United States Patent, [19]
`
`Sauerbier et al.
`
`[54]
`
`[75]
`
`IFOSFAMIDE LYOPHILISATE AND
`PROCESS FOR ITS PREPARATION
`
`Inventors: Dieter Sauerbier, Wcrthcr;
`Uwe-Peter Dammann, Detmold; Otto
`Isaac, Hanan, all of Fed. Rep. of
`Germany
`
`[73] Assignee:
`
`Asta Pharma Aktiengesellschaft, Fed.
`Rep. of Germany
`
`[21] App1.No.: 703,703
`
`[22] Filed:
`
`May 21, 1991
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 418,089, Oct. 5, 1989, aban-
`doned, which is a continuation of Ser. No. 113,154,
`Oct. 27, 1987, abandoned.
`
`Foreign Application Priority Data
`[30]
`Oct. 31, 1986 [DE]
`Fed. Rep. of Germany ....... 3637089
`
`[51]
`
`Int. Cl.5 ..................... .. C07F 9/547; C07F 9/576;
`A61K 31/675
`[52] U.S. Cl. .................................... .. 514/105; 514/79;
`558/81; 544/1
`[58] Field of Search .................. .. 558/81; 514/79, 105;
`544/1
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,732,340
`4,537,883
`
`...................... .. 568/12
`5/1973 Arnold etal.
`8/1985 Alexander et al.
`............... .. 514/110
`
`US005204335A
`
`[11] Patent Number:
`
`5,204,335
`
`[45] Date of Patent:
`
`Apr. 20, 1993
`
`4,623,742 11/1986 Schefller :1 a1.
`
`..................... 558/81
`
`FOREIGN PATENT DOCUMENTS
`
`1215649 12/1986 Canada ................................ 514/110
`(B83439 7/1983 European Pat. Off.
`.............. 568/12
`2750207 11/1978 Fed. Rep. of Germany .... .. 514/557
`4203570 10/1987 Fed. Rep. of Germany .... .. 514/110
`
`1347582
`2/1974 United Kingdom .............. 128/155
`
`OTHER PUBLICATIONS
`
`Remington Pharmaceutical Sciences Textbook, 15th
`Ed, 1975, Mack Publ. Co., Easton, Pa., pp. 1361, 1483,
`1484.
`'
`
`Vanlerberghe et al., CA, vol. 92, 1980, 92:112612g.
`Svito, CA, vol. 82, 1975, 85:47680e.
`Norpoth et 111., CA, vol. 83, 1975, 83:188122g.
`“Lehrbuch der pharmazeutischen Technologie”, Voigt,
`Rudolph, Chemie Verlag (Weinheim (1982), pp. 58-61,
`431, 432 and 536.
`“Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und
`Angrenzende Gebiete”, Fiedler, Editio Cantor (Aulen-
`dorf1981), pp. 588-589.
`“Die Tablette”, Ritschel, W. A., Editio Cantor (Aulen-
`dorf 1966), p. 88.
`
`Primary Examiner—-Alan L. Rotman
`Attorney, Agent, or F1'rm—Cushman, Darby & Cushman
`
`[57]
`
`ABSTRACI‘
`
`Ifosfamide lyophilizate consisting substantially of ifosfa-
`mide and 0.1 to 17 parts by weight of a hexitol.
`
`11 Claims, No Drawings
`
`FRESENIUS KABI 1007-OOO1
`
`

`
`1
`
`5,204,335
`
`IFOSFAMIDE LYOPHILISATE AND PROCESS
`FOR ITS PREPARATION
`
`This is a continuation of application Ser. No.
`07/418,089, filed on Oct. 5, 1989, now abandoned,
`which was a continuation of application Ser. No.
`07/113,154, filed Oct. 27, 1987, now abandoned.
`The present invention relates to a novel form of ifos-
`famide which has improved properties.
`BACKGROUND OF THE INVENTION
`
`The chemical name of the active substance ifosfamide
`3-(2-chloroethyl)-2-(chloroethylamino)-tetrahydro-
`is
`2H-1,3,2-oxazaphosphorin-2-oxide, which has the for-
`mula:
`
`Cl—CH2-CH2—NH
`
`\ /
`P
`/ \
`
`0
`
`CIIH2-'CH2—Cl
`N-‘CH1
`\
`
`CH2
`
`/
`
`0- CH2
`
`In common with cyclophosphamide, ifosfamide be-
`longs to the cherriical group of oxazaphosphorins and is
`used therapeutically for the treatment of tumor diseases.
