomycin C in ausreichender Konzentration und geeigneter Zusammensetzung für die klinische Anwendung enthält. Insbesondere soll ein Arzneimittel in Form einer Instillationslösung bereitgestellt werden, das sich zur Behandlung von Harnblasen-Tumoren eignet.BESTATIGUNGSKOPIE It is therefore an object of the present invention to provide a sufficiently stable, preferably long-term stable mitomycin solution which contains mitomycin C in sufficient concentration and suitable composition for clinical use. In particular, a drug is to be provided in the form of an instillation solution which is suitable for the treatment of bladder tumors.
Erfindungsgemäß wird die Aufgabe durch eine auf einen pH-Wert im Bereich von 6,0 bis 9,0 eingestellte gepufferte wäßrige, dextrosefreie Mitomycin C-Lösung gelöst, die 0,1 bis 0,45 mg/ml Mitomycin C enthält und bei der das Verhältnis von Mitomycin C- Konzentration zur Ionenstärke der Puffersubstanzen etwa 0,005 bis 0,2 beträgt, d.h. die Ionenstärke im Bereich von etwa 7,5 bis 60 mmol/1 liegt.According to the invention the object is achieved by a buffered aqueous, dextrose-free mitomycin C solution which is adjusted to a pH in the range from 6.0 to 9.0 and contains 0.1 to 0.45 mg / ml mitomycin C and in which the The ratio of mitomycin C concentration to the ionic strength of the buffer substances is approximately 0.005 to 0.2, ie the ionic strength is in the range of about 7.5 to 60 mmol / 1.
Im Rahmen der vorliegenden Erfindung wurde überraschenderweise festgestellt, daß die Lagerfähigkeit wäßriger Mitomycin C- Lösungen bei im wesentlichen unveränderter Wirkstoff-Konzen- tration, d.h. im wesentlichen unveränderter Aktivität, erhalten bleibt, wenn man zur Herstellung der Lösung einen Puffer niedriger Ionenstärke, vorzugsweise im Bereich von 7,5 bis 60 mmol/1 zubereitet. Die zur therapeutischen Anwendung geeigneten Mitomycin C-Konzentrationen liegen üblicherweise im Bereich von etwa 0,1 bis 0,45 mg/ml Mitomycin C, entsprechend etwa 0,30 bis 1,35 mmol/1. Obwohl für viele Anwendungen auch höhere Wirkstoff-Konzentrationen in Frage kommen können, weisen Mitomycin C-Lösungen mit mehr als 0,45 mg/ml Mitomycin C den Nachteil auf, daß langfristige Lagerung der Lösungen im Kühl- schrank zur Auskristallisation des Wirkstoffs führt. Eine Mitomycin C-Konzentration von weniger als 0,1 mg/ml dürfte ebenfalls von untergeordneter praktischer Bedeutung sein, da, zum Beispiel bei der Instillation der Harnblase zur Behandlung von Blasentumoren, dem Patienten große Flüssigkeitsmengen instilliert bzw. infundiert werden mußten, um eine entsprechende Wirkstoffmenge zu applizieren. Es hat sich erfindungsgemäß gezeigt, daß Mitomycin C-Lösungen, die 0,1 bis 0,45 mg/ml Wirkstoff enthalten und bei denen das Verhältnis von Mitomycin C-Konzentration zur Ionenstärke der Puffersubstanzen im Bereich von etwa 0,005 bis 0,2 liegt, bei Aufbewahrung im Kühlschrank (etwa 5 °C) eine sehr hohe Lagerstabilität aufweisen und der Wirkstoffverlust (Aktivitätsverlust) nach einjähriger Lagerung bei weniger als 10 % liegt. Bei Verwendung von Puffern mit sehr geringer Ionenstärke, vorzugsweise > 30 mmol/1 bzw. > 15 mmol/1, kann der Aktivitätsverlus sogar auf unter 5 % nach einjähriger Lagerung gesenkt werden.In the context of the present invention, it was surprisingly found that the storage stability of aqueous mitomycin C solutions is maintained with an essentially unchanged concentration of active substance, ie essentially unchanged activity, if a buffer of low ionic strength, preferably in the range, is used to prepare the solution prepared from 7.5 to 60 mmol / 1. The mitomycin C concentrations suitable for therapeutic use are usually in the range from about 0.1 to 0.45 mg / ml mitomycin C, corresponding