DK169308B1 - Lyophilized preparation, process for preparing an ifosfamide lyophilizate preparation and the ifosfamide lyophilizate preparation obtained by the method - 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

in DK 169308 B1

The present invention relates to a lyophilized preparation, a process for preparing an ifosfamide lyophilizate preparation and the ifosfamide lyophilizate preparation obtained by the process.

The chemical name for the active compound ifosfamide is 3- (2-chloroethyl) -2- (chloroethylamino) -tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide CH, -CH, -Cl I 2 2 10 Cl-CH, -CH, -NH N-CH-, 2 2 \ / ά ·> ^ ch? O-O-CH 2

Ifosfamide belongs as the cyclophosphamide to the chemical group of oxazaphosphorins and is used therapeutically for the treatment of tumor diseases.

Ifosfamide is a white crystalline powder having a melting point of 48-51 ° C and highly hygroscopic properties. Already below the melting point, ifosfamide 20 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 be avoided as far as possible.

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

Ifosfamide is administered exclusively parenterally. The vials contain 200 to 5000 mg ifosfamide in the form of a sterile crystallate which, before administration, is dissolved in water for injection, so that a 4% concentration is not exceeded. This solution is suitable for intravenous injection. For short-term intravenous infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution or similar infusion solutions. The infusion time amounts to approx. 30 minutes, optionally 1 to 2 hours. At the 24 hour infusion, ifosfamide solution is dissolved, e.g. in a total of 3 liters of 5% dextrose boiling salt solution.

Ifosfamide causes many different problems during manufacture and processing. In the preparation of the sterile crystallized ifosfamide a product of varying physical nature is obtained. In particular, the dosing accuracy of filling is greatly influenced by the varying flow characteristics.

The administration of the ifosfamide is further hampered by its hygroscopicity and low melting point. For longer storage, the sterile crystalline sinters and the dissolution rate decreases. With the initial sintering of the ifosfamide, the clarity and pH of the resulting solution also decrease during simultaneous yellowing. Therapeutic use is thus generally no longer possible.

U.S. Patent No. 4,537,883 discloses a hydrated lyophilizate composition containing about 20 parts by weight of cyclophosphamide, approx. 1 1 / 4-2 parts by weight of water and from 20 approx. 10 to 85 parts by weight of mannitol, the water present being either residual water from the lyophilization or added after the lyophilization. If ifosfamide is used in place of cyclophosphamide, an unstable product is obtained which is partially already liquid. Therefore, the teachable extract of U.S. Patent No. 4,537,883 cannot be used to bring ifosfamide in better and more stable form.

It is thus an object of the invention to present ifosfamide in a form having improved properties, such as improved stability, durability, dosing and solubility, which form is easier to use, and is particularly suitable for preparing injectable solutions.

It has now surprisingly been found that the present disadvantages and difficulties in handling and storing ifosfamide can be avoided by the use of a particular ifosfamide lyophilisate. It is especially surprising that the ifosfamide lyophilisate of the invention has a greater heat stability than the previously used ifosfamide dry filling composition.

The present invention thus relates to a lyophilized composition which is characterized in that it consists of ifosfamide and 0.1 to 17 parts by weight of hexitol on the basis of a part by weight ifosfamide and possibly other pharmaceutical excipients.

10 Ifosfamide dry filling preparations darken already after a 1 month residence time at 40 ° C.

After 2 months, the bottle contents are sintered together and colored yellow. At a storage temperature of 55 ° C, the dry-filled ifosfamide already melts within 4 days.

In contrast, neither a discoloration of the ifosfamide nor a change in its consistency can be recognized by the ifosfamide lyophilisate preparation prepared according to the invention under the above storage conditions.

20 The dissolution rate of the ifosfamide lyophilisate is also significantly increased over that of the ifosfamide dry filling material. While the lyophilizate is immediately dissolved immediately by the addition of the solvent, the vials of the dry filler material must be shaken vigorously for 1A to 3 minutes after injection of the solvent. When the solution does not immediately complete in this case, and this is the case for long-term vials, it is even necessary to leave the solution for some 30 minutes. The use of the preparation in the clinic is thereby made more difficult.

