DK175808B1 - Ifosfamide mesna lyophilisate and process for its preparation - Google Patents

Description

DK 175808 B1 i i! The chemical name for the active ifosfamide is 3- (2-chloroethyl) -2- (chloroethylamino) -tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide 5 I 2 2

If-phosphamide, like cyclophosphamide, belongs to the chemical group of oxazaphosphorins and is used therapeutically for the treatment of tumor diseases.

The chemical name for the uroprotector mesna is sodium 2-mercaptoethanesulfonate 15

Na + {HS-CH2-CH2-S03} "

Mesna protects e.g. the urine-releasing organs in the treatment of tumor diseases with ifosfamide, where this non-protective effect of the mesna, especially in concomitant and synchronous administration, is given together with ifosfamide.

Ifosfamide is a white crystalline powder having a melting point of 48-51 ° C with strong hygroscopic properties. Even before the melting point, ifosfamide begins to sinter; it must therefore be stored at the lowest possible temperatures (room temperature and below). In addition, contact with the humidity of the air should preferably be avoided.

Ifosfamide dissolves to approx. 10% by weight in water, but 30 is only limited durable in aqueous solution (maximum 0 0 3-4 hours at 20-22 C or 36 hours at 4-6 C).

Ifosfamide is administered exclusively parenterally. The vials contain 200 to 5000 mg of ifosamide in the form of a sterile crystalline solution which, before use, is dissolved in water for injection, so that a 4% concentration is not exceeded. This solution is suitable

DK 175808 B1 I

net for intravenous injection. For intravenous short-term

infusion, dissolve the ifosfamide solution in 500 ml of Ringer-H

solution or similar infusion solutions. Infusion H

time is approx. 30 minutes, possibly 1-2 hours. H

5 In 24-hour infusion, the ifosamide solution H is dissolved

eg. in a total of 3 liters of 5% dextrose boiling salt solution. H

Ifosfamide causes many problems in manufacturing H

gene and processing. In the manufacture of the ste H

rilt crystallized ifosfamide, product H appears

10 with varying physical characteristics. Because of the for- H

different flow properties are greatly reduced dose- H

ring accuracy in filling. H

The processing of ifosfamide is extremely difficult- H

even more because of its hygroscopicity and low melting- H

15 point. For prolonged storage, sterile creep sinks- H

the stall and dissolution rate decrease. By means of

advancing sintering of ifosfamide also decreases clear-solution H

the similarity and the pH of the solution at the same yellow color H

up; Therapeutic use is then generally non-H

20 more. H

Mesna is also a substance that is only stable H

and durable under special conditions. H

A combination option of ifosfamide and mesna, H

which is a major advantage in terms of storage and H

25 practical handling, so far has not existed. H

In the present invention it is intended to be H

to provide ifosfamide and mesna in a form with H

improved properties such as improved pharmaceutical H

quality, dosage ability and solubility, which form H

30 are easier to use and which are particularly suitable for use

position of injectable solutions. H

It has now surprisingly been found that so far, H

known disadvantages and difficulties in handling and up- H

storage of ifosfamide and mesna can be overcome by using H

Formation of a particular ifosfamide mesna lyophilisate. It is h

especially surprising that the lyophilisate in question exhibits H

H

DK 175808 B1 3 has greater thermostability of ifosfamide than the previously used ifosfamide dry fillings.

Dry refills of ifosfamide darken at 40 C already after a storage period of 1 month; after 2 months the contents of the bottle are sintered and yellow in color.

At a storage temperature of 55 ° C, the dry, filled ifosfamide has already melted within 4 days.

In contrast, for the lyophilisate prepared according to the invention, under the above storage conditions, no clear staining or change in the consistency of ifosfamide is found. There is also no change in mesna.

The solubility rate of the ifosfamide mesna-lyophilia set relative to ifosfamide dry refill is clearly increased. While the lyophilisate is immediately dissolved by solvent addition regardless of storage time, vials of dry filling must be shaken vigorously after addition of the solvent for one to three minutes. If the solution is not immediately complete, and this is the case for prolonged storage of the vials, it is even necessary to leave the solution for a few minutes. The use of the preparation in the clinic is thereby made more difficult.