to about 0.30 to 1.35 mmol / 1. Although higher active substance concentrations can also be considered for many applications, mitomycin C solutions with more than 0.45 mg / ml mitomycin C have the disadvantage that long-term storage of the solutions in the refrigerator leads to crystallization of the active substance. A mitomycin C concentration of less than 0.1 mg / ml should also be of subordinate practical importance, since, for example, when instilling the urinary bladder for the treatment of bladder tumors, the patient had to be instilled or infused with large amounts of liquid in order to obtain a corresponding one To apply the amount of active ingredient. It has been shown according to the invention that mitomycin C solutions which contain 0.1 to 0.45 mg / ml of active ingredient and in which the ratio of mitomycin C concentration to the ionic strength of the buffer substances is in the range from about 0.005 to 0.2, have a very high storage stability when stored in a refrigerator (approx. 5 ° C) and the loss of active ingredient (loss of activity) after less than a year of storage is less than 10%. When using buffers with very low ionic strength, preferably> 30 mmol / 1 or> 15 mmol / 1, the loss of activity can be reduced to less than 5% after one year of storage.
Die Mitomycin C-Lösungen werden auf einen Bereich von 6 bis 9, vorzugsweise 7 bis 8, eingestellt. Besonders bevorzugt sind Lösungen mit pH-Wert 7,75.The mitomycin C solutions are adjusted to a range from 6 to 9, preferably 7 to 8. Solutions with a pH of 7.75 are particularly preferred.
Im Rahmen der vorliegenden Erfindung hat sich die Verwendung eines Phosphat-Puffers als besonders vorteilhaft erwiesen, bei dem Dinatriumphosphat (NazHP04"12 H20) und Natriumdihydrogenphosphat (NaHzP04-2 H20) im molaren Verhältnis von etwa 6 : 1 verwendet werden. Gemäß einer Aus fuhrungsform der Erfindung werden zur Herstellung dieses Phosphat-Puffers 6,7 g/1 (entsprechend etwa 18,72 mmol/1) Dinatriumhydrogenphosphat und 528 mg/1 (entsprechend etwa 3,38 mmol/1) Natriumdihydrogenphosphat verwendet, wobei dieser Puffer eine Ionenstärke von etwa 60 mmol/1 aufweist.In the context of the present invention, the use of a phosphate buffer has proven to be particularly advantageous in which disodium phosphate (Na z HP0 4 "12 H 2 0) and sodium dihydrogen phosphate (NaH z P0 4 -2 H 2 0) in a molar ratio of about 6: 1. According to one embodiment of the invention, 6.7 g / l (corresponding to approximately 18.72 mmol / l) disodium hydrogen phosphate and 528 mg / l (corresponding to approximately 3.38 mmol / l.) Are used to produce this phosphate buffer ) Sodium dihydrogen phosphate used, this buffer having an ionic strength of about 60 mmol / 1.
Gemäß einer besonderen Aus fuhrungsform der Erfindung wird ein Phosphat-Puffer mit einer Ionenstärke von etwa 30 eingesetzt, der durch Verwendung von 3,350 g/1 Dinatriumhydrogenphosphat und 264 mg/ml Natriumdihydrogenphosphat erhalten wird. Es hat sich ferner gezeigt, eine nochmalige Halbierung der Phosphat-Konzentrationen (d.h. 1,675 g/1 Dinatriumhydrogenphosphat und 132 mg/ml Natriumdihydrogenphosphat; Ionenstärke etwa 15 mmol/1) zu einer weiteren Erhöhung der Lagerstabilität der Mitomycin C-Lösungen führt.According to a particular embodiment of the invention, a phosphate buffer with an ionic strength of about 30 is used, which is obtained by using 3.350 g / 1 disodium hydrogen phosphate and 264 mg / ml sodium dihydrogen phosphate. It has also been shown that halving the phosphate concentrations again (i.e. 1.675 g / 1 disodium hydrogen phosphate and 132 mg / ml sodium dihydrogen phosphate; ionic strength about 15 mmol / 1) leads to a further increase in the storage stability of the mitomycin C solutions.
