Lyophilized preparation of platinum compound

The present invention relates to a lyophilized preparation comprising cis-1,1-cyclobutanedicarboxylate-(2R)-2-methyl-1,4-butanediamine platinum (II), which is useful as an antitumor drug, and dextran. This preparation has a greatly improved resolubility.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a lyophilized preparation comprising 
cis-1,1-cyclobutanedicarboxylate-(2R)-2-methyl-1,4-butanediamine platinum 
(II) (hereinafter referred to as the platinum compound) which is useful as 
an antitumor drug. 
2. Description of the Prior Art 
Generally, preparations for injection are prepared in the form of a 
solution, a lypophilized preparation or a powder preparation. 
The platinum compound is relatively unstable in aqueous solutions so that 
it is highly desirable that the platinum compound be used in the form of a 
lyophilized preparation or a powdery preparation of its bulk drug powder, 
because the preparation is usually stored at room temperature over a long 
period of time. However, a preparation obtained merely by lyophilizing an 
aqueous solution of the platinum compound dissolves in water so slowly 
that it is necessary to conduct heating or stirring over a long period of 
time, when the preparation is to be redissolved. Furthermore the powder 
preparation dissolves more slowly than the lyophilized preparation so that 
redissolution is further difficult. 
SUMMARY OF THE INVENTION 
The inventors made intensive studies to find out that when dextran is added 
to a solution of the platinum compound and the solution is lyophilized, 
the resulting preparation has a greatly improved resolubility. 
The present invention has been accomplished on the basis of the 
above-described finding. Namely, the present invention relates to a 
lyophilized preparation comprising dextran and 
cis-1,1-cyclobutanedicarboxylate-(2R)-2-methyl-1,4-butanediamine platinum 
(II). 
DETAILED DESCRIPTION OF THE INVENTION 
Dextran which can be used in the present invention has a molecular weight 
of, e.g., 40,000 to 150,000, preferably 40,000 to 70,000. 
The amount of dextran to be added is not less than about 0.2 part by 
weight, preferably not less than about 0.5 part by weight per part by 
weight of the platinum compound in order to obtain a sufficient effect in 
the invention. Although the addition of an excess amount of the additive 
does not have any adverse effect, it will cause lowering in the efficiency 
of lyophilization and a container having a large volume must be used for 
preparation. Accordingly, the practical upper limit is about 5 parts by 
weight, preferably about 2 parts by weight per part by weight of the 
platinum compound. 
The preparation of the present invention can be produced in the following 
manner. The platinum compound and dextran are mixed with optionally, 
conventional excipients, extenders, tonicity agents, etc. The mixture is 
dissolved in distilled water for injection at a temperature of 15.degree. 
to 70.degree. C. to obtain the solution containing 0.1-1.4%, preferably 
0.5-1.4% of the platinum compound and the resulting solution is made 
germfree or sterilized. The treated solution is then freezed at a 
temperature not higher than 0.degree. C., preferably from -10.degree. to 
-40.degree. C. and dried in vacuo at a shelf temperature of -40.degree. to 
40.degree. C. by a conventional method. 
Now, the effect of the invention will be illustrated by referring to 
Experimental Example.

EXPERIMENTAL EXAMPLE 
10 ml of distilled water for injection was added to each preparation of 
Examples 1 to 4 and Referential Examples 1 and 2 which will be described 
hereinafter. The mixture was shaken and a time taken until the solid was 
dissolved and disappeared was measured. The results are shown in the 
following Table. 
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Preparation Time taken for dissolution 
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Example 1 10 sec 
Example 2 10 sec 
Example 3 15 sec 
Example 4 15 sec 
Ref. Example 1 5 min 
Ref. Example 2 30 min or longer 
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It is apparent from the Table that all of the solids in the preparations 
(Examples 1 to 4) of the present invention are rapidly dissolved within 15 
sec, while the preparation of Referential Example 1 takes 5 min. to 
dissolve in water and some part of the preparation of Referential Example 
2 is left undissolved even after 30 min. Accordingly, the present 
invention can provide a lyophilized preparation of the platinum compound, 
which has an improved solubility. 
EXAMPLE 1 
10 g of the platinum compound and 10 g of Dextran 40 were dissolved in 
distilled water for injection to a volume of one liter in total. The 
resulting solution was filtered through a membrane filter to remove germs. 
10 ml of the solution was put into each of 20-ml glass vials and 
lyophilized by a conventional method to obtain a preparation. 
EXAMPLE 2 
10 g of the platinum compound and 20 g of Dextran 40 were dissolved in 
distilled water for injection to a volume of one liter in total. The 
resulting solution was filtered through a membrane filter to remove germs. 
10 ml of the solution was put into each of 20-ml glass vials and 
lyophilized by a conventional method to obtain a preparation. 
EXAMPLE 3 
10 g of the platinum compound and 5 g of Dextran 70 were dissolved in 
distilled water for injection to a volume of one liter in total. The 
resulting solution was filtered through a membrane filter to remove germs. 
10 ml of the solution was put into each of 20-ml glass vials and 
lyophilized by a conventional method to obtain a preparation. 
EXAMPLE 4 
10 g of the platinum compound and 20 g of Dextran 70 were dissolved in 
distilled water for injection to a volume of one liter in total. The 
resulting solution was filtered through a membrane filter to remove germs. 
10 ml of the solution was put into each of 20-ml glass vials and 
lyophilized by a conventional method to obtain a preparation. 
REFERENTIAL EXAMPLE 1 
10 g of the platinum compound was dissolved in distilled water for 
injection to a volume of one liter in total. The resulting solution was 
filtered through a membrane filter to remove germs. 10 ml of the solution 
was put into each of 20-ml glass vials and lyophilized by a conventional 
method to obtain a preparation. 
REFERENTIAL EXAMPLE 2 
100 mg of the bulk drug powder of the platinum compound sterilely produced 
was put into each of 20-ml glass vials to obtain a preparation.