Ifosfamide-mesna-lyophilisate, in contrast to the sterile crystallate, even with storage for several years, still exhibits optimal dissolution properties. In addition, the ifosfamide dry charge (called the pure ifosfamide crystallate) is extremely sensitive to the humidity of the air. Thus, ifosfamide-dry filling already melts at a relative humidity of less than 75%, while the lyophilizate, even at 100% relative humidity, becomes moist but retains its outer shape.

When filling the sterile crystallate, the danger of a particulate or microbial contamination is present on a substantially larger scale than when filling the lyophilisate.

I DK 175808 B1 I

I I

In preparing the ifosfamide mesna lyophilisate

In contrast, the sterile filtration of the solution occurs first

Immediately before filling into vials. Hereby I

greater microbiological safety is achieved in contrast I

I 5 for filling the sterile crystallate. Also particulate- I

re impurities which, in the dry filling, sometimes

With regard to prosecution, with greater certainty can und- H

Yeast by filtration of the solution. IN

In Lyophilization of ifosfamide together with mesna I

However, in 10 not only leads to a product improvement but I

H is also more I in manufacturing and practical application

In economical than the separate manufacture of sterile cryo- I

stallisate and mesna injection solution. IN

In addition, the combination in question also exhibits I

In use, a surprisingly better effect than I

hitherto recognized use of ifosfamide and mesna:

thus, e.g. by the present combination I

I by intravenous continuous infusion (eg with co- I)

In the composition 5.0 g ifosfamide + 2.0 g mesna) a conti- I

In 20 current unrest protection, and that by the concurrent con- I

tinous renal elimination of urotoxic metabolite- H

In utes and mesna. This minimizes the uroprotection memory H

In effect for bladder emptying. The fixed dose I

In relation between ifosfamide and mesna in the lyophilisate, I

For use as a continuous intravenous infusion

In sion (eg continuous infusion of 5 g ifosfamide + I)

2 g mesna over 6 hours or 10 g ifosfamide + I

In 4 g mesna over 24 hours) an insufficient turmoil

In patronage, as may occur with repeated bolus I

In 30 injections of the mesna or by a too low infusion dose

I say. The use of the combination lyophilizate as

In time infusion over 30 minutes to 2 hours in I

In quantities of e.g. 500 mg to 5 g ifosfamide together with I

20% of the amount of ifosfamide as mesna guarantees an additional I

35 extensive uroprotection for the first 4 hours. Preferred I

For example, the dosage for human use is: I

5 DK 175808 B1 0.5 g ifosfamide + 0.1 g mesna 1 g ifosfamide + 0.2 g mesna 2 g ifosfamide + 0.4 g mesna 5 g ifosfamide + 1.0 g mesna 5 g ifosfamide + 2.0 g mesna! It has been found that the process of the present invention utilizes a hexitol, e.g. mannitol, provides an improved ifosfamide mesna lyophilisate. Eg. obtained by the addition of boiling salt, as is usual in the dry filling of other oxazaphosphorins, no lyophilisate is obtained.

According to the invention, e.g. an aqueous solution containing 1-13% by weight ifosfamide and 0.05-13% by weight mesna, as well as as binder 0.1-17 parts by weight of hexitol, calculated on the basis of 1 part by weight ifosfamide. An aqueous solution preferably contains 5-12% by weight ifosfamide and 0.5-12% by weight mesna, especially 8-10% by weight ifosfamide and 0.8-10% by weight mesna.

Alternatively, ethanol-water-20 solutions of ifosfamide and mesna can be used instead of a pure aqueous solution (the ethanol content of such a solution is up to 45% m / m1; 1) definition according to German Medicines Book, 9th ed .:% mass in mass), e.g. 1-20% ethanol. In such cases, the ethanol is first removed as much as possible in vacuum before sublimating residual ice. The conditions for the first ethanol removal are

1 0 * 0 eg: pressure 5-10 mbar, temperature of -25 C to -5 C

increasing within 10 hours, then the setting plate temperature is increased to 15 C. These conditions also depend more in detail on the different layer thicknesses of the dry-prepared material in the vials and can be varied accordingly.

