DE19540132C2 - Ifosfamide lyophilizate - Google Patents

Description

The invention relates to an ifosfamide lyophilisate, an ifosfa mid solution and a method of making an ifosfamide Lyophilisate.

Ifosfamide is the free, international short name for the cytostatic agent, which is sometimes also called isophosphamide, and Im muppressive 3- (2-chloroethyl) -2 - [(2-chloroethyl) amino-2H-1,3,2-oxazaphosphinan-2-oxide (C ₇ H ₁₅ Cl ₂ N ₂ O ₂ P, MG. 261.07) of the formula:

Ifosfamide is a nitrogen mustard derivative and isomer with cyclo phosphamide. It is a white, crystalline powder with one Melting point from 39 to 41 ° C and very hygroscopic companies. Because of this relatively low melting point and The high hygroscopicity must ifosfamide at the lowest possible Temperatures and stored in the absence of humidity become. Ifosfamide undergoes an enol tautomerism and forms a medium strong, weakly dissociated acid in water. A 10% aqueous ifosfamide solution has a pH of 4 to 5. In aqueous solution has a limited shelf life (maximum 3 up to 4 hours at 20 to 22 ° C, or 36 hours at 4 to 6 ° C).

DE-A-37 35 614 describes the difficulties encountered in ver Ifosfamid work. A sterile crystal from Ifosfamide sinters after prolonged storage, which causes the sol speed reduced. With the beginning of sintering of the Ifosfamids also decreases the clear solubility and pH of the  Detachment with simultaneous yellowing; a therapeutic Use is then generally no longer possible. dry Bottles with ifosfamide are already at 40 ° C after a La darkened after one month, after two months the bottle contents are sintered and colored yellow. With a location The dry temperature of 55 ° C is the dry filled ifosfamide already melted within 4 days. To overcome ei less of these disadvantages and handling difficulties and storage of Ifosfamid suggests the aforementioned German Of filed the use of an Ifosfamid-Hexit-Lyophi lisats, especially an ifosfamide-mannitol lyophilisate.

It has been found that an ifosfamide mannitol Lyophilisate poured with the solvent for at least 1 minute must be telt until ifosfamide is completely dissolved. more there was evidence that ifosfamide in a neutral to weak acidic, aqueous ifosfamide-mannitol solution with a pH of 4 to 7 is still subject to a significant reduction (4% Ifosfamide solution, pH 5.5: 0.61% degradation after 4 days, 3.55% degradation after 23 days).

WO 95/07083 discloses lyophilisates of ifosfamide which, with the addition of 20-50% by weight Sodium chloride can be produced as the only scaffolding agent. For improvement The appearance and handling of these lyophilisates can be up to 10% Carrier such. B. contain lactose.

The production of these lyophilisates requires a (time) consuming, especially for solutions freeze-drying process with a high sodium chloride content, known as "thermal Treatment "or" annealing "process is known. In contrast to the Lyophilisates according to the invention cannot be lyophilisates according to WO 95/07083 produce using conventional, less expensive freeze-drying processes.

Further disadvantages of these previously known lyophilisates are their low storage stability and the high sodium chloride content that requires it after the Reconstitution strongly hypertonic solution obtained before intravenous administration to dilute. In WO 95/07083 there is no indication that Storage-stable lyophilisates of ifosfamide using lactose as the sole Have scaffolders preserved.

It is therefore an object of the present invention, an Ifos famid lyophilisate ready with improved solution properties to deliver.

It is another object of the present invention, one provide aqueous ifosfamide solution, wherein ifosfamide a has improved stability.

It is another object of the present invention To provide methods by which an ifosfamide Lyophilisate can be prepared, which after dissolution in What leads to improved stability of the ifosfamide.

The first task is solved by an ifosfamide lyophilisate, which contains lactose as the only scaffolding auxiliary. Surprisingly, it was found that if the ifosfamide-lactose-lyophilisate according to the invention is wetted with water, ifosfamide dissolves completely after 2 to 40 seconds (Table 1 and FIG. 1).

Table 1

Comparison of the dissolution rates of ifosfamide

Fig. 1

Because an ifosfamide solution has a limited shelf life sits and therefore has to be manufactured more often, offers the increased dissolution rate of the Lyophi according to the invention lisats compared to the well-known ifosfamide mannitol Lyophilisate an essential advantage for the concerned Hospital staff.