In contrast to the sterile crystallate, the ifosfamide lyophilisate still exhibits optimal dissolution properties after several years of storage. In addition, the ifosfamide dry filler material (i.e., the pure ifosfamide crystallate) is more sensitive to humidity than the lyophilizate. Thus, ifosfamide dry filler material is already liquid at a relative humidity of less than 75%, while the lyophilizate, even at 100% relative humidity, although moist, still retains its outer shape.

Furthermore, in the loading of the sterile crystallate, the danger of a particulate or microbial contamination is substantially greater than that of the lyophilisate.

In contrast, in the preparation of the ifosfamide lyophilisate, the sterile filtration of the solution is carried out immediately prior to filling into the vials. This provides greater microbiological safety than the filling of the sterile crystallate. Also, particulate contaminants, which occasionally cause 15 problems in the dry filling, can be avoided with greater certainty in the filtration of the solution.

However, the lyophilization of the ifosfamide not only results in a product improvement, but is also more advantageous in terms of manufacturing costs than the filling of the sterile crystallate.

The invention further relates to a process for preparing an ifs amide lyophilate which is characterized by freezing an aqueous or aqueous ethanolic solution of ifosfamide containing 1 to 13% by weight ifosfamide and 0.1 to 17 additional parts by weight of hexitol on the basis of 1 part by weight ifosfamide and optionally 0 to 16.9 parts by weight (on the basis of 1 part by weight ifosfamide) of additional pharmaceutical excipients, to between -70 ° C and 0 ° C and of driver water from the product thus obtained in frozen condition.

Finally, the invention relates to the ifosfamide lyophilisate preparation obtained by the above method.

It has been found that only the process of the invention using a hexitol, e.g.

35 mannitol, provides an improved ifosfamide lyophilisate.

Eg. for example, a lyophilizate could not be prepared by admixture of boiling salt, such as e.g. is usual in dry filling preparations of other oxazaphosphorins.

According to the invention, an aqueous solution of ifos amide containing 1 to 13% by weight ifos-5 famide and 0.1 to 17 parts by weight of hexitol on the basis of a part by weight ifosfamide is freeze dried. Preferably, this aqueous solution contains 5 to 12 wt%, especially 8 to 10 wt% ifosfamide.

Corresponding ethanol-water-10 solutions of ifosfamide may also be used in place of an aqueous solution (ethanol content of such a solution is up to 45% by weight, e.g. 1 to 20% ethanol). In such cases, the ethanol is removed as much as possible in advance in vacuo before the remaining ice is sublimated. The conditions for the first ethanol removal are, for example: pressure 5 x 10-1 mbar, temperature increasing from -25 ° C to -5 ° C within 10 hours and then increased to 22 ° C. In detail, these conditions also depend on the different layer thicknesses of the material to be dried in the vials and must be varied accordingly.

The amount of hexitol in this aqueous or aqueous-ethanol solution is generally 1 to 17, preferably 3 to 12, especially 5 to 9% by weight. If the hexitol amount is based on 1 part by weight ifosfamide, the amount of hexitol is 0.1 to 17, preferably 0.1 to 2.5, especially 0.6 to 0.8 parts by weight of hexitol per liter. 1 part by weight ifosfamide. As hexitol comes mannitol, glucitol, sorbitol, such as D-sorbitol, dulcitol, allitol, altritol (e.g., D- and L-altritol), iditol (e.g., D- and L-iditol) , the optically active forms thereof (D or L forms) and the corresponding racemates on speech. In particular, mannitol such as D-mannitol, L-mannitol, DL-mannitol, sorbitol and / or dulcitol are used, and of these preferably D-mannitol. As hexitol, mixtures of said hexitols, such as e.g. mixtures of mannitol and sorbitol and / or dul- citol. Since dulcitol is less water soluble than e.g. mannitol, the dulcitol content of the aqueous solution, e.g. do not exceed 3% by weight. Mannitol and sorbitol, on the other hand, can e.g. mixed in all conditions.