The amount of hexitol in this aqueous or aqueous ethanolic solution is usually 1-17, preferably 3-12, most preferably 5-9% by weight. When referring to the amount of hexi-tol on the basis of a part by weight ifosfamide,

I DK 175808 B1 I

I I

In the toll amount 0.1-17, preferably 1-2.5. especially 0.6-0.8 in parts by weight of hexitol. 1 part by weight ifosfamide. On the basis of

1 part by weight mesna performs the amount of hexitol e.g. 0.1-17, I

Preferably 1-6, especially 3-4 parts by weight.

I Like hexitol, these are: mannitol, gluci- I

I tol (sorbitol, such as D-sorbitol), dulcitol, allitol, I

In altritol (eg D- and L-altritol), iditol (eg D-I

I and L-iditol), their optically active forms (D- or I

L shapes), as well as corresponding racemates. In particular, I

10 mannitol, such as D-mannitol, L-mannitol, DL-mannitol and I

preferably D-mannitol. As hexitol may also be employed

mixtures of said hexitols, e.g. mixed I

In yeasts of mannitol and sorbitol and / or dulcitol. H

In addition to hexitol, others may also be added

In conventional pharmaceutical excipients, e.g. glycine,

lactose, polyvinylpyrrolidone, glucose, fructose, elbow

min and corresponding binders. The total amount of such I substances in the solution suitable for freeze drying, e.g. 0-16.8 parts by weight, calculated on the basis of - 20 1 parts by weight ifosfamide or mesna. In the completed lyophilia-

set, the total amount of such excipients may be up to I

I to 16.8 parts by weight calculated on the basis of 1 part by weight

In xitol. The amount of such aids is arranged according to H

the available amount of hexitol and so that two- H

In the number of hexitol and other excipients therein

In lye lyophilizate, the maximum does not exceed 17 weight- H

In le, calculated on the basis of 1 part ifosfamide or mesna. H

I If there is only e.g. 0.1 part by weight of hexitol in lyophil

thus, up to 16.9 parts by weight of I may be added

In 30 other excipients; if e.g. there are 8.5 weight- I

In le hexitol, the amount of other excipients may be I

Up to 8.5 parts by weight, calculated on the basis of 1 part ifosf-I

In amide or mesna. IN

I For the preparation of it for freeze-drying I

35 solution is used approx. 70-80%, preferably 75% of I

In the required volume of water or ethanolic amount of water, I

B1 and the corresponding amounts of ifosfamide, mesna and mannitol are dissolved according to the circumstances under stirring or under constant motion (i.e. first ifosfamide, then mesna and finally hexitol, eg mannitol). The water used to prepare the solution is purged with an inert gas, e.g. nitrogen, carbon dioxide or a noble gas for displacing oxygen, during the preparation of the solution, the inert gas is also fed into the solution. The displacement of oxygen is important as the mesna is easily oxidized to disulfide. After complete dissolution, the final volume is filled and the pH is measured. For example, the pH of this solution should be: after dilution are between 4 and 7.

For pH measurement, a 4% solution is preferably prepared on ifosfamide.

The ifosfamide mesna solution thus obtained; is then sterilized by filtration through a suitable germ-tight filter for which nitrogen gas is used. The storage time until filling into the vial should not exceed 3-4 hours, including the solution-making time, if done at room temperature (18-22 C).

If the subsequent freeze drying is not immediately possible, such a solution, possibly even after 25 filling in the vial, can be stored further up to 36 hours at lower temperatures, e.g. between 0 0 0 0 I -5 C and + 10 C, preferably from +4 C to +6 C, before freeze drying begins.

For carrying out the process according to the invention, the thus obtained ifosfamide mesna solution is charged into a container for injection preparations, e.g. ampoules or other glass containers. The containers must be exhausted before and after filling with sterile and particulate free inert gas (eg nitrogen). Then the freeze-drying drops are added and lyophilized. For sterilization, conventional germ-sealing filters are used, e.g. usual