The framework-forming lactose (lactose monohydrate) is a double sugar (disaccharide from glucose and galactose (C ₁₂ H ₂₂ O ₁₁ .H ₂ O (monohydrate), MW. 360.32 (monohydrate), melting point: 201 to 202 ° C (α-lactose monohydrate)) and crystallizes as a pure white, crystalline or granular powder.

Lactose monohydrate contains approx. 5% water, corresponding to 1 mole of water of crystallization, and is slightly influenced by the relative humidity at room temperature. Drying at 80 ° C removes only the adsorptively bound water (approx. 0.1%) from the monohydrate. At higher relative humidity, especially above 80% relative humidity, the anhydrous lactose forms the monohydrate. In addition, larger amounts of water are bound by adsorption. This means in particular that the ifosfamide lactose lyophilisate becomes moist at over 80% relative humidity, but retains its external shape. It has neither an analytically detectable proportion of residual moisture in the freeze-dried product (determined according to K. Fischer), nor does it lead to a loss of all properties and product qualities comparable to the Ifosfa mid-mannitol lyophilisate. Lactose monohydrate is compatible with the active substance ifosfamide; Lactose-typical incompatibilities, such as the ability to react with primary amino groups (amines, amino acids, peptides, proteins) - with the formation of a Schiff base (brown color) - or between reducing sugars and amino acids with the formation of CO ₂ and complicated brown-colored compounds (Maillard- Reaction) do not exist. In addition to the framework-forming auxiliary agent lactose (lactose monohydrate) used, no other pharmaceutical auxiliary agents (such as glucose, fructose and albumin) are used as framework-forming substances according to the invention.

The lactose forms with the ifosfamide during freeze drying a porous scaffold that is easy to add by adding water can dissolve.

The ifosfamide lyophilisate according to the invention preferably contains 0.1 to 10 parts by weight, most preferably 0.5 to 2 Ge parts by weight, lactose (lactose monohydrate) to 1 part by weight Ifosfamide.

It is preferred that the ifosfamide lyophilisate be a residual moisture te less than 1%, preferably less than 0.75%.

The second object of the present invention is achieved by a Ifosfamid solution solved, which by dissolving the above be written lyophilisate is obtained in water and a pH Value in the range of 7 to 9, preferably in the range of 7.5 to 8.5, most preferably in the range of 7.8 to 8.2.

It has surprisingly been found that ifosfamide in one aqueous solution at the above pH values a higher Sta is more stable than at pH values below pH 7.

The ifosfamide concentration in the solution is preferably in Range from 2 to 6% by weight and is most preferred 4% by weight.

The third object of the present invention is achieved by a Process solved, in which ifosfamide and lactose in water are dissolved, the pH of the solution obtained to 7 to 9 is placed and the solution thus obtained is lyophilized.  

It has surprisingly been found that ifosfamide in one Ifosfamide lactose solution starting from one after which Ifosfamide lyophilisate prepared according to the method is obtained, has a significantly improved stability (4% ifosfamide solution, pH 7.95: 0.125% degradation after 4 days, 3.31% degradation after 23 days).

To produce the solution to be used for freeze drying solution are preferably 80% of the amount of water required submitted and first the appropriate amount of lactose (lactose Monohydrate) and then the corresponding amount of ifosfamide dissolved with stirring. After complete dissolution the volume is topped up and the pH is measured.

The pH of this solution is preferably from 7 to 9 7.5 to 8.5, most preferably set to 7.8 to 8.2.

The pH is preferably set using a Alkali metal hydroxide, most preferably with NaOH.

The ifosfamide lactose solution thus obtained can preferably sterile filtered and then in appropriate containers (Injection bottles or vial bottles), especially re in an amount of 200 mg to 5 g ifosfamide per container, be filled.

The storage of the ifosfamide lactose solution until the beginning of Freeze drying is preferably carried out for 3 to 4 hours at + 18 ° C up to + 22 ° C, preferably at + 4 ° C to + 8 ° C or up to 36 hours at -5 ° C to + 10 ° C, preferably at + 4 ° C to + 6 ° C.

The solution is then frozen in a conventional manner dries until the residual moisture of the lyophilisate, preferably below 1% (determined according to K. Fischer), most preferably below 0.75%.  

The freeze-drying process for the production of the lyophilizate the ifosfamide lactose solution is generally structured in three consecutive steps: freeze, main drying and drying.

