JPH06100452A - Pharmaceutical container for iphosphamide - Google Patents

Abstract

PURPOSE: To obtain a pharmaceutical vessel for ifosfamide attaining remarkably rapid and perfect dissolution of ifosfamide. CONSTITUTION: The volume of this pharmaceutical vessel is 2-40 ml in case of 100 mg ifosfamide and 1-20 ml soln. is produced from 100 mg ifosfamide.

Description

Detailed Description of the Invention

[0001]

The present invention relates to ifosfamide (Ifosfamide).
pharmaceutical container for amid).

[0002]

An important application form for the cytostatic agent ifosfamide is injection. In this case, the corresponding injection solutions are in solid form (eg as powder or lyophilisate).
It is prepared just before use from the cytostatic agent of interest present. In this case, the solution is prepared by adding water to a suitable unit dose of the cytostatic agent present in the injection vial and shaking. Corresponding dissolution should take place as quickly and completely as possible. However, in this case, ifosfamide, which is a cytostatic agent, has drawbacks due to its poor solubility in water and its low dissolution rate. Especially this is 500m
This is true for high doses of g and 1 g.

[0003]

The object of the present invention was to eliminate the abovementioned drawbacks.

[0004]

Surprisingly by the way, surprisingly, by filling the unit dose of these cytostatic agents in a larger container than has heretofore been common, and by providing a large volume for making a solution. It was found that a remarkably quick and complete dissolution was achieved.

The present invention provides a pharmaceutical container for ifosfamide according to claim 1.

According to the invention, at least 20 ml of free shaking space per 100 ml of solution, preferably 50-160.
Dissolution of the cytostatic agent ifosfamide is carried out in a container with ml, in particular 70-130 ml. Corresponding containers are made of plastic (eg polypropylene or polyvinyl chloride)
Alternatively, it may be made of glass (tubular glass, blow-molded glass).

In the case of a plastic container, the wall thickness of the container is about 0.5 mm. In the case of tubular glass containers, the wall thickness is 1 to 1.2 mm, in the case of blow-molded glass containers it is 0.7 to 1.0 mm. In particular, a vial for injection corresponds to a container for dissolution. Containers, for example injection vials, are filled with the cytostatic agent in solid form, optionally mixed with further auxiliaries and then sealed, for example with rubber stoppers, for example injection stoppers. The rubber stopper is then punctured (eg, by injection cannula) immediately before use to make the solution, an appropriate amount of solvent is added and the solution is made by shaking. The rubber stopper is resealed after removing the cannula. The solution thus prepared is then suitable for direct injection. Of course, the rubber stopper can also be removed to make the solution and reattached for the shaking process.

Shaking can be performed by shaking by hand (vigorous shaking), but mechanical shaking is also possible (right-angle movement or linear reciprocating movement). For example, a sufficient degree (for example, 5 cm) and a sufficient frequency (for example, 10 to 25).
A shaking machine that carries out (0 times / minute) longitudinal movements is also suitable.

When shaking by hand, for example, 1 per second
~ 5 reciprocating movements, preferably 2 reciprocating movements.

The volume or size of the container also depends on the respective unit dose of cytostatic agent and the volume of solution to be produced therefrom.

For 100 mg of ifosfamide, for example, the volume of the solution to be made is 1.0 to 20 ml, preferably 1.3 to 10 ml, in particular 2.0 to 3.3 ml. For larger amounts of ifosfamide the volume is correspondingly larger, for smaller amounts it is correspondingly smaller. For a quantity of 100 mg of ifosfamide and the corresponding container size for a solution made from it is 2 ~ 40 ml, preferably 3-20 ml, especially 4-6 ml.

For an amount of ifosfamide of 500 mg and the solution produced therefrom, for example 5.0 to 1000
ml, preferably 6.5 to 50 ml, especially 10 to 16.5
A volume of ml is required, the container for the dissolution required for this being, for example, 10-200 ml, preferably 1
Volumes of 3 to 100 ml, especially 20 to 33 ml are required. For a dose of 1000 mg ifosfamide, the volume of the solution to be made and the corresponding volume of the container are, for example, 10 times the range given for the 100 mg dose each time.

The container according to the invention is suitable for large unit doses of ifosfamide, for example 500 mg or more (500 mg, 1 g, 2 g, 3 g). For an ifosfamide amount of 500 mg, it is advantageous to use vials (containers) of 50 ml or more.

The container according to the present invention is, for example, 1: 1 to 1:
3.5, preferably 1: 1.5 to 1: 3, especially 1:20 to
It has a diameter to height ratio in the range of 1: 2.5.