I DK 175808 B1 I

I I

In bacterial filters with a pore size of approx. 0.2 pm. The H

In used glass containers or ampoules H is sterilized

In advance in the usual way. H

In It used hexltol (preferably mannitol, H

In 5 especially D-mannitol) must meet the requirements of British H

In pharmacopoeia 1980. The hexltol used must be pyro-H

In gene-free (pyrogen, fever-producing endotoxins that H

You are formed by bacteria). The same goes for the use- H

In the ifosfamide and mesna. The removal or destruction of H

In the pyrogen, it is done in the usual way (eg active H is treated

In the fabric solution before sterile activated charcoal filtration). H

The injection water used must also be sterile H

I and pyrogen-free and meet the requirements of German drug H

In Part Book, 9th Edition, 1986. H

I 15 For injection purposes, H, is used appropriately

In hydrolytic Class III H tube or vials

I (e.g. 10 R, 30 R and 50 H). (See related to H

In German Drug Book, 9th edition, 1986, pages 161-164 and H

In DIN standard 58366, part 1 and part 5). Injection containers H

I and the additional auxiliary materials, such as rubber stoppers H

In and bracket caps also comply with the requirements of DIN-H

In standard 58366, part 2 and part 3 as well as 58367, part 1. H

In the amount of ifosfamide mesna solution that solid- H

You add to the lyophilization, lies for the individual be- H

In 25 containers (ampoules) or equivalent containers for in- H

In erection preparations, per. container of e.g. between H

In 1 and 500, preferably 1 and 250, especially 2 and 50 ml. Behol- H

The inside is always adjusted so that the H contained herein

In lyophilizate can later dissolve in a larger amount of liquid. H

Thus, the containers must have a volume that is- H

sufficient to produce a ready-to-use finish H

solution that has approx. 2-5, preferably 2-4, especially 2-2.5 H

times the volume of the initially filled lyophilia- H

satopløsning. H

I 35 As mentioned earlier, each ampoule or H is filled

In each glass container preferably with a single dose of H

- - - in DK 175808 B1 9 ifosfamide and mesna, whereby the amount of ifosfamide is from 100 mg to 10 g, preferably 200 mg to 5 g per day. The glass amount is 10 mg to 10 g, preferably 20 mg to 5 g. The solution in this glass container or ampoule is then lyophilized in the usual manner. It is also possible to lyophilize larger amounts of ifosfamide mesna, ie. a correspondingly larger volume of solution of the ifosfamide-mesna solution in a correspondingly larger container, and then dividing or prepackaging the lyophilisate thus obtained into correspondingly smaller dosages.

The lyophilization itself is carried out so that the vials or glass containers or other containers containing the ifosfamide mesna solution are immediately placed on a dispensing plate or in trays on a dispensing plate in a freeze-drying chamber.

After closing the chamber, the vials or containers are cooled to temperatures below 0 ° C so that the water is completely frozen. Eg. the temperature is lowered to 0 0 0 0 20 between -70 ° C and 0 ° C, preferably between -70 ° C and -5 ° C, especially -50 ° C and -30 ° C, or from -45 ° C to -35 ° C. As soon as the solution is completely freeze-dried, the freeze-drying chamber is evacuated gradually and the drying begins. Here, the non-adsorptive bound solvent is first removed and more specifically at temperatures from -30 ° C to + 40 ° C, preferably from 0 ° C to 0 ° 0 + 30 C, especially from + 10 C to + 20 C, thereby setting a pressure of from 10 "3 to 6, preferably from 10-2 to 2, especially from 10-1 to 1 mbar. For the above-mentioned 30 temperatures or temperature ranges, the temperature of the guide plate is about. The process is controlled so that the heat supplied above the plate temperature is completely consumed as sublimation heat and the freeze-dried ifosfamide-mesna-containing solution temperature 35 remains around its eutectic temperature.

I DK 175808 B1 I

I I

In res using program disks or computer. Time H

To remove this non-absorbent bonded solvent

Lubricant depends on the size of the individual container I

In and lies e.g. between approx. Θ-50 hours at a recommend- H

H

5 plate temperature of +15 C and a pressure of 0.8 mbar.