In addition to hexitol, other conventional pharmaceutical excipients such as e.g. glycine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin and similar skeletal agents. The total amount of such substances in the solution used for the freeze drying is e.g. 0-16.9 parts by weight, in particular 0.1 to 7 parts by weight, based on 1 part by weight ifosphamide. In the final lyophilizate, the total amount of such excipients may be up to 16.9 parts by weight based on one part by weight hexitol. In detail, the amount of such adjuvants adjusts to the amount of hexitol present, namely that the total amount of hexitol and such other adjuvants in the final lyophilizate is a maximum of no more than 17 parts by weight on the basis of part by weight of phosphosamide. Thus, if only 0.1 parts by weight of hexitol is present in the lyophilisate, up to 16.9 parts by weight of other excipients may be present.

For example, if If there are 8.5 parts by weight of hexitol, the amount of other excipients, e.g. constitute up to 8.5 parts by weight based on parts by weight ifosfamide.

To prepare the solution for use in freeze drying, 70 to 83%, preferably 80% of the required amount of water or ethanol-water mixture is taken, and a suitable amount of ifosfamide and mannitol is dissolved successively (i.e., first ifosfamide and then mannitol) for 30 minutes. stirring or moving. After complete dissolution, make up to the final volume and measure the pH. The pH of the solution should e.g. after dilution being between 4 and 7, preferably a 4% ifosfamide solution is prepared.

The ifosfamide solution thus obtained is then sterilized by filtration through a conventional, germ-sealed filter and then filled into appropriate containers for injection preparations. The storage time before filling in the injection container, including the time of solvent preparation, should not exceed 5 to 4 hours, unless stored at room temperature (18 to 22 ° 0). If the subsequent freeze-drying is still not possible immediately, such a solution, possibly after filling in the injection container, e.g. stored for a further 36 hours at low temperatures, e.g. between -5 ° C and + 10 ° C, preferably +4 to + 6 ° C before freeze drying begins.

In order to carry out the process according to the invention, the aqueous phosphorus solution thus obtained is then filled into containers for injection preparations, e.g. vials or other glass containers and the solution is freeze-dried.

For sterilization, conventional seed-tight filters, e.g. usual bacterial filters with a pore size of about 20 0.2 µm. The used glass containers or ampoules are pre-sterilized in the usual manner.

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

The hexitol used must as far as possible be pyrogen-free (pyrogens are fever-causing endotoxins formed by bacteria). The same applies to the ifosfamide used. The removal or degradation of the pyrogens is carried out in the usual manner (for example, the solution of the active substance is treated prior to sterile activated carbon filtration). Likewise, the injection water used must be strict and pyrogen-free and meet the requirements of "Deutschen Arznei-35 buches", 9th edition 1986. Suitable vials or tubes of III 169308 Bl 8 vials should be used. hydrolytic class (eg 10 R, 30 R and 50 H) (see in this connection Deutsches Arznei-buch, 9th edition 1986, pages 161-164 and DIN standard 58366 part 1 and part 5).

5 In addition, the injection containers and other auxiliaries, such as rubber stoppers and caps, must meet the requirements of DIN standards 58366, part 2 and part 3, and 58367, part 1.

The amount of solution of the phosphorus solutions determined for lyophilization in each of the vials (vials) or other vials for injection is per unit dose. container e.g. between 1 and 500, preferably 1 and 2 and 50, especially 52 ml. The containers must be adjusted each time so that the lyophilisate contained therein can later be dissolved in a larger amount of liquid. Thus, they should generally have a volume sufficient to produce a ready-to-use final solution having a volume of 2 to 5, preferably 2 to 4, especially 2 to 2.5 times the volume of the initially filled lyophilizate solution. equipment.

As already mentioned, each ampoule or glass container is preferably filled with a unit dose of ifos-famide, whereby the amount of glass container 25 e.g. is between 100 mg and 10 g, preferably 200 mg and 5 g. Next, the solution in this glass container or ampoule is freeze-dried in the usual manner. However, it is also possible to lyophilize larger amounts of phosphorus. mid, ie a correspondingly larger volume of solution of the ifosfamide solution in a correspondingly larger container and then divide or package the obtained lyophilisate into correspondingly smaller doses.