`Ifosfamide is a white crystalline powder which has a
`melting point of 48°-51° C. and which is highly hygro-
`scopic.
`Ifosfamide begins to sinter at
`temperatures
`below its melting point and must, therefore, be stored at
`temperatures that are as low as possible (room tempera-
`ture and below). In addition, contact with moisture in
`the air should be avoided whenever possible.
`Ifosfamide dissolves in water to the extent of about 10
`percent by weight, but is only stable to a limited extent
`in aqueous solution (maximum of 3 to 4 hours at 20° to
`22" C. or 36 hours at 4° to 6° C.)
`Ifosfamide is exclusively administered parenterally. It
`normally is supplied in injection vials which contain 200
`to 5000 mg of ifosfamide in the form of a sterile crystal-
`lizate. This active ingredient is dissolved in water for
`injection purposes before administration, at a concen-
`tration of at most 4%. This solution is suitable for intra-
`’ venous injection. For intravenous short infusion, the
`ifosfamide solution is dissolved in 500 ml of Ringer’s
`solution or similar infusion liquid. The duration of the
`infusion is generally about 30 minutes, but may be 1 to
`2 hours. In the case of the 24-hour infusion, the ifosfa-
`mide solution is, for example, dissolved in a total of 3
`liters of 5% dextrose sodium chloride solution.
`Ifosfamide gives rise to numerous practical problems
`during preparation and processing. During preparation
`of the sterile crystallized ifosfamide there is a change of
`physical characteristics. In particular, dosage accuracy
`during filling is greatly impaired by variable flow prop-
`erties.
`
`The processing of ifosfamide is further impeded by its
`hygroscopic properties and low melting point. When
`stored for a long period of time, the sterile crystallizate
`sinters and the rate of dissolution decreases. When the
`
`ifosfamide begins to sinter, this is accompanied by a
`decrease in clear solubility and in the pH of the solution,
`with simultaneous yellow coloration. Once this hap-
`pens, therapeutic use is generally no longer possible.
`SUMMARY OF THE INVENTION
`
`The object of the present invention is therefore to
`make available a form of ifosfamide with improved
`
`2
`properties, such as improved stability, shelf-life, dosabil-
`ity and solubility, which is easier to use, and which is in
`particular suitable for the preparation of injectable solu-
`tions.
`
`5
`
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`20
`
`25
`
`30
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`35
`
`45
`
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`60
`
`65
`
`It has now surprisingly been found that the previous
`disadvantages and difficulties associated with 'the use
`and storage of ifosfamide can be overcome by the use of
`a specific ifosfamide lyophilizate. In accordance with
`the present invention, therefore, a lyophilizate is pro-
`duced by freeze drying an aqueous or aqueous/al-
`coholic (preferably aqueous/ethanolic) solution of ifos-
`famide and a hexitol. It has been found that the process
`of the invention alone, involving the use of a hexitol
`such as for example mannitol, produces an improved
`ifosfamide lyophilizate. By contrast, a mixture of ifosfa-
`mide and sodium chloride, such as is conventional for
`the dry filling of other oxazaphosphorins, does not yield
`a lyophilizate.
`It is surprising that the ifosfamide lyophilizate of the
`invention has greater thermostability than the hitherto
`used ifosfamide dry crystallizate.
`The difference between the conventional form of
`ifosfamide and the composition of the present invention
`is evident from the properties of the respective materials
`after storage. At 40° C., the conventional type of dry
`fillings of ifosfamide turn dark after only one month’s
`storage. After 2 months the contents of the vial have
`sintered and turned yellow. At a storage temperature of
`55° C., the dry filled ifosfamide fuses after as little as 4
`days.
`In contrast, the ifosfamide lyophilizate prepared ac-
`cording to the present invention displays neither discol-
`oration nor any change in the consistency of the ifosfa-
`mide under the same storage conditions.