The ifosfamide solution very quickly reaches temperatures below frozen their eutectic temperature so that all mov Degrees of freedom of the dissolved components in the ice crystal frozen. At the beginning of the following The first phase of the main drying under vacuum is carried out over the Shelves by an increasing temperature gradient Warming the ice to ice temperatures close below the eu tectic temperature of the frozen solution. In the inside the main drying phase that follows becomes non-adsorptive bound water (ice) by sublimation, driven by the Isothermal heat supply removed via the setting plates the vacuum gas phase completely removed on a cold trap. (Desublimate). In the subsequent post-drying takes place under extreme vacuum the removal of the remaining, adsorptive bound solvent at significantly higher shelf space temperatures than during the main drying.

The present invention is illustrated by the following example he explains.

Fig. 1 shows a diagram illustrating the dissolution properties specified in the Table 1 samples graphically.

example Preparation of the solution approach

To make 400 ml of freeze drying putting sterile ifosfamide lactose solution are 320 ml of water  for injections (WFI), d. H. 80% of the total batch volume mens presented in a 1 liter wide neck Erlenmeyer flask.

36.0 g of lactose is first added to this, with constant stirring (Lactose monohydrate, pyrogen free) until the solution is clear is. The resolution is fully within 30 to 45 minutes constantly.

Then 40.0 g ifosfamide is ge in this lactose solution solves until the solution is clear; the resolution takes place within 45 to 60 minutes completely.

After complete dissolution and leave the acidic ifosfamide lactose solution, the pH is determined. The The pH of the ifosfamide lactose solution is 4.1 to 4.9 and is brought to pH 8.0 with 0.1 normal sodium hydroxide solution (target: pH 8.0 +/- 0.2).

The preliminary batch is then set to the final batch volume of 1 Liters filled with water for injections (WFI).

sterile filtration

The ifosfamide solution thus obtained is then placed in a steam sterile lized receptacle using the usual germ-proof filter with a steam sterilized pressure filtration device trated.

filling

The sterile-filtered batch is then washed into steam-sterilized injection bottles.

Freeze drying the ifosfamide lactose solution

• - Freezing the ifosfamide lactose solution:
  as soon as possible to -40 ° C,
• - Duration of main drying:
  10 ml 48 hours 1000 mg ifosfamide
  20 ml 48 hours 2000 mg ifosfamide
  at a shelf temperature of -10 ° C,
  at a pressure of 0.12 mbar
• - Duration of post-drying:
  12 to 18 hours,
  at a shelf temperature of + 25 ° C,
  at a pressure of 0.0001 mbar.

Comparative example

In accordance with Example 3 of WO 95/07083, a lyophilizate from a solution was included
66.67 mg / ml ifosfamide
40.00 mg / ml NaCl
14.00 mg / ml NaH ₂ PO ₄
6.00 mg / ml mannitol
produced using the freeze-drying process described there.

After storage of the lyophilizate obtained at 25 ° C. for 6 months, it showed the following properties:

• - strong sintering of the lyophilisate cake
• - Degradation rate approx. 4% per year
• - Reconstitution time approx. 1.5 minutes (in individual cases up to 2 minutes).

In contrast, the lyophilizate according to the invention produced according to the above example showed the following properties after storage for 2 years at 25 ° C.

• - no sintering or discoloration of the product
• - Degradation rate below 2% per year
• - Reconstitution time less than 1 minute.

This clarifies the advantages of the lyophilizate according to the invention over those from the WO 95/07083 known.

Claims (8)

1. Ifosfamide lyophilisate, characterized in that it contains lactose as the only scaffolding auxiliary. 2. Ifosfamide lyophilisate according to claim 1, characterized in that it is 0.1 to Contains 10 parts by weight of lactose per 1 part by weight of ifosfamide. 3. Ifosfamide lyophilisate according to any one of claims 1 to 2, characterized characterized that it has a residual moisture below 1%. 4. Ifosfamide solution, characterized in that it by dissolving the Ifosfamid lyophilisate according to one of claims 1 to 3 is obtained in water and has a pH in the range of 7 to 9. 5. ifosfamide solution according to claim 4, characterized in that it 2 to 6 wt .-% Contains ifosfamide.   6. A process for producing an ifosfamide lyophilizate according to one of claims 1 to 3, characterized by the following process steps:

• a) dissolving ifosfamide and lactose in water,
• b) adjusting the pH of the solution obtained to 7 to 9 and
• c) lyophilizing the solution thus obtained.

7. The method according to claim 6, characterized in that the pH with NaOH is set. 8. The method according to any one of claims 6 to 7, characterized in that the Solution is sterile filtered before lyophilization.