The lyophilization itself is carried out so that the vials, glass containers or other containers containing the ifosfamide-hexitol solution are placed in a freeze-drying chamber immediately on a dispensing plate or in trays on a dispensing plate. After the chamber is closed, the vials or containers are cooled to temperatures below 0 ° C, e.g. for temperatures between -70 ° C and 0 ° C, preferably -50 ° C and -30 ° C, especially -45 ° C and 35 ° C. As soon as the solution is completely frozen, the freeze-drying chamber is evacuated little by little, whereby the drying begins. Hereby, the non-adsorbably bonded solvent is first removed, namely at temperatures between -30 and + 40 ° C, preferably 0 ° C and + 30 ° C, in particular + 20 ° C and + 30 ° C, adjusting to pressure between 10- ^ and 6, preferably 10-2 and 2, especially 10-1 and 1 mbar. At the above-mentioned temperatures or temperature ranges, this is the temperature of the recommendation plate. In this connection, the process is controlled so that the heat supplied over the plate temperature is completely consumed as heat of sublimation and the temperature of the frozen ifosfamide-containing solution still remains below its eutectic temperature. The desired temperature of the recommendation plate each time may be e.g. be programmed using program disks or a computer. The duration of removal of this non-adsorptively bound solvent depends on the size of the individual containers and is e.g. between approx. 4 and 40 hours at a plate temperature of + 25 ° C and a pressure of 0.8 mbar. Reference is made e.g. in this context to the times indicated in the example.

The complete removal of the non-adsorptively bound water is as follows: non-adsorptively bound water is present as ice. the so-called pressure rise measurement determines whether such water is still present in the lyophilisate. To this end, a valve is closed between the drying chamber and the condenser compartment, to which the vacuum pump is also connected. Next, ice present would rapidly sublimate and thus cause a rise in pressure in the drying chamber. When the pressure rises, the pressure in the DK 169308 B1 chamber after 15 minutes must only rise 1 mbar from the initial value, e.g. 0.8 mbar. A larger increase would mean that the main drying was not completed yet.

The remaining, adsorptively bound solvent present is then removed by post-drying. This includes e.g. 3 to 12 hours at a vacuum of 10 "1 to 10-4 mbar, especially 3-4 hours at a vacuum of 10" 3-10 "4 mbar.

The lyophilization process is completed when the residual moisture content (determined by K. Fischer) is below 1%, preferably below 0.5%.

The post-drying to remove adsorptively bound water is carried out especially at temperatures between 0 and 40, preferably 10 and 35, especially 20 and 30 ° C, and a pressure of 15 between 10-4 and 10_1, preferably 10-3 and 10-2, especially 10-3 and 5 x 10-3 mbar, whereby this post-drying e.g. 2 to 36, preferably 6 to 24, especially 3 to 12 hours.

After the freeze drying is completed, the containers are closed. The process of the invention is carried out in all steps under sterile conditions.

The closure of the vials is then performed e.g. after aeration of the freeze-drying chamber to normal pressure by supplying dry, sterile air or nitrogen with special freeze-drying rubber plugs which are siliconized to prevent tearing and to improve sliding performance.

Example 30

The following solution is used for freeze drying:

Ifosfamide 100 mg D-mannitol 70 mg 35 Water for injection in 1 ml DK 169308 B1 11

The bulk density of this solution is 1.0563 g / ml at + 6 ° C and 1.0527 g / ml at + 20 ° C.

The amount of solution to be used each time depends on the filling and freeze-drying capacity.

t

Preparation of the solution:

Approx. 80% of the injection volume of water, and the respective amounts of ifosfamide and mannitol, are dissolved completely successively in water while still stirring. After complete dissolution, make up to the final volume and measure the pH.

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

15 Sartorium SM 11107 or SM 11307, 0.2 μπι pore size, Pali Filter NRP (pore size 0.2 μπι) and stored, avoiding particulate and bacterial contamination until filling. A room temperature storage (20-22 ° C), including the time taken to prepare the 20 solution, should not exceed 3-4 hours. In case of non-obvious subsequent freeze drying, the solution can be stored for another 36 hours at + 4 ° C to + 6 ° C.

