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WO2001039741A2 - Solution de mitomycine c - Google Patents

Solution de mitomycine c Download PDF

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Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
mitomycin
mmol
solution
buffer
solutions
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.)
Ceased
Application number
PCT/EP2000/011903
Other languages
German (de)
English (en)
Other versions
WO2001039741A3 (fr
Inventor
Hans-Peter SCHRÖER
Wilfried Mohr
Ferdinand Bach
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.)
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Original Assignee
Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
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 Medac Gesellschaft fuer Klinische Spezialpraeparate mbH filed Critical Medac Gesellschaft fuer Klinische Spezialpraeparate mbH
Priority to AU26699/01A priority Critical patent/AU2669901A/en
Publication of WO2001039741A2 publication Critical patent/WO2001039741A2/fr
Publication of WO2001039741A3 publication Critical patent/WO2001039741A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/40—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
    • 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
    • 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%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une solution aqueuse stable du cytostatique mitomycine C ainsi que des produits pharmaceutiques contenant de la mitomycine C.
PCT/EP2000/011903 1999-11-29 2000-11-29 Solution de mitomycine c Ceased WO2001039741A2 (fr)

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 (de) 1999-11-29 1999-11-29 Mitomycin C-Lösung
DE19957371.9 1999-11-29

Publications (2)

Publication Number Publication Date
WO2001039741A2 true WO2001039741A2 (fr) 2001-06-07
WO2001039741A3 WO2001039741A3 (fr) 2001-12-13

Family

ID=7930703

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/011903 Ceased WO2001039741A2 (fr) 1999-11-29 2000-11-29 Solution de mitomycine c

Country Status (3)

Country Link
AU (1) AU2669901A (fr)
DE (1) DE19957371A1 (fr)
WO (1) WO2001039741A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6793358B2 (en) 2002-06-04 2004-09-21 Ichikoh Industries Ltd. Outer mirror for vehicle
WO2023042107A1 (fr) * 2021-09-17 2023-03-23 Intas Pharmaceuticals Ltd. Formulation pharmaceutique injectable, stable et prête à diluer de mitomycine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT2865391T (pt) 2013-10-22 2017-12-22 Medac Ges Für Klinische Spezialpräparate Mbh Processo para a produção de uma composição farmacêutica liofilizada com um conteúdo de mitomicina c

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5914005B2 (ja) * 1976-06-14 1984-04-02 協和醗酵工業株式会社 マイトマイシンｃの安定化法
JPS61501848A (ja) * 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 マイトマイシンの溶液

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6793358B2 (en) 2002-06-04 2004-09-21 Ichikoh Industries Ltd. Outer mirror for vehicle
WO2023042107A1 (fr) * 2021-09-17 2023-03-23 Intas Pharmaceuticals Ltd. Formulation pharmaceutique injectable, stable et prête à diluer de mitomycine
EP4401727A4 (fr) * 2021-09-17 2025-07-23 Intas Pharmaceuticals Ltd Formulation pharmaceutique injectable, stable et prête à diluer de mitomycine

Also Published As

Publication number Publication date
AU2669901A (en) 2001-06-12
WO2001039741A3 (fr) 2001-12-13
DE19957371A1 (de) 2001-06-13

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