FI87140B - FOERFARANDE FOER FRAMSTAELLNING AV ETT IFOSFAMIDLYOFILISAT. - 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

1 87140

Process for the preparation of ifosfamide lyophilisate

The chemical name of the active substance ifosfamide is 3- (2-chloroethyl) -2- (chloroethylamino) tetrahydro-2H-5 1,3,2-oxazaphosphorine-2-oxide CH-j-CH-j-C 1 I 2 2

Cl-CH, -CH - NH N-CH, 2 2 \ / / \ ^ 2 10 s 0- CH2

Ifosfamide, such as cyclophosphamide, belongs to the chemical group of oxazaphosphorines and is used therapeutically in the treatment of tumor diseases.

Ifosfamide is a white, crystalline powder with a melting point of 48-51 ° C and a strong hygroscopic appearance. Ifosfamide starts to sinter below its melting point and must therefore be stored at the lowest possible temperature (room temperature and below 20 ° C). Contact with humidity must also be avoided as much as possible.

The solubility of ifosfamide in water is about 10% by weight, but the stability of the aqueous solution is limited (maximum 3-4 hours at 20-22 ° C or 36 hours at 4-25 6 ° C).

Ifosfamide is administered parenterally only. The ampoules contain 200 to 5,000 mg of ifosfamide in the form of a sterile crystalline mass which is dissolved in water for injections before use to a maximum concentration of 4%. This solution can be injected intravenously. When used as a short-term intravenous infusion, the ifosfamide solution is dissolved in 500 ml of Ringer's solution or equivalent infusion solutions. The duration of the infusion is about 30 minutes, possibly 1-2 hours. For a 24-hour infusion, the ifosfamide solution is dissolved, for example, in a total of 3 liters of 5% dextrose-saline solution.

2,87140

There are a number of problems associated with the manufacture and processing of ifosfamide. The production of sterile, crystallized ifosfamide yields a product with varying physical structures. Fluctuations in flow affect the filling accuracy of the ampoules to a particularly large extent.

Hygroscopicity and low melting point are additional disadvantages of ifosfamide processing. During prolonged storage, the sterile crystalline mass sinks and the dissolution rate decreases. As the degree of sintering of ifosfamide increases, the ability of 10 ifosfamide to dissolve in clear and the pH of the solution also decreases, and at the same time the solution turns yellow. This generally makes therapeutic use impossible.

Accordingly, it is an object of the invention to provide ifosfamide in a form which has improved properties, such as improved stability, storability, dosing and solubility, which is easier to use and which is particularly suitable for the preparation of injectable solutions.

It has now surprisingly been found that the disadvantages and difficulties which have hitherto been associated with the handling and storage of ifosfamide can be eliminated by the use of a given ifosfamide lyophilisate. It is particularly surprising that the ifosfamid lyophilisate prepared according to the invention has a better thermal stability than ifosfamide, which has hitherto been dry-packed in ampoules.

25 Ifosfamide, when packaged dry, gradually darkens after only one month of storage at 40 ° C; after two months, the contents of the ampoule have sintered and turned yellow. At a storage temperature of 55 ° C, the dry-filled ifosfamide has already melted after four days and 30 days.

In comparison, the ifosfamide lyophilisate prepared according to the invention did not show any discoloration or change in consistency of ifosfamide under the above-mentioned storage conditions.

Compared to ifosfamide dry-packed in an ampoule, the dissolution rate of ifosfamide lyophilisate has also clearly improved 3,871,140. The lyophilisate dissolves immediately upon addition of the solvent, regardless of the storage time, but ampoules containing dry ifosfamide should be shaken vigorously for 0.5 to 3 minutes after the addition of the solvent. If ifosfamide does not dissolve completely and immediately in this way, which is not the case with syringes stored for a long time, it may even be necessary to allow the solution to stand for a few minutes. This complicates the clinical use of the product.

Compared to its sterile crystal mass, the solubility of ifosfamide lyophilisate is optimal even after many years of storage. In addition, ifosfamide (i.e., pure ifosfamide crystal mass) dry when filled into ampoules is much more sensitive to humidity than lyophilizate. Thus, ifosfamide filled in ampoules dry-15 na is already liquefied at less than 75% relative humidity, while lyophilisate is moist even at 100% relative humidity, but retains its external shape.

When filled with sterile crystal mass, the risk of particulate or microbial contamination is considerably greater than that of lyophilizate.

In the preparation of ifosfamide lyophilisate, the solution is instead sterile-filtered only immediately before addition to the vials. Compared to filling 25 with sterile crystal mass, this is microbiologically safer. Particulate impurities, which are sometimes suspected to be present in dry filling, can also be more reliably avoided by filtering the solution.