`The dissolution rate of the ifosfamide lyophilizate
`produced by the present invention is also markedly
`increased in comparison to a conventional ifosfamide
`crystallizate. Whereas, the lyophilizate of the present
`invention dissolves immediately on addition of solvent,
`notwithstanding the length of time it has been stored,
`injection vials containing conventional dry filling have
`to be vigorously shaken for Q to 3 minutes after intro-
`duction of the solvent. In those cases where dissolution
`is not immediately completed, as is the case with injec-
`tion vials stored for a longer period of time, it even is
`necessary to let the solution stand for a few minutes.
`This impedes the use of the preparation in the hospital.
`In contrast to sterile crystallizate, ifosfamide lyophili-
`zate according to the present invention still shows opti-
`mum solubility properties after storage over several
`years.
`In addition, the ifosfamide dry filling (i.e., the pure
`ifosfamide crystallizate) is far more sensitive to atmo-
`spheric moisture than is the lyophilizate. Thus, the ifos-
`famide dry filling liquefies at a relative humidity of less
`than 75%, whereas the lyophilizate of the present in-
`vention, although becoming moist, retains its outer
`form, even at 100% relative humidity.
`Moreover, during filling of the sterile crystallizate,
`the risk of particulate or microbial contamination is far
`greater with the conventional material than with the
`lyophilizate.
`In contrast, during preparation of the ifosfamide lyo-
`philizate, sterile filtration of the solution only occurs
`immediately before filling into injection vials. This en-
`sure greater microbiological safety than does the filling
`of sterile crystallizate. In addition, particulate impuri-
`
`FRESENIUS KABI 1007-OOO2
`
`

`
`5,204,335
`
`3
`ties, which have occasionally given rise to complaints in
`the case of the dry filling, can be more reliably avoided
`by filtration of the solution.
`Not only does the lyophilization of the ifosfamide
`improve the product, it is also less expensive than the
`cost of filling the sterile crystallizate.
`For example, in accordance with the invention, an
`aqueous solution of ifosfamide containing 1 to 13 per-
`cent by weight of ifosfamide, as well as 0.1 to 17 parts
`by weight of a hexitol, for each part by weight of ifosfa-
`mide is freeze-dried. This aqueous solution advanta-
`geously contains 5 to 12 percent by weight, in particular
`8 to 10 percent by weight of ifosfamide.
`It is also possible to use corresponding ethanol-water
`solutions of ifosfamide in place of a purely aqueous
`solution (ethanol proportion of such a solution up to
`45% weight by weight, for example 1—20% of ethanol).
`In such cases, the ethanol is, if possible, first removed
`under a vacuum before the remaining ice is sublimed.
`The conditions for the initial ethanol removal are for
`example: pressure 5)<lO"1 mbar,
`temperature rising
`from --25° to -5“ C. within 10 hours, subsequently
`being raised to +22° C. The selection of freeze drying
`conditions depends on the thickness of the layer of
`material to be dried.
`The amount of the hexitol in this aqueous or aqueous-
`ethanolic solution is generally l to 17, preferably 3 to
`12, in particular 5 to 9 percent by weight. The amount
`of the hexitol may also be expressed in relation to the
`weight of ifosfamide, in which case the amount of the
`hexitol is 0.1 to 17, preferably 0.1 to 2.5, in particular 0.6
`to 0.8 parts by weight of the hexitol for each part by
`weight of ifosfamide.
`I-lexitols which may be used include: mannitol, gluci-
`tol, sorbitol, such as D-sorbitol, dulcitol, allitol, altritol
`(for example D- and L-altritol), iditol (for example D-
`and L-iditol), their optically active forms (D- or L-
`forms) as well as the corresponding racemates. Use is
`preferably made of mannitol, such as D-mannitol, L-
`mannitol, DL-mannitol, sorbitol and/or dulcitol, and in
`particular preferably D-mannitol. The hexitol may also
`be mixtures of the hexitols mannitol, glucitol, sorbitol,
`dulcitol, allitol, altritol, iditol. Such a mixture could be,
`for example, mixtures of mannitol and sorbitol and/or
`dulcitol. Since dulcitol is less water-soluble than for
`example mannitol, the dulcitol content in the aqueous
`solution should for example not exceed 3 percent by
`weight. In contrast, mannitol and sorbitol may for ex-
`ample be mixed in all ratios.
