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WO1995007083A1 - Composition de lyophilisat d'ifosfamide - Google Patents

Composition de lyophilisat d'ifosfamide Download PDF

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Publication number
WO1995007083A1
WO1995007083A1 PCT/AU1994/000523 AU9400523W WO9507083A1 WO 1995007083 A1 WO1995007083 A1 WO 1995007083A1 AU 9400523 W AU9400523 W AU 9400523W WO 9507083 A1 WO9507083 A1 WO 9507083A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical
approximately
composition
lyophilisate
weight
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/AU1994/000523
Other languages
English (en)
Inventor
Alan Duncan Robertson
Ross Andrew Shalliker
Jimmy Sosic
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.)
Mayne Pharma International Pty Ltd
Original Assignee
FH Faulding and Co Ltd
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 FH Faulding and Co Ltd filed Critical FH Faulding and Co Ltd
Priority to AU76470/94A priority Critical patent/AU7647094A/en
Publication of WO1995007083A1 publication Critical patent/WO1995007083A1/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
    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to an ifosfamide lyophilisate composition and a process for preparing same.
  • Ifosfamide is a pharmaceutical useful in the treatment of tumour diseases, and has the chemical formula 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-l,3 ,2- oxazaphosphorin-2-oxide
  • Ifosfamide thus belongs to the chemical group of oxazaphosphorins. It was included in a series of cytostatic compounds disclosed and claimed by Arnold et al., in United States Patent No. 3,732,340 which issued
  • the anhydrous form of ifosfamide is a white crystalline powder having a melting point of between 48°C and 51°C and is highly hygroscopic. Thus contact with moisture in the air must be avoided where possible.
  • Ifosfamide dissolves in water to the extent of about 10% by weight, and is stable only to a limited extent in aqueous solution, e.g. approximately 3 to 4 hours maximum at around 22°C.
  • ifosfamide gives rise to numerous difficulties during preparation and processing.
  • ifosfamide for example in a sterile crystallisation form begins to sinter and the rate of dissolution decreases. This is accompanied by a drop in clear solubility and the pH of the solution, with simultaneous yellow colourisation.
  • a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition, of ifosfamide; and approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride. It has been found that contrary to the teachings of the prior art, it is possible to form a stable lyophilisate composition utilising sodium chloride.
  • the pharmaceutical lyophilisate composition according to the present invention may be characterised by improved stability and shelf life.
  • the lyophilisate may have the appearance of a good freeze dried plug having the crystalline structure and visual appearance of a dry firm powder. The plug may reconstitute quickly, e.g. in. two to three seconds, to form a solution on addition of a solvent.
  • the pharmaceutical lyophilisate composition may further include supplementary excipients or conventional pharmaceutical additives such as lactose, dextrose, Na 2 C0 3 , hexitols such as mannitol, C,, sugars and dextrans or mixtures thereof.
  • the supplementary excipients may be present in the pharmaceutical lyophilisate composition in any suitable amount.
  • the supplementary excipients are preferably present in amounts of from 0 to 10% by weight based on the total weight of the pharmaceutical lyophilisate composition, more preferably approximately 4.0% by weight to 7.5% by weight.
  • a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition, of ifosfamide, and approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride wherein said composition excludes mannitol.
  • the pH of the composition should be within the range of approximately 6.0 to 7.2, preferably approximately 6.5 to 7.1, on reconstitution.
  • a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition, of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; and a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2.
  • the buffer may be added to the pharmaceutical lyophilisate composition in any suitable amount.
  • the buffer is preferably present in an amount effective to maintain the pH on reconstitution within the range of approximately 6.5 to 7.1.
  • the buffer is preferably present in amounts of up to approximately 15% by weight, based on the total weight of the pharmaceutical composition, more preferably approximately 10 to 15% by weight.
  • the buffer is a phosphate buffer.