For example, in used in this context are those used in the example

In given times. H

I The total removal of the non-adsorptive H

In bound water, as follows: non-adsorptive bottom

In the water there is ice. Through the so-called I

The pressure rise measurement determines whether there is still I

In water in the lyophilisate. In connection with this, there are-

You connected a valve between the drying chamber and the capacitor- I

In the room, to which also the vacuum pump is connected. Present- I

Thus, in ice, 15 can be rapidly sublimated and cause an H

In pressure rise in the dry chamber. In the pressure rise measurement H

You must not increase the pressure in the chamber by 1 mbar after 15 H

In minutes from the initial value, e.g. 0.8 mbar. A bigger one. IN

Increasing means that head drying is not completed. IN

I The remaining adsorptively bound, present-I

The solvents are then removed via a post-drying agent

ring. This constitutes e.g. 3-12 hours in a vacuum of 'I

For 10_1-10-4 mbar, especially 3-4 hours at a vacuum of 10-3-1

In 10 ~ 4 mbar. IN

In the lyophilization process is over when residual moisture H

In the heath (determined by K. Fischer) is less than 1%, I

preferably below 0.5%. The post-drying is mainly done to I

In adsorptively bound water removal at temperatures I

At between 0 and 40 ° C, preferably from 10 to 35 ° C, especially I

At 20 to 30 ° C and at a pressure between 10-4 and 10_1, I

In steps 10-3 and 10-2, especially 10-3 and 5 x 10 "3 mbar, I

where the post-drying e.g. takes from 2-36, preferably I

6-24, especially 3-12 hours. IN

After closing the freeze drying, the container is closed

35 there. The process of the present invention is carried out in all of them

In equal steps under aseptic conditions. IN

11 DK 175808 B1

The injection vials are closed, e.g. under aeration of the freeze-drying chamber under normal pressure, with the supply of a dry, inert gas (e.g., nitrogen) with special freeze-drying rubber stoppers treated with silicone to reduce wear and improve slip performance.

Except for freezing and removing the solvent in vacuo, all operations are carried out under an inert gas atmosphere (e.g., nitrogen, carbon dioxide, noble gases).

j

Example 1

The following solution is used for freeze drying: 15 Mesna 20 mg In phosphamide 100 mg D-mannitol 70 mg

Injection water at 1 ml 20 Density of this solution is 1.061 g / ml at + 20 ° C.

The dissolved amounts determined are based on the filling and freeze-drying capacity available at all times.

All process steps were carried out during the preparation of the filling of the solution under nitrogen or nitrogen aeration.

Preparation of the solution: 30

Approx. 80% injection water volume and the corresponding amounts of mesna, ifosfamide and mannitol are dissolved in the water in succession while still stirring and nitrogen aeration. After complete dissolution, make up to the final volume and measure the pH.

The final solution is sterilized by filtration through a suitable germ-tight filter (e.g.

I DK 175808 B1 I

I 12 I

Sartorius SM 11107 or SM 11307, 0.2 µm pore size

See, Pall filter NRP (pore size 0.2 µm) and store

is avoided by particulate and bacterial contamination

In mincing until filling. As pressure gas by filtration I

In nitrogen 5 is used. A storage at room temperature I

I (20-22 * 0) including the time for solution preparation I

do not exceed 3-4 hours. Do not know immediately after-

In the following freeze-drying, the solution can be stored externally

IN

even 36 hours at +4 C to +6 C.

I 10 For sterile filtration I may further be used

usual prefilters (eg Sartorius SM 13400 or I

In Pall LPA) to protect the sterile filter. IN

Cleaning the vials:

I I

The vials are flushed with demineral I

In leased hot and cold water and purged with air. IN

All cleaning media is filtered free of nitrogen. IN

To prevent re-contamination with particles from I

The air is dried and the bottles are heated with hot air I

I (discontinuously at 180 ° C / 2 hours). IN

I Cleaning the rubber stoppers with which I-

The bottles are closed, using demin I

realized water and e.g. a cleaning agent comprising I

In 25 of nonionic surfactants and phosphoric acid esters in water I

In you resolution. IN

Wash the cleaned plugs with non-lint and lint-free I

without the use of demineralized water or filtered I

In demineralized water. The plugs thus purified I

30 is then recharged by steam. IN

In the thus purified and sterilized injection

bottles are now filled antiseptically with ifosfamide-mesna-op-I

In the solution and provided with the rubber plugs, keeping the container I

Nitrogen is exhausted with nitrogen before and after filling. IN

13 DK 175808 B1 Load volumes: - In phosphamide Mesna Load volume Application volume1 200 mg 40 mg 2 ml 5 ml 500 mg 100 mg 5 ml 12.5 ml 5 1 g 0.2 g 10 ml 25 ml 2 g 0.4 g 20 ml 50 ml 5 g 1.0 g 50 ml 125 ml 5 g_2.0 g 50 ml_125 ml_ 'for later, diluting the lyophilizate 10 The filling volumes must not exceed the following limits: _____ Filling Limit values for Average limit volume The individual filling points for filling 2 volumes 1.9 - 2.1 ml 1.95 - 2.05 ml 5 ml 4.8-5.2 ml 4.9-5.1 ml 10 ml 9.7 - 10, 3 ml 9.85 - 10.15 ml 20 20 ml 19.4 - 20.6 ml 19.7 - 20.3 ml 50 ml_ 48.5 - 51.5 ml_49.25 - 50.75 ml The loading volumes are checked statistically, the filling volume at each filling point 25 having to be measured once at least every 30 minutes.

The pre-filled vials are then frozen freeze- O.

as close as possible to -40 C.

The conditions for freeze-drying are different for the individual sizes of vials. That applies. E.g. the following values: 0

Main drying time at a plate temperature of +15 C and 0.6 mbar: approx. 8-10 hours for containers with 200 mg ifosfamide + 40 mg mesna

I DK 175808 B1 I

14 I

ca. 12 - 15 hours for containers with 500 mg ifosfamide + I

100 mg mesna I

ca. 13 - 16 hours for containers with 1000 mg ifosfamide + I

200 mg mesna I

! 5 approx. 25 - 32 hours for containers with 2000 mg ifosfamide + I

In the 400 mg mesna I

For approx. 44 - 50 hours for containers with 5000 mg ifosfamide + I

In 1000 mg of mesna I

The post-drying time is approx. 3-4 hours below va- I

vacuum of 5 x 10 mbar, at a plate temperature of - »- 25 C.

The residual moisture (determined by K. Fischer) must be:

You are below 0.5%. IN

After the freeze drying is complete, I-

In the 15 jars. IN

I To secure the rubber plugs, apply bristles- I

sheaths that are bent. The finished vials I

Check for mechanical defects (cracks, failure I

In closing etc.). IN

I 20 I

Example 2 I

The following solution is used for freeze drying:

Mesna 100 mg I

Ifosfamide 100 mg I

D-mannitol 70 mg I

Injection water in 1 ml I

The density of this solution is 1.101 g / ml at 1

30 + 20 C. The amount of dissolved solution adheres to

In the filling and freeze-drying capacity. IN

All process steps in the preparation of I

In the solution and the filling is carried out under nitrogen I

In or nitrogen blow-through. IN

I / B

15 DK 175808 B1

Preparation of the solution:

Approx. 80% injection water volume and the corresponding amounts of mesna, ifosfamide and mannitol are dissolved in the water in succession while still stirring and nitrogen blasting. After complete dissolution, make up to the final volume and measure the pH.

The final solution is sterilized by filtration through a suitable germ-tight filter {e.g. 0.2 10 µm pore size) and avoiding particulate and bacterial contamination until filling. Nitrogen is used as pressure gas for filtration. A storage by

A

room temperature (20-22 C) must not exceed 3-4 hours including the time for the solution preparation. If the following freeze drying is not performed immediately, the solution 0 o can be stored for an additional 36 hours at +4 C to +6 C.

For sterile filtration, customary pre-filters (e.g., Sartorius SM 13400 or Pall LPA) can further be used to protect the sterile filter.

20

Cleaning the vials:

The vials are flushed with hot and cold demineralized water and purged with air.

25 All cleaning agents are filtered free of sulfur.

To avoid contamination with particles. from the air, the bottles are dried and sterilized using 0 of hot air (discontinuous at 180 C / 2 hours).

The cleaning of the rubber stoppers with which the injection vials are closed is done using demineralized water and e.g. a cleaning agent consisting of nonionic surfactants and phosphoric acid esters in aqueous solution.