In addition, in the case of sterile filtration, a conventional pre-filter (eg Sartorius SM 13400 or 25 Pall LPA) can be used to protect the sterile filter.

Cleaning the vials:

Rinse the vials with demineralized water, hot and cold air. All cleaning media is frozen by filtration for sulfur.

30 In order to avoid re-contamination with particles from the air, the bottles are dried and sterilized by hot air (discontinuously at 180 ° C / 2 hours).

The cleaning of the rubber stoppers with which the injection vials are closed is performed using de-miralized water and e.g. a detergent comprising DK 169308 B1 12 of nonionic surfactants and phosphoric acid esters in aqueous solution.

The cleaned plugs are rinsed free of fibers and lint using demiralized water or filtered, demiralized water. The plugs thus purified are then sterilized by steam.

The thus purified and sterilized vials are then filled aseptically with the ifosfamide solution and provided with rubber stoppers.

10

Amount filled: _Filled volume Usage volumex 15 Ifosfamide 200 mg 2 ml 5 ml 500 mg 5 ml 12.5 ml 1 g 10 ml 25 ml 2 g 20 ml 50 ml _5 g_50 ml_125 ml_ 20 x for the subsequent dilution of the lyophilisate.

The filled volumes must not exceed the following limits:

Filled volume Limit value for the Average individual filled volume value for it - _men_filled volume 30 2 ml 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 ml. 19.4 - 20.6 ml 19.7 - 20.3 ml 50 ml_48.5 - 51.5 ml_49.25 - 50.75 ml DK 169308 B1 13

The filled volumes must be statistically monitored, with the filled volume at each filling point measured at least once every 30 minutes.

The pre-filled vials are frozen as quickly as possible to -40 ° C.

The conditions for freeze-drying are different for the individual sizes of the vials. For example, the following values: 10 Duration of the main drying at a plate temperature of + 25 ° C and at 0.6 mbar: approx. 6-8 hours for containers with 200 mg ifosfamide approx. 10-12 hours for containers with 500 mg ifosfamide approx. 10 - 14 hours for containers with 1000 mg ifosfamide 15 approx. 20 - 28 hours for containers with 2000 mg ifosfamide approx. 34 hours for containers with 5000 mg ifosfamide

The post-drying duration is approx. 3-4 hours under a vacuum of 5 x 10-4 mbar, and at a plate temperature 20 of + 25 ° C.

The residual moisture content (determined by K. Fischer) should be less than 0.5%.

After the freeze drying, the vials are closed.

25 To secure the rubber plugs, cap and roll cap. The completed vials are checked for mechanical defects (cracks, incorrect closure, etc.).

30

Claims (6)

1. Lyophilized preparation, characterized in that it consists of ifosfamide and 0.1 to 17 parts by weight of 5 hexitol on the basis of a part by weight ifosfamide and possibly other pharmaceutical excipients. Lyophilized preparation according to claim 1, characterized in that it contains as mannitol as hexitol. Process for the preparation of an Ifosphamide lyophilizate composition characterized by freezing an aqueous or aqueous-ethanolic solution of ifosfamide containing 1 to 13% by weight ifosfamide and 0.1 to 17 parts by weight of hexitol on the basis of 1 part by weight ifosfamide and optionally 0 to 16.9 parts by weight (based on 1 part by weight ifosfamide) additional pharmaceutical excipients, to between -70 ° C and 0 ° C, and stripping water from the product thus obtained in the frozen state. The process according to claim 3, characterized in that first the non-adsorbably bound water is removed at a temperature between -30 ° C and + 40 ° C and a pressure of between 10 ”3 and 10 mbar. and then the adsorptively bound water at a temperature of between 0 ° C and 40 ° C and a pressure of between 10 ° 4 and 10-1 mbar. Process according to claims 3 and / or 4, characterized in that mannitol is used as hexitol. An ifosfamide lyophilisate composition obtained according to one or more of claims 3-5. 30