Gemäß einer besonders bevorzugten Ausfuhrungsform der Erfindung werden Mitomycin C-Lösungen unter Verwendung der obengenannten Phosphat-Puffer zur Verfügung gestellt, die 0,4 mg/ml (entsprechend etwa 1,2 mmol/1) Mitomycin C enthalten.According to a particularly preferred embodiment of the invention, mitomycin C solutions are made using the above Phosphate buffers are provided that contain 0.4 mg / ml (corresponding to approximately 1.2 mmol / 1) mitomycin C.
Die Erfindung betrifft somit ferner ein Mitomycin C-enthaltendes Arzneimittel, das eine oben beschriebene Lösung umfaßt, die in einer zur Infusion oder Instillation geeigneten Form vorliegt und zusätzliche pharmazeutisch verträgliche Hilfsstoffe, wie z.B. Natriumchlorid oder Mannit, enthält. Vorzugsweise handelt es sich bei dem Arzneimittel um ein pharmazeutisches Präparat zur Behandlung von Harnblasen-Tumoren, wobei das Arzneimittel in einer zur Instillation in die Harnblase geeigneten Form vorliegt.The invention thus further relates to a mitomycin C-containing medicament which comprises a solution described above, which is in a form suitable for infusion or instillation, and additional pharmaceutically acceptable auxiliaries, such as e.g. Contains sodium chloride or mannitol. The medicament is preferably a pharmaceutical preparation for the treatment of bladder tumors, the medicament being in a form suitable for instillation into the bladder.
Die vorliegende Erfindung wird nachfolgend anhand von Beispielen beschrieben.The present invention is described below using examples.
BeispieleExamples
Beispiel 1: Herstellung von Mi omycin-LösungenExample 1: Preparation of mi omycin solutions
Zur Herstellung von Mitomycin-Lösungen wurde Mitomycin in Phosphat-Puffer gelöst, steril filtriert und für analytische Untersuchungen z.B. in 5 ml-Probenröhrchen gefüllt, die im Kühl- schrank aufbewahrt wurden.To produce mitomycin solutions, mitomycin was dissolved in phosphate buffer, sterile filtered and e.g. for analytical tests filled into 5 ml sample tubes, which were kept in the refrigerator.
Folgende Mitomycin-Lösungen wurden hergestellt:The following mitomycin solutions were made:
Mitomycin Lösungen 0,4 mg/mlMitomycin solutions 0.4 mg / ml
Aseptische Abfüllung nach Sterilfiltration:Aseptic filling after sterile filtration:
Lagerung bei 4 bis 8 °C Mitomycin-Lösungen; SOLL-KonzentratJonen:Storage at 4 to 8 ° C Mitomycin solutions; DESIRED concentrate Jonen:
1) 0,4 mg/ml Mitomycin in PPIII Puffer pH: 7,61 60 mOsmol/kg1) 0.4 mg / ml mitomycin in PPIII buffer pH: 7.61 60 mOsmol / kg
2) 0,4 mg/ml Mitomycin in PPIII Puffer + 7,5 g NaCl/1 Puffer pH: 7,42 294 mOsmol/kg2) 0.4 mg / ml mitomycin in PPIII buffer + 7.5 g NaCl / 1 buffer pH: 7.42 294 mOsmol / kg
3) 0,4 mg/ml Mitomycin in PPIV Puffer pH: 7,62 29 mOsmol/kg3) 0.4 mg / ml mitomycin in PPIV buffer pH: 7.62 29 mOsmol / kg
4) 0,4 mg/ml Mitomycin in PPIV Puffer + 8,3 g NaCl/1 Puffer pH: 7,41 290 mOsmol/kg4) 0.4 mg / ml mitomycin in PPIV buffer + 8.3 g NaCl / 1 buffer pH: 7.41 290 mOsmol / kg
Lösunqsmittelrezeptur "Phosphatpuffer III" (PPIII)Solvent formulation "Phosphate Buffer III" (PPIII)