35 The cleaned plugs are rinsed turbidity and lint-free using demineralized water or filtered demineralized water.

! ____

H DK 175808 B1 I

16 I

The plugs thus purified are then sterilized

using steam. IN

H The thus and sterilized vials I

is then aseptically fulfilled with ifosfamide-mesna solution-I

5 and provided with the rubber plugs, the container being removed

is blown with nitrogen before and after filling. IN

Refills:

Ice Phosphamide Mesna Filling Application Volume 'I

10 _ Quantity__ I

200 mg 200 mg 2 ml 5 ml I

500 mg 500 mg 5 ml 12.5 ml I

I 1 g 1 g 10 ml 25 ml I

I 2 g 2 g 20 ml 50 ml I

15 5 g_5__g_50 ml_125 ml_ I

For the later dilution of the lyophilizate I

The filling volumes must not exceed the following I

In limits: _ I

I 20 Filling Limit Values for Average Limit I

By volume, the individual filling points for I

fill volumes fill volume I

_; _ not_ I

I 2 ml 1.9 - 2.1 ml 1.95 - 2.05 ml I

5 ml 4.8 - 5.2 ml 4.9 - 5.1 ml I

I 10 ml 9.7 - 10.3 ml 9.85 - 10.15 ml I

I 20 ml 19.4 - 20.6 ml 19.7 - 20.3 ml I

I 50 ml_48.5 - 51.5 ml_49.25 - 50.75 ml I

I The filling volumes are statistically monitored, I

In that the filling volume at each filling point I

You should measure once at least every 30 minutes. IN

The pre-filled vials are then frozen

IN

as quickly as possible to -40 C. I

I 35 The conditions for freeze drying differ

In for the individual sizes of vials. There you

17 DK 175808 B1 applies e.g. the following values: o

The heating cycle time at a plate etorpor ^ t -irir> A +15 c or 0.6 mbar: approx. 8-10 hours for containers with 200 mg ifosfamide + s in 5 200 mg mesna approx. 12 - 15 hours for containers with 500 mg ifosfamide + * 500 mg mesna approx. 13-16 hours for containers with 1 g ifosfamide + 1 g mesna 10 approx. 25 - 32 hours for containers with 2 g ifosfamide + 2 g mesna approx. 44 - 50 hours for containers with 5 g ifosfamide + 5 g mesna 15 The post-drying time is approx. 3-4 hours under vacuum Å. 0

of 5 IQ- * mbar at a plate temperature of +25 C. Remain- I

the humidity (after K. Fischer) should be below 0.5%.

After the freeze drying, the vials are closed.

To secure the rubber plugs, brush caps are attached and fastened. The completed vials are checked for mechanical defects (cracks, incorrect closure, etc.).

«

Claims (6)

A lyophilized composition, characterized in that it contains ifosfamide, 0.05-1.0 parts by weight of mesanol and 0.1-17 parts by weight of hexitol, wherein mesna and hexitol are 1H calculated on the basis of 1 part by weight ifosfamide, and * In 5 other usual pharmaceutical excipients. IN A lyophilized preparation according to claim 1, characterized in that it contains, as hexitol, I mannitol. IN Process for the preparation of a phosphorus-10 amide mesna lyophilisate, characterized in that, under an inert gas between -70 ° C and 0 ° C, an aqueous or aqueous-ethanolic solution containing 1 -13% by weight ifosfamide and 0.05-13 parts by weight mesna, II 0.1-17 parts by weight hexitol (mesna and hexitol are calculated on the basis of 1 part by weight ifosfamide) and optionally 0-16.9 in parts by weight (based on (1 part by weight ifosfamide) additional II pharmaceutical auxiliaries and from the product thus obtained in frozen state removes the water. IN A method according to claim 3, characterized in that it is suitable for first removing non-absorptive I Η in bound water at a temperature between -30 ° C and +40 ° C and at a pressure between 10 ° and 10 mbar, and then adsorptively bound water is removed at a temperature between 0 CII and 40 ° C and at a pressure between 10-4 and 10-1 mbar. I I 25 A process according to any one of the preceding claims, characterized in that mannitol is used as I I hexitol. IN 6. Ifosfamide mesna lyophilisate, characterized in that it is obtained according to any of the preceding claims. IN