`In addition to a hexitol, it is also possible to add other
`conventional pharmaceutical auxiliary substances such
`as for example glycine, lactose, polyvinylpyrrolidone,
`glucose, fructose, albumin and equivalent body building
`substances. The total amount of such substances, i.e.,
`hexitol and auxilliary substances, in the solution which
`is used for freeze-drying is for example 0-16.9 parts by
`weight, for example 0.1 to 7 parts by weight, for each
`part by weight of ifosfamide. Individually the amount of
`such auxiliary substances depends on the amount of the
`hexitol used in such a way that the total amount of the
`hexitol and of such other auxiliary substances in the
`fuiished lyophilizate is not more than 17 parts by
`weight, for each part by weight of ifosfamide. Should
`only 0.1 part by weight of the hexitol be present in the
`lyophilizate, it is therefore possible for up to 16.9 parts
`by weight of other auxiliary substances to be present;
`should for example 8.5 parts by weight of the hexitol be
`present, the amount of other auxiliary substances may
`
`10
`
`15
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`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`60
`
`65
`
`4
`for example be up to 8.5 parts by weight for each part
`by weight of ifosfamide.
`To prepare the solution to be used for freeze-drying a
`vessel is charged with about 70 to 83% preferably 80%
`of the requisite amount of water or aqueous ethanol and
`the corresponding amount of ifosfamide and mannitol
`dissolved in succession (i.e., first the ifosfamide and then
`the mannitol) with continuous stirring or continuous
`agitation. After complete dissolution the solution is
`made up to the final volume, and the pH is measured.
`The pH of this solution should, for example, be between
`4 and 7 after dilution. Advantageously a 4% ifosfamide
`solution is prepared.
`The ifosfamide solution so obtained is then sterilized
`by filtration using pathogen-proof filters conventionally
`used for such purposes and then filled one or more
`vessels for freeze drying. Preferably,
`it is filled into
`appropriate containers for injection preparations. The
`storage time up to filling into the injection containers
`should not exceed a period of 3 to 4 hours, including the
`time taken to prepare the solution, if working is at room
`temperature (l8“ to 22° C.). Should freeze-drying not be
`possible immediately, such a solution, optionally also
`after filling into the injection containers, may for exam-
`ple be stored for up to 36 hours at lower temperatures,
`for example between —5° and + 10° C., preferably +4°
`to +6° C., before freeze-drying begins.
`To carry out the process of the invention, the so-
`obtained aqueous ifosfamide solution is filled into con-
`tainers for injection preparations, for example ampoules
`or other glass vessels and the solution is freeze-dried.
`For sterilization purposes, conventional pathogen-
`proof filters, for example conventional bacterial filters
`having a pore size of about 0.2 pm are used. When glass
`vessels or ampoules are used, these are first sterilized in
`the conventional manner.
`The hexitols used (preferably mannitol, in particular
`D-mannitol) should conform to the requirements of the
`British Pharmacopoeia 1980. The hexitols should be as
`pyrogen-free as possible (pyrogens are fever-inducing
`endotoxins formed by bacteria).
`The same applies to the ifosfamide used. The removal
`or destruction of the pyrogens is effected in conven-
`tional manner (for example the solution of active sub-
`stance is treated with activated charcoal prior to sterile
`filtration). In addition, the injection water used should
`be sterile and pyrogen-free and conform to the require-
`ments of the Deutsches Arzneibuch, 9th Edition 1986.
`The injection vessels may advantageously be those
`made from tubular glass or furnace glass of the IIIrd
`hydrolytic class (for example 10 R, 30 R and 50 H) (see
`in this connection Deutsches
`Arzneibuch, 9th Edition, 1986, pages 161-164 and
`DIN standard 58366 part 1 and 5).
`Furthermore, the injection vessels as well as the addi-
`tional auxiliary substances such as rubber stoppers and
`flanged caps conform to the requirements of DIN stan-
`dard 58366, Part 2 and Part 3 as well as DIN 58367, Part
`1.
