NO873860L - IFOSPHAMIDE LYOPHILIZATE AND PROCEDURE FOR THEIR PREPARATION. - Google Patents

Abstract

1. A lyophilized preparation consisting of ifosfamide and 0.1 to 17 parts by weight hexitol per part by weight ifosfamide and, optionally, other standard pharmaceutical auxiliaries.

Description

The chemical name for the active substance ifosfamide is 3-(2-chloroethyl)-2-(chloroethylamino)-tertrahydro-2H-1,3,2-oxazaphosphorin-2-oxide

As cyclophosphamide, ifosfamide belongs to the chemical group of oxazaphosphorines and is used therapeutically for the treatment of tumor diseases.

Ifosfamide is a white, crystalline powder with a melting point of 48°C to 51°C and strongly hygroscopic properties. Already below the melting point, ifosfamide begins to sinter, so it must be stored at the lowest possible temperatures (room temperature and lower). Also, it is best to avoid contact with humidity.

Ifosfamide dissolves to approx. 10 wt-# in water, however, has only limited durability in aqueous solution (maximum 3-4 hours at 10°C to 22°C, respectively 36 hours at 4<0>C to 6°C.

Ifosfamide is applied exclusively parenterally. The injection bottles contain 200-5000 mg ifosfamide in the form of a sterile crystallisate which before application is dissolved in water for injection purposes, so that a 4&-Ig concentration is not exceeded. This solution is suitable for intravenous injection. For short intravenous infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution, or similar infusion fluids. The infusion duration is approx. 30 minutes, possibly 1-2 hours. During the 24-hour infusion, the ifosfamide solution is dissolved, for example, in a total of 3 liters of 5&dextrose saline solution.

Ifosfamide causes many problems during production and processing. In the preparation of the sterile crystallized ifosfamide, a product of varying physical nature appears. In the case of a different trickling capacity, the dosing accuracy in particular is affected to a great extent when filling.

The processing of ifosfamide is further complicated by its hygroscopicity and low melting point. With longer storage, the sterile crystallisate sinters and the dissolution rate decreases. With the beginning of sintering of the ifosfamide, the clear solubility also decreases, and the pH value of the solution with simultaneous yellowing, a therapeutic application is then usually no longer possible.

The task of the invention is therefore to provide ifosfamide in a form with improved properties such as improved stability, storability, doseability and solubility, which is easier to use, and is particularly suitable for the preparation of injectable solutions.

It has now surprisingly been found that the previous disadvantages and difficulties in handling and storing ifosfamide can be avoided by using a specific ifosfamide lyophilisate. In particular, it is surprising that the ifosfamide lyophilisate according to the invention has a greater thermostability than the ifosfamide dry filling used until now.

The dry filling with ifosfamide is at 40°C already after a storage time of 1 month. turned dark, after 2 months. the bottle is sintered and yellow-coloured. At a storage temperature of 55° C, the dry-filled ifosfamide has already melted within 4 days.

In contrast, with ifosfamide lyophilisate produced according to the invention under the above-mentioned storage conditions, there is neither visible discoloration nor a change in the ifosfamide's consistency.

The dissolution rate of the ifosfamide lyophilisate is also clearly increased in relation to the ifosfamide cross-filling. While the lyophilisate immediately dissolves regardless of storage time when the solvent is added, the injection bottles with the dry filling must be shaken vigorously for 1/2 to 3 minutes after injecting the solvent. When the dissolution does not take place immediately and completely, and this is the case with long-stored injection bottles, it is even necessary to let the solution stand for a few minutes. The use of the preparation in the clinic is thereby made more difficult.

In contrast to sterile crystallisate, ifosfamide lyophilizate still exhibits optimal dissolution properties even after storage over several years.

Moreover, the ifosfamide dry filling (ie the pure ifosfamide crystallisate) is much more sensitive to humidity than the lyophilisate. Thus, the ifosfamide dry filling already liquefies at a relative humidity of less than 75%, while the lyophilisate even at 100% relative humidity does indeed become moist, but retains its outer shape.

When filling the sterile crystallisate, there is also the risk of particulate or microbial contamination to a significantly greater extent than with the lyophilisate.

In the production of the ifosfamide lyophilisate, however, the sterile filtration of the solution only takes place immediately before filling the injection bottles. Thereby, in relation to filling the sterile crystallisate, greater microbiological safety is provided. Particle-clear contaminants, which dry filling in the meantime gives rise to difficulties, can also be avoided by filtering the solution with greater safety.

However, the lyophilization of the ifosfamide not only leads to a product improvement, but is also cheaper in terms of manufacturing costs than filling with sterile crystallisate.