  • a phosphate buffer such as disodium hydrogen phosphate
  • Na2-HPO4. sodium dihydrogen phosphate
  • NaH ConstantP0 4 sodium dihydrogen phosphate
  • KH ConstantP0 4 potassium dihydrogen phosphate
  • K ? HP0 4 dipotassium hydrogen phosphate
  • the pharmaceutical lyophilisate composition may further include supplementary excipients or conventional pharmaceutical additives such as lactose, dextrose, Na opinionCO_, hexitols such as mannitol, C.. sugars and cyclodextrans or mixtures thereof.
  • the supplementary excipients may be present in the pharmaceutical lyophilisate composition in any suitable amount.
  • the supplementary excipients are preferably present in amounts of from 0 to 10% by weight based on the total weight of the pharmaceutical lyophilisate composition, more preferably approximately 4.0% by weight to 7.5% by weight.
  • a pharmaceutical lyophilisate composition including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; approximately 5 to 15% by weight, based on the total weight of the pharmaceutical composition, of a phosphate buffer.
  • a lyophilisate composition falling within the scope of the preferred ranges specified above may exhibit significantly improved stability, such that after storage at approximately 40°C, for at least a month, no change in appearance is apparent.
  • the lyophilisate composition is also readily reconstituted to a colourless solution for injection, having a pH in the range of approximately 6.0 to 7.2.
  • a stable pharmaceutical lyophilisate composition suitable for parenteral administration on reconstitution including approximately 50 to 80% by weight, based on the total weight of the pharmaceutical composition of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition of sodium chloride; a buffer in an amount sufficient to provide a pH of the composition on reconstitution in the range of approximately 6.0 to 7.2; wherein mannitol is not present in the composition.
  • the lyophilisate is formed utilising a thermal cycling process such that a crystalline product is produced.
  • the thermal cycling or annealing process may function as follows.
  • the ingredients are subjected to a first freezing step as is standard in the art to induce glass formation. This may be followed by a second step in which the temperature is raised slightly. The temperature may be raised above the collapse temperature to permit a vitreous transformation and crystallisation. The temperature may then be lowered again to permit complete solidification.
  • the pharmaceutical lyophilisate compositions of the present invention may be prepared by dissolving ifosfamide and other components in a suitable solvent.
  • the solvent may be an aqueous or alcoholic solvent or mixtures thereof.
  • An aqueous solvent is preferred.
  • Water of suitable quality for example Water for Injection ("W.F.I.”), is particularly preferred.
  • the components are added to the solvent in the following order:
  • the pre-lyophilization solution may be purified in a conventional manner, for example by filtration using microbial retentive filters and nitrogen gas for pre-filter pressure.
  • the sterilized solution may be then aseptically filled into sterile packaging of appropriate size to allow reconstitution to give an intended volume of solution of desired ifosfamide concentration for administration.
  • vials are used and may contain sufficient fill solution to provide from approximately 0.5 to 5 g of ifosfamide per vial.
  • the contents of the vials may be lyophilised.
  • a process for preparing a pharmaceutical lyophilisate composition which process includes providing a pharmaceutical formulation including an effective amount of ifosfamide; sodium chloride; a buffer in amount sufficient to provide a pH of the formulation in the range of approximately 6.0 to 7.2; optionally supplementary excipients; and a solvent therefor; and cooling the pharmaceutical formulation to a temperature of approximately -50°C to -20°C; subjecting the cooled pharmaceutical formulation to a first drying step at elevated pressure and at a temperature of approximately -30°C to approximately -10°C; and subjecting the partially dried product to a second drying step at a lower pressure and at a temperature of approximately 0 to 10°C to form a pharmaceutical lyophilisate.
  • a lyophilisate may be formed from ifosfamides utilising sodium chloride as the principal adjuvant.
  • the ifosfamide is present in an amount sufficient to provide a concentration of approximately 50% to 80% by weight, in the final pharmaceutical lyophilisate composition formed, and the sodium chloride is present in an amount of approximately 20% to 50% by weight, in the pharmaceutical lyophilisate composition formed.