`
`The amounts of solution of the ifosfamide solutions to
`be used for lyophilization, in the appropriate containers
`(ampoules) or other containers for injection prepara-
`tions, are, for example, between 1 and 500 ml, prefera-
`bly l and 250 ml, and in particular 2 and 50 ml per
`container . The containers should in each case be s
`dimensioned that the lyophilizate contained therein may
`later be dissolved in a larger amount of liquid. They
`should therefore in general have a volume that is suffi-
`
`FRESENIUS KABI 1007-OOO3
`
`

`
`5,204,335
`
`5
`ciently large for the preparation of a ready-to-use final
`solution having about 2 to 5 times, preferably 2 to 4
`times, and in particular 2 to 2.5 times the volume of the
`originally filled lyophilizate solution.
`As already mentioned, it is preferred that the solution
`is freeze dried in ampoules used for injection purposes.
`Each ampoule or each glass vessel is advantageously
`filled with a single dosage unit of ifosfamide, so that the
`amount of ifosfamide in each glass vessel is for example
`between 100 mg and 10 g, preferably 200 mg to 5 g.
`Subsequently, the solution is freeze-dried in the custom-
`ary manner in this glass vessel or ampoule. It is, how-
`ever, also possible to lyophilize larger amounts of ifosfa-
`mide, i.e., a correspondingly larger solution volume of
`the ifosfamide solution in a correspondingly larger ves-
`sel and subsequently to subdivide or fill the lyophilizate
`obtained into correspondingly smaller dosages. The
`lyophilization itself is carried out in such a way that the
`ampoules or glass vessels or other vessels which contain
`the ifosfamide-hexitol solution are placed directly on a
`stand or on a rack in a freeze-drying chamber. Once the
`chamber has been closed, the ampoules or vessels are
`cooled to temperatures below 0° C., for example to
`temperatures between -70° and 0° C., preferably -50‘
`to -30° C., in particular —45° to -35‘ C. As soon as
`the solutions are completely frozen the freeze-drying
`chamber is progressively evacuated and drying com-
`mences. Firstly, the non-adsorptively bound solvent is
`removed at temperatures between —30° and +40° C.,
`preferably 0° to +30° C., in particular +20” to +30° C.,
`for which purpose a pressure between l0-’3 and 6, pref-
`erably l0*‘2 to 2, and in particular 10-1 to 1 mbar is
`selected. In all cases the temperature or temperature
`range refers to the temperature of the racks.
`The process is so controlled that the heat applied via
`the plate temperature is completely used as heat of
`sublimation and the temperature of the froze ifosfamide-
`containing solution always remains below its eutectic
`temperature. The desired temperature of the plates in
`each case may for example be programmed via program
`disks or computers.
`The time taken to remove this non-adsorptively
`bound solvent depends on the size of the individual
`containers and is, for example, between about 4 and 40
`hours at a plate temperature of +25° C. and a pressure
`of 0.8 mbar. Reference is made by way of example to
`the times given in the example below.
`The complete removal of the non-adsorptively bound
`water is indicated as follows: Non-adsorptively bound
`water is present in the form of ice. Using a so-called
`pressure rise measurement,
`it
`is determined whether
`such water is still present in the lyophilizate. For this
`purpose, a valve is closed between the drying chamber
`and the condenser to which the vacuum pump is also
`connected. Any ice present would then quickly sublime
`and lead to a rise in pressure in the drying chamber.
`In the case of pressure rise measurement, the pressure
`in the chamber after 15 minutes may rise to a maximum
`of 1 mbar from the starting value, for example 0.8 mbar.
`A rise in excess of this figure would indicate that the
`main drying has not yet been completed.
`Residual adsorptively-bound solvent is then removed
`by post drying. This takes for example 3 to 12 hours at
`a vacuum of l0*‘ to 10-4 mbar, in particular 3-4 hours
`at a vacuum of l0~3 to 10"‘ mbar.
`The lyophilization process is completed when the
`residual moisture (determined by the method of K.
`Fischer) is below 1%, preferably below 0.5%.
`
`10
`
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`
`6
`In particular, the post-drying for removal of adsorp-
`tively bound water takes place at temperatures between
`0° and 40° C., preferably 10° to 35° C., in particular 20
`to 30° C. and a pressure between 104 and 10- ‘, prefer-
`ably l0*3 to 10-2, and in particular 10-3 to 5X 10-3
`mbar, and this post-drying takes for example 2 to 36,
`preferably 6 to 24, and in particular 3 to 12 hours.