It has been shown that only the method according to the invention using a hexite, which e.g. mannitol, gives an improved ifosfamide lyophilisate. For example, by mixing in common salt, as is common with dry filling of other oxazaphosphorines, no lyophilisate could be obtained.

According to the invention, for example, an aqueous solution of ifosfamide containing 1-13 parts by weight of ifosfamide and 0.1-17 parts by weight of hexite, referred to 1 part by weight of ifosfamide, is freeze-dried. Preferably, this aqueous solution contains 5-12 wt.-$, especially 8-10 wt.-$ ifosfamide.

Corresponding ethanol-water solutions of ifosfamide can also be used instead of a pure aqueous solution (ethanol part of such a solution up to 45% by weight, for example 1-20% ethanol). In such cases, it is best to remove the ethanol first under vacuum before the remaining ice is sublimated. The conditions for the first ethanol removal are, for example: pressure x 10"!mbar, Temperature from -25°C to -5°C, rising during 10 hours, then increased to 22°C. In detail, these conditions also depend on the different layer heights of the material to be dried in the injection bottle, and are to be varied accordingly.

The amount of hexite in this aqueous or aqueous ethanolic solution is usually 1-17, preferably 3-12, especially 5-9 by weight. If the amount of hexite is referred to 1 part by weight of ifosfamide, then here the amount of hexite is 0.1 to 17, preferably 1-2.5, especially 0.6-0.8 parts by weight of hexite per 1 part by weight ifosfamide. Examples of hexite include: mannite, glycite (sorbitol such as D-sorbitol), dulcite, allite, altrite (for example D- and L-altrite), idite (for example D- and L-idite), their optically active forms (D - respectively L-forms) as well as the corresponding racemates. In particular, mannitol is used as D-mannitol, L-mannitol, DL-mannitol, sorbitol and/or dulcit, and namely preferably D-mannitol. Mixtures of the aforementioned hexites can also be used as hexite, for example mixtures of mannitol and sorbitol, and/or dulcite. As dulcite is less water-soluble than, for example, mannitol, the dulcite content in the aqueous solution must not exceed, for example, 3% by weight. Mannitol and sorbitol, on the other hand, can, for example, be mixed in any ratio.

In addition to hexite, other common pharmaceutical excipients can also be added, such as, for example, glycine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin, and equivalent structure-forming substances. The total amount of such substances in the solution used for the freeze-drying is, for example, 0-16.9 parts by weight, for example 0.1-7 parts by weight referred to 1 part by weight ifosfamide. In the finished lyophilisate, the total amount of such auxiliary substances can amount to up to 16.9 parts by weight, referred to 1 part by weight of hexite. Detail according to the amount of such excipients depends on the amount of hexite present, namely so that the total amount of hexite and such other excipients in the finished lyophilisate amounts to a maximum of more than 17 parts by weight, referred to 1 part by weight of ifosfamide. If only 0.1 parts by weight of hexite are present in the lyophilisate, there may be up to 16.9 parts by weight of other excipients, if for example there are 8.5 parts by weight of hexite, for example the amount of other excipients may amount to up to 8.5 parts by weight referred to 1 part by weight Ifosfamide.

For the preparation of the solution that can be used for freeze-drying, approx. 70-83$, preferably 80$ of the required amount of water, respectively ethanolic amount of water, and the corresponding amount of ifosfamide and mannitol are dissolved one after the other, i.e. first dissolve ifosfamide and then the mannitol, with constant stirring and respectively with constant movement. After complete dissolution, the final volume is filled and the pH value is measured. The pH value of this solution should, for example, after dilution be between 4 and 7. A 4% ifosfamide solution is preferably prepared.

The ifosfamide solution formed in this way is then sterilized by filtering over conventional germ-tight filters and then filled into corresponding containers for injection preparations. The storage time until filling in the injection container, including the time for the preparation of the solution, must not exceed a time of 34 hours if it is at room temperature (18-22°C). If the subsequent freeze-drying is not yet possible immediately, such a solution can possibly also be stored in the injection container for up to 36 hours at lower temperatures, for example between -5 and +10°C, preferably 4-6Q°C, before the freeze-drying begins.

To carry out the method according to the invention, the thus formed aqueous ifosfamide solution is then filled into containers for injection preparations, for example ampoules or other broken glass, and the solution is freeze-dried.

For sterilization, normal germ-proof filters are used, e.g. ordinary bacteria filters with a pore size of approx. 0.2y. The glass shards or ampoules used are sterilized beforehand in the usual way.