Lyophilization of ifosfamide not only results in improvement of the product 30, but is also a less expensive method than filling with sterile crystal mass.

It has been found that only the process of the invention using hexitol, such as mannitol, provides an improved ifosfamide lyophilisate. Lyophilizate-35 is not obtained if it is mixed with saline, as is the case with 4,871,140 when filling ampoules with other dry oxazophosphorines.

The method according to the invention is characterized by what is stated in claim 1. Freeze-dried e.g.

An aqueous solution of ifosfamide containing 1 to 13% by weight of ifosfamide and 0.1 to 17 parts by weight of hexitol per part by weight of phosphamide. This aqueous solution preferably contains 5-12% by weight, in particular 8-10% by weight of ifosfamide.

Instead of the aqueous solution alone, 10 corresponding ethanol-aqueous solutions can also be used (the ethanol solution of such a solution is up to 45% by weight, e.g. 1 to 20% ethanol). In such cases, the ethanol is carefully removed, if possible, first in vacuo before sublimation of the remaining ice. The conditions for the first removal of ethanol-15 are, for example, a pressure of 5 x 10 mbar and a temperature of -25 ° C, which first rises to -5 ° C in 10 hours and then rises to + 22 ° C. More specifically, these conditions depend on the layer height of the product in the injection vials and the conditions must be varied accordingly. The amount of hexitol in this aqueous or aqueous-ethanol solution is generally 1 to 17, preferably 3 to 12 and especially 5 to 9% by weight. The amount of hexitol per part by weight of ifosfamide is 0.1 to 17, preferably 0.1 to 2.5 and in particular 0.6 to 0.8 parts by weight of hexitol per part by weight of ifosfamide.

Suitable hexitols are mannitol, glucitol, sorbitol, eg D-sorbitol, dulsitol, allitol, altritol (eg D- and L-altritol), iditol (eg D- and L-iditol), their optically active forms (D or L form) and the corresponding racemates. In particular, mannitol is used, such as D-mannitol, L-mannitol, DL-mannitol, sorbitol and / or dulsitol, and of these, preferably D-mannitol. Mixtures of said hexitols, e.g. mixtures of mannitol and sorbitol and / or dulsitol, can also be used as hexitol. Since the solubility of dulsitol in water is lower than e.g. mannitol, the concentration of dulsitol in aqueous solution must not be higher than e.g.

t.

5,87140 3% by weight. But mannitol and sorbitol can be mixed in all ratios.

In addition to hexitol, other conventional pharmaceutical excipients such as glycine, lactose, polyvinylpyrrolidone, glucose, fructose, albumin and the like may be added. The total amount of such substances in the solution to be lyophilized is e.g.

0 to 16.9 parts by weight, e.g. 0.1 to 7 parts by weight per part by weight of ifosfamide. In the finished lyophilisate, the total amount of such excipients may be 16.9 parts by weight of precipitate per part by weight of hexitol. More specifically, the amount of such excipients depends on the amount of hexite used, so that the total amount of hexitol and other such excipients in the finished lyophilisate may not exceed 17 parts by weight per part by weight of ifosfamide. If the lyophilisate contains only 0.1 part by weight of hexitol, other excipients may be present up to 16.9 parts by weight; if the amount of hexitol is e.g. 8.5 parts by weight, the amount of other excipients may be e.g. up to 8.5 parts by weight based on one part by weight of ifosfamide.

To prepare the lyophilized solution, about 70-83%, preferably 80% of the required amount of water or ethanol-water is taken and the corresponding amount of ifosfamide and mannitol is dissolved in it successively (i.e. first ifosfamide 25 and then mannitol) with constant stirring or constant shaking. After complete dissolution, make up to volume and measure the pH. After dilution, the pH of this solution must be e.g. 4-7. Preferably a 4% ifosfamide solution is prepared.

The ifosfamide solution thus obtained is then sterilized by filtration through conventional antimicrobial filters, and the solution is then filled into injection preparation containers. The time elapsed before filling into the rye-summer containers, which also includes the time taken to prepare the solution, should not exceed 3-4 hours if the temperature is room temperature (18-22 ° C). If subsequent freeze-drying is not possible immediately, such a solution may be stored, optionally also added to the injection tanks, e.g. for up to 36 hours at low temperature, e.g. -5 to + 10 ° C, preferably 5 + 4 to + 6 ° C, before freeze-drying.

The process according to the invention is carried out by filling the injection preparations containers, e.g. ampoules or other glass containers, with the aqueous ifosfamide solution thus obtained and freeze-drying the solution.