3,350 g Na2HP04 • 12 H203.350 g Na 2 HP0 4 • 12 H 2 0
0,264 g NaH2POA • 2 H20 ad 500,00 ml mit Wasser für Injektionszwecke (WFI) pH = 7,620.264 g NaH 2 PO A • 2 H 2 0 ad 500.00 ml with water for injections (WFI) pH = 7.62
Lösunqsmittelrezeptur "Phosphatpuffer IV" (PPIV)Solvent formulation "Phosphate Buffer IV" (PPIV)
PPIV Puffer = 1 Teil PPIII + 1 Teil WFI pH = 7,70PPIV buffer = 1 part PPIII + 1 part WFI pH = 7.70
Phosphatsalze; IST Einwaagen:Phosphate salts; ACTUAL weights:
Na2HPOA • 12 H20 : 13 , 42 g NaH2P04 • 2 H20 : 1 , 06 g ad 2000,00 ml mit Wasser für Injektionszwecke Mitomycin IST-Einwaagen:Na 2 HPO A • 12 H 2 0: 13, 42 g of NaH 2 P0 4 • 2 H 2 0: 1, 06 g ad 2000.00 ml with water for injection purposes Mitomycin actual weights:
Lösung 1: 202,13 mg in 500,00 ml PPIII PufferSolution 1: 202.13 mg in 500.00 ml PPIII buffer
Lösung 2: 205,55 mg in 500,00 ml PPIII Puffer + 7,5 g NaCl/1 PufferSolution 2: 205.55 mg in 500.00 ml PPIII buffer + 7.5 g NaCl / 1 buffer
Lösung 3: 206,11 mg in 500,00 ml PPIV PufferSolution 3: 206.11 mg in 500.00 ml PPIV buffer
Lösung 4: 197,90 mg in 500,00 ml PPIV Puffer + 8,3 g NaCl/1 PufferSolution 4: 197.90 mg in 500.00 ml PPIV buffer + 8.3 g NaCl / 1 buffer
Eingesetzte Chemikalien:Chemicals used:
Mitomycin rein Charge 961201Mitomycin pure lot 961201
Wasser für Injektionszwecke, 1000 ml, Braun, Charge 8023A44A, Verfall 12.2002 Na2HP04 • 12 H20, Merck Art. 6579, Charge 961025-NP NaH2P04 • 2 H20, Merck Art. 6345, Charge A146/2Water for injections, 1000 ml, brown, batch 8023A44A, expiration 12.2002 Na 2 HP0 4 • 12 H 2 0, Merck Art. 6579, batch 961025-NP NaH 2 P0 4 • 2 H 2 0, Merck Art. 6345, batch A146 / 2
Eingesetzte Hilfsmittel:Aids used:
Werkbank Klasse II, medac HamburgClass II workbench, medac Hamburg
Mikrozid Liquid Desinfektionslösung, Schülke & Mayr, ChargeMikrozid Liquid disinfectant solution, Schülke & Mayr, batch
PJ2251, Verfall 07.2000PJ2251, expiration 07.2000
Sterile Einmalfilter, 0,20 μ , Sartorius Minisert, ChargeSterile disposable filters, 0.20 μ, Sartorius Minisert, batch
16534/970209, Verfall 04.2000 Sterile Einmalspritze 30 ml, Henke-Sass, Wolf, Charge 94234,16534/970209, expiration 04.2000 sterile disposable syringe 30 ml, Henke-Sass, Wolf, batch 94234,
Verfall 30.06.1999Expiration June 30, 1999
Sterile Probenröhrchen, Greiner, Charge 8945Sterile sample tubes, Greiner, batch 8945
Einmalhandschuhe UniglovesDisposable gloves Unigloves
Beispiel 2: Bestimmung der Mitomycin-StabilitätExample 2: Determination of Mitomycin Stability
Die Bestimmung des Mitomycin C-Gehaltes der hergestellten Lösungen erfolgte mittels High Performance Liquid Chromatography (HPLC) unter folgenden Bedingungen: 1 ) Analytisches SystemThe mitomycin C content of the solutions prepared was determined using high performance liquid chromatography (HPLC) under the following conditions: 1) Analytical system
HPLC-Pumpentyp: Knauer HPLC-Pumpe Typ 364.00HPLC pump type: Knauer HPLC pump type 364.00
Integrator Typ/Auswertesystem: Jasco/BorwinIntegrator type / evaluation system: Jasco / Borwin