  • the buffer is a phosphate buffer present in an amount sufficient of approximately 5% to 15% in the final pharmaceutical composition formed.
  • the pharmaceutical lyophilisate so formed includes approximately 50 to 80% by weight, based on the total weight of the pharmaceutical lyophilisate composition, of ifosfamide; approximately 20 to 50% by weight, based on the total weight of the pharmaceutical composition, of sodium chloride; approximately 5 to 15% by weight, based on the total weight of the pharmaceutical composition, of a phosphate buffer.
  • the solvent may be an aqueous or alcoholic solvent or mixtures thereof.
  • An aqueous solvent is preferred.
  • Water of suitable quality for example Water for Injection ("W.F.I.”
  • W.F.I. Water for Injection
  • the process is carried out in a freeze drying apparatus.
  • the freeze drying process may include a thermal cycling or annealing process. Accordingly, the process may include the preliminary step of pre-chilling the freeze drying apparatus to a temperature of approximately -20°C to -5°C, prior to loading the pharmaceutical formulation for a period of up to about 1 hour.
  • the preliminary step may subsequently include cooling the * pharmaceutical formulation to a temperature of approximately -55°C to -40°C for a period of approximately 1 to 2 hours; raising the temperature of the freeze drying apparatus to approximately -25°C to -15°C for approximately 1 to 5 hours; and recooling the pharmaceutical apparatus to a temperature of approximately -55°C to -40°C for approximately 1 to 5 hours.
  • the first drying step may be conducted in a range of pressures of approximately 150 to 350 ⁇ bars.
  • the first drying step may be conducted at a temperature of approximately -20°C to -30°C and may continue for approximately 12 to 48 hours.
  • the shelf temperature may then be raised to a temperature of approximately -10°C to -20°C and maintained for a further 6 to 15 hours.
  • the second drying step may be conducted at a pressure of approximately 10 to 15 ⁇ bar, and at a temperature of approximately 0 to 10°C, and may continue for an extended period for example approximately 3 to 24 hours.
  • Dosage forms according to the present invention may comprise a pharmaceutical lyophilisate composition as hereinbefore described, contained in a suitable container, usually a vial but also an ampoule, syringe, or other container commonly used for packaging, reconstitution and, optionally, delivery of intravenous or other parenteral solutions.
  • a suitable container is meant a container capable of maintaining a sterile environment such as a vial capable of being hermetically sealed by a stopper means.
  • suitable container implies appropriateness of size, considering the volume of solution to be held upon reconstitution of the improved ifosfamide lyophilizate composition. While such containers are usually glass, generally type I glass; they may also be of other suitable materials which do not interact with the lyophilisate components.
  • the closure typically a stopper and preferably a sterile rubber stopper or an equivalent which gives a hermetic seal, and capable of maintaining a sterile environment will also allow entry for the purpose of introduction of diluent such as sterile water for reconstitution of the ifosfamide solution.
  • Preferred dosage forms containing the ifosfamide lyophilisate compositions may be vials from about 10 to 250 ml and preferably about 25 to 200 ml in capacity. It will be recognized that larger or smaller dosage forms may be readily accommodated as part of the present invention.
  • the pharmaceutical lyophilisate compositions of the present invention are intended to be reconstituted with common diluents, such as W.F.I.
  • compositions of the present invention may be characterised by rapid reconstitution in standard solvents, for example, within approximately 1 minute or ' less.
  • the reconstituted products may exhibit . minimal foaming.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à une composition de lyophilisat pharmaceutique comprenant approximativement 50 à 80 % en poids d'ifosfamide, par rapport au poids total de la composition pharmaceutique; et approximativement 20 à 50 % en poids de chlorure de sodium, par rapport au poids total de la composition pharmaceutique.
PCT/AU1994/000523 1993-09-10 1994-09-05 Composition de lyophilisat d'ifosfamide Ceased WO1995007083A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76470/94A AU7647094A (en) 1993-09-10 1994-09-05 Ifosfamide lyophilisate composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPM111393 1993-09-10
AUPM1113 1993-09-10

