Lyophilized preparation of stabilized anthracycline compounds

Abstract

The present invention provides a lyophilized preparation of amrubicin, which contains L-cysteine or a salt thereof and has a water content of 0 to about 4% by weight within the preparation, and is stable even in a long-term storage, and further provides a method for production of said preparation. Said preparation is useful as a chemotherapeutic agent for cancers.

1 . A lyophilized preparation comprising amrubicin or a salt thereof, which is a stabilized preparation characterized by the following features:
 (1) containing L-cysteine or a salt thereof; and   (2) having a water content within the preparation in an amount of 0 to 3.5% by weight based on the weight of the lyophilized powder.   
     
     
         2 . The stabilized preparation according to  claim 1 , wherein the water content within the preparation is in the range of 0.5 to 3.5% by weight based on the weight of the lyophilized powder. 
     
     
         3 . The stabilized preparation according to  claim 1 , wherein the water content within the preparation is in the range of 0.5 to 2.0% by weight based on the weight of the lyophilized powder. 
     
     
         4 . The stabilized preparation according to any one of  claims 1  to  3 , wherein the content of L-cysteine or a salt thereof is in the range of 0.5 to 250 mg to 100 mg (potency) of amrubicin or a salt thereof. 
     
     
         5 . The stabilized preparation according to any one of  claims 1  to  3 , wherein the content of L-cysteine or a salt thereof is in the range of 3 to 45 mg to 100 mg (potency) of amrubicin or a salt thereof. 
     
     
         6 . The stabilized preparation according to  claim 1 , wherein the salt of amrubicin is a hydrochloride thereof. 
     
     
         7 . The stabilized preparation according to  claim 1 , wherein the salt of L-cysteine is a hydrochloride thereof. 
     
     
         8 . The stabilized preparation according to  claim 1 , wherein L-cysteine or a salt thereof is (1) L-cysteine in an amount of 5 to 20 mg or (2) a salt of L-cysteine in an amount corresponding thereto, to 100 mg (potency) of amrubicin hydrochloride. 
     
     
         9 . The stabilized preparation according to  claim 1 , which further comprises an excipient. 
     
     
         10 . The stabilized preparation according to  claim 9 , wherein the excipient is lactose. 
     
     
         11 . The stabilized preparation according to  claim 1 , wherein the salt of amrubicin is crystalline amrubicin hydrochloride showing main peaks at the diffraction angles (2θ) of 6.3°±0.3, 10.1°±0.3, 20.3°±0.3, 26.5°±0.3 and 26.9°±0.3 in the powder X-ray diffraction pattern. 
     
     
         12 . A method for producing a stabilized lyophilized preparation comprising (i) amrubicin or a salt thereof and L-cysteine or a salt thereof; and (ii) wherein the water content within the preparation is 0.5 to 3.5% by weight based on the weight of the lyophilized powder, which comprises the following Steps (1) to (4):
 (1) preparing an aqueous solution of (a) amrubicin or a salt thereof, and (b) L-cysteine or a salt thereof by dissolving them in water;   (2) adjusting the pH value of the aqueous solution of the above (1) to pH 2 to pH 5;   (3) sterilizing the aqueous solution of the above (2) by aseptic filtration; and   (4) lyophilizing the aqueous solution obtained in the above (3) under conditions for controlling the water content within the preparation so that the water content is in the range of 0.5 to 3.5% by weight based on the weight of the lyophilized powder.   
     
     
         13 . The method according to  claim 12 , wherein the salt of amrubicin is a hydrochloride thereof. 
     
     
         14 . The method according to  claim 12 , wherein the salt of L-cysteine is a hydrochloride thereof. 
     
     
         15 . The method according to  claim 12 , wherein the pH value is adjusted into the range of pH 2.0 to pH 3.5 in Step (2). 
     
     
         16 . The method according to  claim 12 , wherein Steps (1) to (3) are conducted at a temperature of about 15° C. or below. 
     
     
         17 . The method according to  claim 12 , wherein Steps (1) to (3) are conducted at a temperature of about 10° C. or below. 
     
     
         18 . The method according to  claim 12 , wherein the salt of amrubicin is crystalline amrubicin hydrochloride showing main peaks at the diffraction angles (2θ) of 6.3°±0.3, 10.1°±0.3, 20.3°±0.3, 26.5°±0.3 and 26.9°±0.3 in the powder X-ray diffraction pattern. 
     
     
         19 . A method for producing a stabilized lyophilized preparation of amrubicin having suppressed generation of desaccharified compound during storage thereof, which comprises the following Steps (1) to (4):
 (1) preparing an aqueous solution containing amrubicin hydrochloride, L-cysteine in an amount of 5 to 20 mg (or a corresponding amount of a salt of L-cysteine) to 100 mg potency of amrubicin hydrochloride, and an excipient;   (2) adjusting the pH value of the aqueous solution of the above (1) into the range of pH 2.0 to pH 3.5;   (3) sterilizing the aqueous solution of the above (2) by aseptic filtration;   (4) lyophilizing the aqueous solution obtained in the above (3) under conditions for controlling the water content within the preparation so that the water content of the preparation is in the range of 0.5 to 3.5% by weight based on the weight of the lyophilized powder.   
     
     
         20 . A method for suppressing the generation of desaccharified compound in a lyophilized preparation of amrubicin during the storage thereof, which comprises the following steps:
 (1) preparing an aqueous solution containing amrubicin hydrochloride and L-cysteine in an amount of 5 to 250 mg or a corresponding amount of a salt of L-cysteine per 100 mg of amrubicin hydrochloride;   (2) sterilizing the above aqueous solution by aseptic filtration; and   (3) lyophilizing the aqueous solution obtained above under conditions so that the water content within the preparation is controlled so as to be in the range of 0.5 to 3.5% by weight based on the weight of the lyophilized powder.