`Following completion of the freeze-drying, the ves-
`sels containing the lyophilizate are sealed. All stages of
`the process of the invention are conducted under sterile
`conditions. The injection vials may be sealed for exam-
`ple after ventilation of the freeze-drying chamber to
`normal pressure through addition of dry, sterile air or
`nitrogen with special freeze-drying rubber stoppers
`which are treated with silicone to avoid abrasion and to
`improve lubricity.
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENT
`
`The invention is illustrated by the following example:
`EXAMPLE
`
`The following solution is used for freeze-drying:
`
`lfosfarnide
`D-mannitol
`Water of injection ad
`
`1(1) mg
`70 mg
`1 ml
`
`The density of this solution is 1.0563 g/rril at +6” C.
`and 1.0527 g/ml at +20’ C.
`The amount of solution to be prepared depends on
`the appropriate filling and freeze-drying capacity.
`Preparation of the solution:
`A vessel is charged with 80% of water and appropri-
`ate amounts of ifosfamide and mannitol are added suc-
`cessively to the water with constant stirring. Following
`complete dissolution the mixture is made up to the final
`volume and the pH is measured.
`The prepared solution is sterilized by filtration using
`pathogen proof filters conventionally used for this pur-
`pose (for example Sartorius SM lll07 or SM 11307, 0.2
`pm pore size, Pall filter NRP (pore size 0.2 pm) and
`stored until filling while avoiding particulate and bacte-
`rial contamination. Storage at
`room temperature
`(20°—22° C.) should not exceed 3-4 hours, including the
`time required to prepare the solution. Should freeze-
`drying not take place immediately, the solution may be
`stored for about 36 hours at +4‘ to +6° C.
`For purposes of sterile filtration, it is also possible to
`use conventional prefilters (for example Sartorius SM
`13400 or Pall LPA) to protect the sterile filter.
`Cleaning of the injection vials:
`The injection vials are washed with hot and cold
`demineralized water and with air. All cleaning media
`are freed from suspended matter by filtration.
`While avoiding re-contamination due to particles
`from the air, the vials are dried with hot air and steril-
`ized (discontinuously at 180’ C./2 hours).
`The rubber stoppers used to close the injection vials
`are cleaned using demineralized water and for example
`a cleaning agent consisting of nonionic surfactants and
`phosphoric acid esters in aqueous solution.
`The cleaned stoppers are rinsed using demineralized
`water or filtered demineralized water to free them of
`fibers and threads. The so—cleaned stoppers are then
`sterilized using steam.
`
`FRESENIUS KABI 1007-0004
`
`

`
`7
`The so-cleaned and sterilized injection vials are then
`filled aseptically with the ifosfamide solution and closed
`using the rubber stoppers.
`Filling amounts:
`
`Filling amount
`2 ml
`lfosfamide 200 mg
`5 ml
`SW mg
`10 ml
`1 g
`20 ml
`2 g
`50 ml
`5 g
`‘For the subsequent dilution of the lyophilinte
`
`Volume used‘
`5 ml
`12.5 ml
`25 ml
`so ml
`125 ml
`
`5
`
`10
`
`The filling volumes should not exceed the following
`limits:
`
`15
`
`Limiting value of
`individual filling
`
`Filling volume
`2 ml
`5 ml
`10 ml
`20 ml
`50 ml
`
`volumes
`1.9-2.1 ml
`4.8-5.2 ml
`9.7-10.3 ml
`19.4-20.6 ml
`48.5-51.5 ml
`
`Average limiting value
`
`of the filling volume
`1.95-2.05 ml
`4.9-5.1 ml
`9.85-10.15 ml
`19.7-20.3 ml
`49.25-50.75 ml
`
`The filling volumes must be statistically monitored,
`with the filling volume per filling station being mea-
`sured at least once every 30 minutes.
`The filled injection vials are frozen as quickly as
`possible to -40” C.