In the case of a glass vial made of tubular glass, it may have a height of 75 mm or less and a diameter of 30 mm or less. In the case of glass vials consisting of blown glass, larger vials can be used.

Such a large glass vial has, for example, the following dimensions: height (mm) diameter (mm) 62.8 ± 0.7 36 ± 0.5 73 ± 0.8 42.5 ± 0.2. 8 99 ± 1 42.5 ± 0.8 94.5 ± 0.9 51.6 ± 0.8 In the case of ifosfamide, the working concentration is, for example, 4%.

Water is used in particular as the solvent. Optionally, small amounts of physiologically tolerated alcohols such as ethanol, propylene glycol, polyglycols, 1,3-butylene glycol can be added to improve dissolution. When such alcohols are added, their amount is 20%, especially 10% or less.

The cytostatic agent used, ifosfamide, can be present in pure form, but it is also possible to use the customary auxiliaries, for example salt, dextrose, mannitol, sorbit,
It can contain sodium lactate, potassium chloride or other electrolytes, or non-electrolytes with which an isotonic pressure can be constituted. Such auxiliaries can be used anhydrous and in the following amounts relative to parts by weight of ifosfamide: dextrose 2.5 parts by weight, mannitol 2.5 parts by weight, sorbit 2.5 parts by weight, sodium lactate. 1.7
5 parts by weight, potassium chloride 0.53 parts by weight.

In particular, such auxiliaries should be used in such an amount that they remain in the isotonic range after being dissolved in water.

Reference Example 534 mg of cyclophosphamide monohydrate having a particle size of 50 to 200 μm (500 mg of anhydrous cyclophosphamide)
Is homogeneously mixed with 225 g of salt (particle size <100 μm) previously crushed twice in a pin mill at 15 to 25 ° C., and the mixture is crushed again in the pin mill (particle size after crushing: NaCl <100 μm , Cyclophosphamide monohydrate (50-200 μm) and the resulting powder are fed by a screw type metering device (for example, a conventional filling machine Typ DOS Mikr).
size 50H (diameter 42.5mm, height 7)
3 mm, volume 60 ml) were filled into round glass vials made of blown glass and sealed with rubber stoppers (for injection).

To make the aqueous solution, insert a needle into the rubber stopper of the vial. After adding 25 ml of water (free shaking volume 35 ml) and shaking by hand for a maximum of 2 minutes, a complete solution of the solid contents of the vial is obtained.

On the other hand, the mixture is, for example, 25
Filling into small vials (30 mm diameter, 65 mm height) as is common for making ml solutions only dissolves after 4 minutes under the same shaking conditions.

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[Procedure amendment]

[Submission date] July 27, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0020

[Correction method] Change

[Correction content]

[0020]

Example 1 Asphosphamide sterile crystals (particle size 90% 425 μm) 50
Screw type metering device (for example, Dos Mikro type ordinary filling machine) for 0 mg at 15 to maximum 25 ° C.
With the size DIN ISO 8362 (Part 4) 1
5H = 26.5 mm diameter, 38.8 mm height, 15 ml nominal fill volume, 17 ml filled volume Round glass vials are filled under aseptic conditions and sealed with a sterile rubber stopper (injection stopper).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0021

[Correction method] Change

[Correction content]

To make an aqueous solution, a rubber stopper of a vial is pierced with an injection needle, 12.5 ml of water for injection is added (free shaking volume of 4.5 ml) and shaken vigorously by hand. After an average of 20 seconds, complete dissolution of the solid vial contents takes place.

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0022

[Correction method] Change

[Correction content]

In contrast, ifosfamide was added to a smaller vial (eg 10H = diameter 25.4 mm, height 5).
3.5 mm, nominal filling volume 10 ml, full volume 15 m
When 1) is filled and 12.5 ml of water for injection is likewise added, complete dissolution is only carried out after an average of 44 seconds under the same shaking conditions.

Claims (4)

[Claims] 1. A sealable pharmaceutical container for ifosfamide having a volume of 100 m ifosfamide.
Pharmaceutical container for ifosfamide, characterized in that it is from 2 to 40 ml / g, in which case 1 to 20 ml of solution is prepared from 100 mg of ifosfamide. 2. When producing a solution of ifosfamide,
The remaining shaking space is at least 20 ml per 100 ml of solution
The pharmaceutical container according to claim 1, wherein 3. The pharmaceutical container according to claim 1 or 2, wherein the container is made of glass or plastic. 4. Any of claims 1 to 3 wherein the container is a vial for injection, wherein the ratio of direct line to height is in the range of 1: 1 to 1: 3.5. The pharmaceutical container according to 1 above.