The hexitol used (preferably mannitol, especially D-mannitol) must correspond to the requirements of the British Pharmacopoeia 1980.

The hexite used must be as pyrogen-free as possible (pyrogens are fever-causing endotoxins formed by bacteria).

The same applies to the ifosfamide used. The removal or splitting of the pyrogens takes place in the usual way (for example, the active substance solution is treated with activated charcoal before the sterile filtration). Likewise, the injection water used must be sterile and pyrogen-free, and corresponding to the requirements for Deutschen Arzneibuches, 9. ug. 1986. Tube glass or outer glass of III.hydrolytic class (e.g. 10R, 30R and 50H) are suitably used as injection vessels (see here Deutsches Arzneibuch, 9th ed. 1986, pages 161-164 and DIN standards 58366 part 1 and part 5).

Furthermore, the injection vessels as well as the additional auxiliary materials such as rubber stoppers and recoating caps must correspond to the requirements of DIN standards 58366, part 2 and part 3, as well as 58367 part 1.

The amount of solution of the Ifosfamide solutions prescribed for lyophilisation in the respective containers (ampoules) or other containers for injection preparations is per container for example between 1 and 500, preferably 1 and 250, especially 2 and 50 ml. The containers are respectively sized so that the lyophilisate contained therein can be dissolved more cleanly in a larger amount of liquid. They must therefore usually have a volume that is sufficient to produce a ready-to-use final solution such as e.g. has 2-5, preferably 2-4 especially 2-2.5 times the volume of the originally filled lyfilizate solution.

As already mentioned, each ampoule or each glass shard is preferably filled with a single dose of ifosfamide, as the amount of ifosfamide per shards of glass, for example, make up between 100 mg to 10 g, preferably 200 mg to 5 g. The solution in this shard of glass or ampoule is then freeze-dried in the usual way. However, it is also possible to lyophilize larger amounts of ifosfamide, i.e. a correspondingly larger solution volume of the ifosfamide solution in the correspondingly larger vessel, and then to divide and pack the formed lyophilisate into correspondingly smaller dosages.

The lyophilization itself is carried out in such a way that the ampoule or bottles or other vessels containing the ifosfamide-hexite solution are immediately placed on a still plate or in trays on a still plate in a freeze-drying chamber. After closing the chamber, the ampoules or vessels are cooled to temperatures below 0°C, for example to temperatures between -70°C to 0°C, preferably -50°C to -30°C, especially -45°C to -35°C. As soon as the solution is completely frozen, the freeze-drying chamber is gradually evacuated and drying begins. In this way, the non-adsorbatively bound solvent is first removed, namely at temperatures between -30 to -40°C, preferably 0°C to +3°C, especially 20"C to 30°C, setting a pressure between 102"<3>to 6, preferably 10"<2> to 2, especially 10"<1> to 1 mbar. In the case of the previously indicated temperatures or temperature ranges, it concerns the temperature of the stationary plates. The process is thereby controlled so that the heat supplied above the plate temperature is completely consumed as sublimation heat, and the frozen ifosfamide-containing solution temperature remains constantly below its autectic temperature. The duration of removal of this non-adsorbatively bound solvent depends on the size of the individual containers, and is, for example, between approx. 4-40 hours, at a plate temperature of 25° C and a pressure of 0.8 mbar. For example, reference is made in this context to the times specified in the examples. The complete removal of the non-adsorbatively bound water appears as follows: Non-adsorbatively bound water is present as ice. The so-called pressure rise measurement determines whether such water is still present in the lyophilisate. In addition, a valve is closed between the drying chamber and the condenser chamber, to which the vacuum pump is connected. Ice present would then quickly sublimate and provide a pressure increase in the drying chamber. During the pressure increase measurement, the pressure in the chamber should increase after 15 minutes from the initial value, for example 0.8 mbar, to a maximum of 1 mbar. A stronger increase would mean that the main drying has not yet ended.

The residual adsorptively bound solvent still present is then removed by post-drying. This amounts to, for example, 3-12 hours at a vacuum of 10"<1> to 10~<4>mbar, especially 3-4 hours at a vacuum of 10~<3> to 10~<4>mbar.

Lyofi 1 in the curing process is finished when the residual moisture (determined according to K.Fischer) is below 1$, preferably below 0.5$.

In particular, the post-drying to remove adsorptive bound water takes place at temperatures between 0-40, preferably 10-35, especially 20-30°C, and a pressure between 10"<4> to 10"<1>, preferably 10~<3> to IO"<2>, especially IO"<3> to 5 x IO"<3>mbar, this post-drying having for example 2-36, preferably 6-24, especially 3-12 hours.