`The conditions for freeze-drying differ according to
`the size of the injection vials. The following are repre-
`sentative examples:
`Duration of main drying at a plate temperature of
`+25° C. and 0.6 mbar:
`
`ca. 6-8 hours for vessels with 200 mg ifosfamide
`ca. 10-12 hours for vessels with 500 mg ifosfamide
`ca. 10-14 hours for vessels with 1000 mg ifosfamide
`ca. 20-28 hours for vessels with 2000 mg ifosfamide
`ca. 34 hours for vessels with 5000 mg ifosfamide
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Duration of post drying ca. 3-4 hours under vacuum
`of 5x104 mbar, at a plate temperature of +25" C.
`The residual moisture (determined by the method of 45
`K. Fischer) should be less than 0.5%.
`Following completion of freeze-drying the injection
`vials are sealed.
`
`To fix the rubber stoppers flanged caps are super-
`imposed and rolled on. The finished injection vials are
`checked for mechanical defects (cracks, faulty closure,
`etc.).
`What is claimed is:
`1. A lyophilized preparation comprising ifosfamide
`and 0.1 to 17 parts by weight of a hexitol selected from
`the group consisting of manriitol, dulcitol and sorbitol
`for each part by weight of ifosfamide.
`2. A lyophilized preparation as set forth in claim 1
`including other conventional pharmaceutical auxiliary
`
`50
`
`55
`
`65
`
`5,204,335
`
`8
`substances, the total amount of hexitol and said other
`conventional pharmaceutical auxiliary substances being
`0.1 to 17 parts by weight for each part by weight of
`ifosfamide.
`
`3. A lyophilized preparation according to claim 1 in
`which the hexitol is marmitol.
`
`4. A process for the preparation of an ifosfamide
`lyophilizate which comprises freezing an aqueous or
`aqueous-ethanolic solution of ifosfamide containing 1 to
`13 percent by weight of ifosfamide and 0.1 to 17 parts
`by weight of a hexitol selected from the group consist-
`ing of mannitol, dulcitol and sorbitol for each part by
`weight of ifosfamide as well as 0 to 16.9 parts by weight
`for each part by weight of ifosfamide, of other conven-
`tional pharmaceutical auxiliary substances,
`the total
`amount of said hexitol and said other conventional
`pharmaceutical auxiliary substances, the total amount of
`said hexitol and said other conventional pharmaceutical
`auxiliary substances being up to 17 parts by weight for
`each part by weight of ifosfamide, at between -70° and
`0' C. and removing the water from the so-obtained
`product while it is in the frozen state.
`5. A process according to claim 4 in which initially
`non-adsorptively bound water is first removed from the
`frozen solution at a temperature between -30° and
`+40° C. and a pressure between l0—3 and 10 mbar and _
`subsequently adsorptively bound water is removed at a
`temperature between 0° and 40° C. and a pressure be-
`tween 10-4 to l0*1mbar.
`6. A process as set forth in claim 5 in which non-
`adsorptively bound water is first removed from the
`frozen solution at a temperature between +20‘ and
`+30° C. and a pressure between 10-1 and 1 mbar and
`adsorptively bound water is removed at a pressure be-
`tween 10-3 and 10-4 mbar.
`7. A process as set forth in claim 5 in which the solu-
`tion is an aqueous/ethanolic solution and ethanol
`is
`removed before removal of water.
`8. A process as set forth in claim 7 in which the solu-
`tion contains up to 45% ethanol.
`9. A process as set forth in claim 7 or claim 8 in which
`the ethanol is removed at a pressure of 5X10"-1 mbar
`and a temperature between 25° and +5‘ C.
`10. A process according to claim 5 in which the hex-
`itol is mannitol.
`11. Ifosfamide lyophilizate produced by a process
`comprising freezing an aqueous or aqueous-ethanolic
`solution of ifosfamide containing 0.1 to 17 parts by
`weight of a hexitol selected from the group consisting
`of mannitol, dulcitol and sorbitol for each part by
`weight of ifosfamide as well as 0 to 16.9 parts by weight
`for each part by weight of ifosfamide, of other conven-
`tional pharmaceutical auxiliary substances,
`the total
`amount of said hexitol and said other conventional
`pharmaceutical auxiliary substances being up to 17 parts
`by weight for each part by weight of ifosfamide, at
`between —70° and 0° C. and removing the water from
`the so-obtained product while it is in the frozen state.
`I
`8
`I
`I
`I
`
`FRESENIUS KABI 1007-OOO5