Publications (1)

Publication Number Publication Date
WO1995007083A1 true WO1995007083A1 (fr) 1995-03-16

Family

ID=3777185

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1994/000523 Ceased WO1995007083A1 (fr) 1993-09-10 1994-09-05 Composition de lyophilisat d'ifosfamide

Country Status (2)

Country Link
WO (1) WO1995007083A1 (fr)
ZA (1) ZA946967B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19540132A1 (de) * 1995-10-27 1997-04-30 Pharma Dynamics Gmbh Ifosfamid-Lyophilisat
US5750131A (en) * 1995-08-08 1998-05-12 Asta Medica Aktiengesellschaft Ifosfamide lyophilizate preparations
WO1999018973A3 (fr) * 1997-10-13 1999-08-26 Stada Arzneimittel Ag Formes galeniques liquides de produits pharmaceutiques a base d'oxazaphosphorine
US6613927B1 (en) * 2002-02-08 2003-09-02 American Pharmaceutical Partners, Inc. Sterile lyophilized ifosfamide and associated methods
US6906047B2 (en) * 2001-12-13 2005-06-14 Gensia Sicor Pharmaceuticals, Inc. Aqueous ifosfamide composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU8052987A (en) * 1986-10-31 1988-05-05 Asta Medica Aktiengesellschaft Ifosphamide lyophilisate and process for its preparation
US4959215A (en) * 1988-03-19 1990-09-25 Asta Pharma Ag Ifosfamide-mesna lyophilizate and process for its preparation
US5036060A (en) * 1988-07-25 1991-07-30 Fujisawa Usa, Inc. Cyclophosphamide
AU2716692A (en) * 1991-10-23 1993-04-29 Bristol-Myers Squibb Company Improved lyophilized ifosfamide compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU8052987A (en) * 1986-10-31 1988-05-05 Asta Medica Aktiengesellschaft Ifosphamide lyophilisate and process for its preparation
US4959215A (en) * 1988-03-19 1990-09-25 Asta Pharma Ag Ifosfamide-mesna lyophilizate and process for its preparation
US5036060A (en) * 1988-07-25 1991-07-30 Fujisawa Usa, Inc. Cyclophosphamide
AU2716692A (en) * 1991-10-23 1993-04-29 Bristol-Myers Squibb Company Improved lyophilized ifosfamide compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AMERICAN JOURNAL OF HOSPITAL PHARMACY, 1992, 49(5), MONTSERRAT MUNOZ et al., "Stability of Ifosfamide in 0.9% Sodium Chloride Solution or Water for Injection in a Portable i.v. Pump Cassette", 1137-1139. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5750131A (en) * 1995-08-08 1998-05-12 Asta Medica Aktiengesellschaft Ifosfamide lyophilizate preparations
DE19529057B4 (de) * 1995-08-08 2007-12-13 Baxter Healthcare S.A. Ifosfamid-Lyophilisat-Zubereitungen
DE19540132A1 (de) * 1995-10-27 1997-04-30 Pharma Dynamics Gmbh Ifosfamid-Lyophilisat
DE19540132C2 (de) * 1995-10-27 2003-04-03 Stada Arzneimittel Ag Ifosfamid-Lyophilisat
WO1999018973A3 (fr) * 1997-10-13 1999-08-26 Stada Arzneimittel Ag Formes galeniques liquides de produits pharmaceutiques a base d'oxazaphosphorine
US6906047B2 (en) * 2001-12-13 2005-06-14 Gensia Sicor Pharmaceuticals, Inc. Aqueous ifosfamide composition
EP1453519A4 (fr) * 2001-12-13 2009-03-11 Sicor Inc Composition d'ifosfamide aqueuse
US6613927B1 (en) * 2002-02-08 2003-09-02 American Pharmaceutical Partners, Inc. Sterile lyophilized ifosfamide and associated methods

Also Published As

Publication number Publication date
ZA946967B (en) 1995-05-08

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