After the end of freeze drying, the vessels are closed. The method according to the invention is carried out in all steps under sterile conditions.

The closure of the injection bottles then takes place, for example, after aerating the freeze-drying chamber to normal pressure by supplying dry, sterile air or hydrogen, with special freeze-drying rubber stoppers that are siliconed to avoid wear and tear and to improve sliding.

Example.

The following solution is used for freeze drying:

This solution density is 1.0563 g/ml at 6°C and 1.0527 g/ml at 20°C.

The amount of solution to be added depends on the respective filling and freeze-drying capacity.

Solution preparation:

It has approx. 80$ amount of injection water and the corresponding amount of ifosfamide and mannitol are dissolved in it to water in sequence with constant stirring. After complete dissolution, fill up to final volume and measure the pH value.

The finished solution is sterilized by filtering through normally germ-proof filters, (for example Sartorius SM 11107 or SM 11307, 0.2p pore size, PalT filter NRP (pore size 0.2p)) and stored to avoid particulate and bacterial contamination until filling. A storage at room temperature (20-22°C), including the time for the preparation of the solution, should not exceed 3-4 hours.If not immediately subsequent freeze-drying, the solution can also be stored for approximately 36 hours at 4° to 6°C.

For sterile filtration, ordinary pre-filters (for example Sartorius SM 13400 or Pall LPA) can also be used to protect the sterile filter.

Cleaning the injection bottles:

The injection bottles are rinsed in demineralized water, hot and cold, and air. All cleaning media are freed by filtration for suspended matter.

To avoid recontamination with particles from the air, the bottles are dried and sterilized using hot air (continuously at 180°C/2 hours).

The cleaning of the rubber caps with which the injection bottles are closed takes place using demineralized water, e.g. a cleaning agent consisting of non-ionic surfactants and phosphoric acid esters in aqueous solution.

The cleaned corks are rinsed fiber- and lint-free using demineralized water, or filtered demineralized water. The corks thus cleaned are then sterilized using steam.

The thus cleaned and sterilized injection bottles were now aseptic with the Ifosfamide solution and fitted with the rubber stoppers.

Filling amounts:

The filling volumes must not exceed the following limit:

The filling volumes are to be monitored statistically, at least every three minutes the filling volume per filling point must be measured once.

The filled injection bottles are frozen as quickly as possible at -40°C.

The conditions for the freeze-drying are different for the individual sizes of injection bottles. The following values apply, for example: Duration of main drying at a plate temperature of +25<0>C and 0.6 mbar: approx. 6 - 8 hours for vessels with 200 mg ifosfamide approx. 10 - 12 hours for vessels with 500 mg ifosfamide approx. 10 - 14 hours for vessels with 1000 mg ifosfamide approx. 20 - 28 hours for vessels with 2000 mg ifosfamide

about. 34 hours for vessels with 5000 mg ifosfamide.

Duration of post-drying approx. 3-4 hours under a vacuum of 5 x 10"<4>mbar at a plate temperature of 25°C.

The residual moisture (determined according to K. Fischer) must be below 0.5$.

After completion of the freeze drying, the injection bottles are closed.

To secure the rubber stoppers, wrap-around covers are attached and rolled over. The finished injection bottles are checked for mechanical defects (cracks, improper closure, etc.).

Claims (6)

1. Lyophilized preparation consisting of ifosfamide and 0.1 to 17 parts by weight of hexite, referred to 1 part by weight of ifosfamide, as well as possibly other common pharmaceutical excipients. 2. Lyophilized preparation according to claim 1, characterized in that the hexite contains mannitol. 3. Process for the production of an ifosfamide lyophilizate, characterized in that an aqueous or aqueous ethanolic solution of ifosfamide containing 1-13 parts by weight ifosfamide on 0.1-17 parts by weight of hexite referred to 1 part by weight ifosfamide, as well as optionally 0-16 .9 parts by weight (referred to 1 part by weight ifosfamide), further pharmaceutical excipients are frozen between -70"C and 0"C, and the water is removed from the product thus formed in the frozen state. 4. Method according to claim 3, characterized by first removing the non-adsorbed bound water at a temperature between -30°C and +40°C, and a pressure between 10"<3> to 10 mbar and then adsorptively bound water at a temperature between 0 °C and 40°C, and a pressure between IO" <4> to 10"<1> mbar. 5. Method according to one or more of the preceding claims, characterized in that mannitol is used as hexite. 6. Ifosfamide lyophilizate formed according to one or more of the preceding claims.