Detektor: Knauer-HPLC-Spektralphotometer mit DigitalanzeigeDetector: Knauer HPLC spectrophotometer with digital display
Nr. A0293/V7026 verwendete Wellenlänge: 365 nm Injektortyp: Rheodyne mit SignalkontaktNo. A0293 / V7026 used wavelength: 365 nm injector type: Rheodyne with signal contact
Injektor-Schleifen-Volumen: 20 μl stationäre Phase: Molnar, EnCa Pharm 100 RP 18Injector loop volume: 20 μl stationary phase: Molnar, EnCa Pharm 100 RP 18
(5 μm) 250 x 4,6 mm mobile Phase: 0 , 05 M Na2HPO -Lösung ( pH 6 , 0 ) +(5 μm) 250 x 4.6 mm mobile phase: 0.05 M Na 2 HPO solution (pH 6.0) +
ACN 85 : 15ACN 85: 15
Flußrate: 1,0 ml/min bei 30 °C Säulenofen- temperaturFlow rate: 1.0 ml / min at 30 ° C column oven temperature
Validierung der HPLC-Gehaltsbestimmung von MitomycinValidation of the HPLC content determination of mitomycin
2) Präzision der Methode2) Precision of the method
Anhand von 10 Einzelinjektionen, ermittelt mit der normal zu analysierenden Lösungskonzentration, wurde die relative Standardabweichung (RSD < 2,0 %) der zu analysierenden Signalfläche aus den Originalmeßdaten ermittelt. Using 10 individual injections, determined with the solution concentration to be analyzed normally, the relative standard deviation (RSD <2.0%) of the signal area to be analyzed was determined from the original measurement data.
Messung Signaltläche Messung Signaltläche Messung Sigiinlllüche IAU] [AU] [AU]Signal area measurement Signal area measurement Signal area measurement IAU] [AU] [AU]
1 10.566.558 6 10.581.770 11 10.645.2271 10,566,558 6 10,581,770 11 10,645,227
2 10.661.777 7 10.628.228 12 10.479.9752 10,661,777 7 10,628,228 12 10,479,975
3 10.643.395 8 10.560.442 13 10.472.0223 10,643,395 8 10,560,442 13 10,472,022
4 10.576.607 9 10.577.316 14 10.562.3554 10,576,607 9 10,577,316 14 10,562,355
5 10.665.616 10 10.401.130 15 10.594.0595 10.665.616 10 10.401.130 15 10.594.059
Mittelwert: 10 .574.431,8 AUAverage: 10,574,431.8 AU
Standardabwi Eichung: + 75.073,636Standard deviation calibration: + 75.073.636
Rel. Standardabweichung: 0.70995 %Rel. Standard deviation: 0.70995%
Zusammenf ssung:Summary:
Die verwendete Methode erfüllt die Forderung nach präzisen Meßergebnissen .The method used fulfills the requirement for precise measurement results.
Die HPLC-Messungen erfolgten etwa wöchentlich über einen Zeitraum von mehr als 1 Jahr. Für die Lösung von Mitomycin C in Phosphat- Puffer des Beispiels 1 wurden die in Figur 1 gezeigten Werte erhalten. Es zeigt sich eindeutig, daß bei Verwendung des Phosphat-Puffers mit einer Ionenstärke von etwa 30 mmol/1 eine sehr hohe Lagerstabilität erzielt wird, wobei der Aktivitätsver- lust nach Lagerung über einen Zeitraum von mehr als 1 Jahr unter 5 % liegt. The HPLC measurements were made approximately weekly over a period of more than 1 year. The values shown in FIG. 1 were obtained for the solution of mitomycin C in the phosphate buffer of Example 1. It is clearly shown that when the phosphate buffer with an ionic strength of approximately 30 mmol / l is used, a very high storage stability is achieved, the loss of activity after storage for more than 1 year being less than 5%.