Sterilization uses conventional antimicrobial filters, e.g. conventional bacterial filters with a pore size of about 0.2.

Used glass containers and ampoules are sterilized in the usual way before use.

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

The hexitol used must be as pyrogen-free as possible (pyrogens are fever-producing endotoxins produced by bacteria). This also applies to ifosfamide itself. The pyrogens are removed or destroyed in the usual way (e.g. by treating the active ingredient solution with activated carbon before sterilization filtration). The water used for injection must also be sterile and pyrogen-free and meet the requirements of Deutsches

Arzneibuch, 9th edition 1986. The most commonly used injection vessels are vessels made of tubular or molten glass, hydrolytic class III (e.g. 10 R, 30 R and 50 H) (refer to the relevant literature: Deutsches 30 Arzneibuch, 9th edition 1986, pp. 161 - 164 and DIN standard 58366, parts 1 and 5).

In addition, injection containers and other aids such as rubber stoppers and capsule closures shall meet the requirements of DlN 58366, parts 2 and 3, and 58367, 35 part 1.

7 87140

The amount of lyophilized ifosfamide solutions in each container (ampoule) or other container suitable for injection preparation is e.g. 1 to 500, preferably 1 to 250 and especially 2 to 50 ml. In each case, the containers must be dimensioned so that the lyophilisate they contain can later be dissolved in a larger amount of liquid. Thus, their volume must generally be sufficient to prepare a ready-to-use solution with a volume of n.

2-5, preferably 2 to 4 and especially 2 to 2.5 times 10 times the initial filling volume of the lyophilisate solution.

As already mentioned above, each ampoule or each glass container is preferably filled with a dosage unit of ifosfamide such that the amount of ifosfamide per glass container is e.g. between 100 mg and 10 g, preferably between 200 mg and 5 g. The solution in this glass vessel or ampoule is then lyophilized in the usual manner. It is also possible to freeze-dry larger amounts of ifosfamide, i.e. correspondingly larger volumes of solution of ifosfamide, in a correspondingly larger container and then divide or package the resulting lyophilisate into correspondingly smaller doses.

The actual freeze-drying is carried out by placing the ampoules or glass containers or other containers containing the ifosfamide-hexitol solution immediately in the freeze-drying chamber on a rack or on trays placed on the rack. After closing the chamber, the ampoules or containers are cooled to a temperature of -70 to 0 ° C, preferably -50 to -30 ° C and especially -45 to -35 ° C. When the solutions have cooled completely, a vacuum is gradually drawn into the freeze-drying chamber 30 and drying begins. First, the non-adsorbably bound solvent is removed and this takes place at a temperature of -30 to + 40 ° C, preferably 0 to + 30 ° C and in particular + 20 to + 30 ° C, the pressure of -3 to 2 being adjusted to 10 to 6, preferably 10 - 2 and 35 in particular 10 ^ - 1 mbar. The above temperatures or temperature ranges refer to the temperature of the gratings.

8 87140

The process is adjusted so that the heat above the grate temperature is completely consumed as the heat of sublimation and that the temperature of the cooled ifosfamide-containing solution is constantly below the eutectic temperature of the solution. The desired temperature for the grating can be programmed, for example, with program discs or a computer. The duration of the removal of this non-adsorbably bound solvent depends on the size of the individual container and the length is, for example, about 4-40 hours at a grate temperature of 25 ° C and a pressure of 0.8 mbar. In this connection, reference may be made, for example, to the times mentioned in the example.

Complete removal of non-adsorbably bound water is as follows: Non-adsorbably bound water is in the form of ice. The so-called pressure rise measurement 15 can be used to determine whether such water is still present in the lyophilisate. To perform the measurement, the valve between the drying chamber and the condensing space, which also includes a vacuum pump, is closed. Any ice then sublimes rapidly and causes a pressure rise in the drying chamber.

20 For pressure rise measurement, the chamber pressure may rise after 15 minutes from an initial value of, for example, 0.8 mbar, up to a maximum of 1 mbar. A stronger rise means that the main drying phase has not yet ended.

The remaining amount of adsorbently bound solvent is then removed by post-drying.

-1 -4 This lasts for example 3-12 hours in a vacuum of 10 - 10 -3 -4 mbar, especially 3-4 hours in a vacuum of 10 - 10 mbar.

The freeze-drying step is completed when the residual moisture 30 (Karl Fischer assay) is less than 1%, preferably less than 0.5%.

Post-drying takes place in particular to remove adsorptively bound water at a temperature of 0 to 40, preferably 10 to 35 and in particular 20 to 30 ° C and at a pressure of 35 10 4 to 10, preferably 10 to 10 and especially 9 87140 to -3 mbar, the duration of the post-drying being e.g. 2 to 36, preferably 6 to 24 and especially 3 to 12 hours.