Claims
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU26699/01A AU2669901A (en) | 1999-11-29 | 2000-11-29 | Mitomycin C solution |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1999157371 DE19957371A1 (en) | 1999-11-29 | 1999-11-29 | Mitomycin C solution |
| DE19957371.9 | 1999-11-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2001039741A2 true WO2001039741A2 (en) | 2001-06-07 |
| WO2001039741A3 WO2001039741A3 (en) | 2001-12-13 |
Family
ID=7930703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2000/011903 Ceased WO2001039741A2 (en) | 1999-11-29 | 2000-11-29 | Mitomycin c solution |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2669901A (en) |
| DE (1) | DE19957371A1 (en) |
| WO (1) | WO2001039741A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6793358B2 (en) | 2002-06-04 | 2004-09-21 | Ichikoh Industries Ltd. | Outer mirror for vehicle |
| WO2023042107A1 (en) * | 2021-09-17 | 2023-03-23 | Intas Pharmaceuticals Ltd. | A stable ready to dilute injectable pharmaceutical formulation of mitomycin |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2865391T (en) | 2013-10-22 | 2017-12-22 | Medac Ges Für Klinische Spezialpräparate Mbh | Method for producing a freeze-dried pharmaceutical composition containing mitomycin c |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5914005B2 (en) * | 1976-06-14 | 1984-04-02 | 協和醗酵工業株式会社 | Stabilization method for mitomycin C |
| JPS61501848A (en) * | 1984-04-10 | 1986-08-28 | バクスタ−、トラベノ−ル、ラボラトリ−ズ、インコ−ポレイテッド | mitomycin solution |
-
1999
- 1999-11-29 DE DE1999157371 patent/DE19957371A1/en not_active Withdrawn
-
2000
- 2000-11-29 AU AU26699/01A patent/AU2669901A/en not_active Abandoned
- 2000-11-29 WO PCT/EP2000/011903 patent/WO2001039741A2/en not_active Ceased
Non-Patent Citations (3)
| Title |
|---|
| BEIJNEN J.H; VAN GIJN R; UNDERBERG W.J: "Chemical stability of the antitumor drug mitomycin C in solutions for intravesical instillation" JOURNAL OF PARENTERAL SCIENCE AND TECHNOLOGY, Bd. 44, Nr. 6, 1990, Seiten 332-335, XP001002008 * |
| DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KONDO, AKIRA ET AL: "Stabilizing aqueous mitomycin C" retrieved from STN Database accession no. 88:177234 XP002169828 & JP 52 151716 A (KYOWA HAKKO KOGYO CO., LTD., JAPAN) 16. Dezember 1977 (1977-12-16) * |
| STOLK L.M.L ET AL: "Stability after freezing and thawing of solutions of mitomycin C in plastic minibags for intravesical use" PHARMACEUTISCH WEEKBLAD SIENTIFIC EDITION, Bd. 8, Nr. 6, 1986, Seiten 286-288, XP001002173 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6793358B2 (en) | 2002-06-04 | 2004-09-21 | Ichikoh Industries Ltd. | Outer mirror for vehicle |
| WO2023042107A1 (en) * | 2021-09-17 | 2023-03-23 | Intas Pharmaceuticals Ltd. | A stable ready to dilute injectable pharmaceutical formulation of mitomycin |
| EP4401727A4 (en) * | 2021-09-17 | 2025-07-23 | Intas Pharmaceuticals Ltd | Stable, ready-to-use, injectable, pharmaceutical formulation of mitomycin |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2669901A (en) | 2001-06-12 |
| WO2001039741A3 (en) | 2001-12-13 |
| DE19957371A1 (en) | 2001-06-13 |
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