At the end of the freeze-drying, the containers are closed. Each step of the process of the Kek-5 invention is performed under sterile conditions.

Once the pressure in the freeze-drying chamber has been restored to normal by allowing dry, sterile air or nitrogen to flow into the chamber, the injection bottles are closed, e.g., with special freeze-drying rubber stoppers siliconized to reduce friction and improve lubricity.

Example 1

The following solution was lyophilized:

Ifosfamidia 100 mg 15 D-mannitol 70 mg

Water for injections ad 1 ml The density of this solution was 1.0563 g / ml at 6 ° C and 1.0527 at 20 ° C.

The amount of batch of solution depends on the respective filling-20 and freeze-drying capacity.

Preparation of the solution:

Approximately 80% of the volume of water for injection was taken and the corresponding amounts of ifosfamide and mannitol were dissolved successively and with constant stirring. When the substances were completely dissolved, they were made up to the final volume and the pH was measured.

The finished solution was sterilized through a conventional antimicrobial filter (e.g., Sartorius SM 11107 or SM 11307, pore size 0.2 μm, Pall Filter NRP, pore size 0.2 μm) and stored protected from particulate and bacterial contamination prior to filling. The storage time at room temperature (20 - 22 ° C) including the preparation time of the solution should not exceed 3-4 hours. If this solution is not freeze-dried immediately, it can still be stored for about 36 hours at 35-6 ° C. In addition, 10,871 40 conventional pre-filters (eg Sartorius SM 13400 or Pall LPA) can be used for sterile filtration to protect the sterilization filters. Cleaning vials:

The spray bottles are rinsed with warm and cold 5 deposited water and air. All cleaning media are fluidized by filtration.

The flasks, protected from re-contamination by airborne particles, are dried with hot air and sterilized (in batches of 180 ° C / 2 hours).

10 The rubber stoppers used to close the vials are cleaned with deposited water and, for example, with a cleaning agent containing non-ionic surfactants and phosphoric acid esters in aqueous solution.

The cleaned plugs are de-fiberized by rinsing with deionized water or filtered, deposited water. The plugs thus cleaned are then steam-sterilized.

Finally, ifosfamide-20 solution is aseptically added to the vials thus purified and sterilized and fitted with rubber stoppers.

Fill volumes: Fill volume Use ____ volume * 25 Ifosfami- 200 mg 2 ml 5 ml slide 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 30 * Fill volumes for subsequent dilution of lyophilisate n 87140 Fill volumes shall not exceed the following limits: Filling space- Single filling- Filling volume capacity limits- average limits_values_values_ 5 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 to 50.75 ml Filling volumes must be monitored statistically by measuring the filling volume at each filling point at least every 30 minutes.

15 Filled pre-filled vials should be frozen at -40 ° C as soon as possible.

Freeze-drying conditions vary depending on the individual size of the vials. For example, the following values apply: Duration of main drying at a grate temperature of 25 ° C and a pressure of 0.6 mbar for approx. 6 to 8 hours for containers with 200 mg ifosfamide approx. 10 to 12 hours for containers with 500 mg ifosfamide approx. 10 to 14 hours for containers with 1,000 mg ifosfamide approx. 20 - 28 hours for containers with 2,000 mg ifosfamide 25 approx. 34 hours for containers with 5,000 mg ifosfamide.

Duration of post-drying approx. 3-4 hours under vacuum - 4 o 5 x 10 mbar and at a grate temperature of 25 C.

The residual moisture (Karl Fischer determination) must be less than 0,5%.

30 At the end of the freeze-drying, close the vials.

To secure the rubber plugs, capsules are placed on them and pressed. Finished injection bottles are checked for mechanical defects (cracks, improper closure, etc.).

Claims (3)

87140 A process for preparing an ifosfamide lyophilisate, characterized in that an aqueous or aqueous-ethanol solution of ifosfamide containing 1 to 13% by weight of ifosfamid and 0.1 to 17 parts by weight of hexitol per part by weight of ifosfamide and optionally 0 to 16.9 parts by weight (per part by weight of ifosfamide) of other pharmaceutical excipients, cooled to -70 to 0 ° C and dehydrated, thus remaining in the frozen state. Process according to Claim 1, characterized in that the non-adsorptively bound water is first removed at a temperature of -30 to +40 eC and at a pressure of 10 to 3 to 10 mbar and then the adsorptively bound water is removed at a temperature of 0 to 40 eC and at a pressure of 10 4 - 10'1 mbar. Process according to Claim 1 or 2, characterized in that mannitol is used as hexitol.