Caspofungin formulations

Abstract

The present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable salt of caspofungin as active ingredient being useful for the prevention and/or treatment of fungal infections. Said compositions additionally comprise specific bulking agents and small amounts or no amounts of an additional pH modifier and may be in a liquid or solid form, e.g. may be lyophilized compositions. Said compositions show good stability and reduced amounts of sub-visible particulate matter formed in solutions which are reconstituted from the lyophilized product.

1 . A pharmaceutical composition comprising:
 a) a pharmaceutically acceptable salt of caspofungin;   b) an additional pH modifier in an amount below 0.3 mole equivalents of said salt of caspofungin; and   c) a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable salt of caspofungin comprises an acid addition salt with an organic acid comprising at least one organic acid selected from the group consisting of acetic, citric, tartaric, propionic, succinic, oxalic, malic, maleic, lactic, glutamic, and pamoic acid. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically acceptable salt of caspofungin is caspofungin diacetate. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of the caspofungin salt to the additional pH modifier is more than 4:1. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the additional pH modifier is acetic acid. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the excipient comprises one or more bulking agents. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the bulking agents comprise mannitol, sucrose or a combination thereof. 
     
     
         8 . The pharmaceutical composition of  claim 1 , comprising a) about 0.1 mg/ml to about 500 mg/ml caspofungin calculated as caspofungin base, b) a pharmaceutically acceptable amount of the pH modifier effective to provide a pH value of about 5 to about 7, and c) about 10 mg/ml to about 200 mg/ml of an excipient, the excipient comprising at least one bulking agent, and water. 
     
     
         9 . The pharmaceutical composition of  claim 1 , comprising a) about 42 mg/ml caspofungin calculated as caspofungin base, corresponding to 46.6 mg caspofungin diacetate, b) a pharmaceutically acceptable amount of the pH modifier effective to provide a pH value of about 6.0, and c) about 50 mg/ml of the excipient comprising a mixture of about 20 mg/ml of mannitol and about 30 mg/ml of sucrose, and water. 
     
     
         10 . (canceled) 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the composition has a pH value of about 5 to about 7. 
     
     
         12 . A lyophilized powder formed from a pharmaceutical composition comprising:
 a) a pharmaceutically acceptable salt of caspofungin;   b) an additional pH modifier in an amount below 0.3 mole equivalents of said salt of caspofungin; and   c) a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake being suitable for reconstitution to form a liquid composition for parenteral administration.   
     
     
         13 . A reconstituted pharmaceutical composition formed from a lyophilized powder reconstituted with an aqueous solution, wherein the lyophilized powder comprises a pharmaceutical composition comprising a pharmaceutically acceptable salt of caspofungin, an additional pH modifier in an amount below 0.3 mole equivalents of said salt of caspofungin, and a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake being suitable for reconstitution to form a liquid composition for parenteral administration. 
     
     
         14 . The reconstituted pharmaceutical composition of  claim 13 , wherein the composition has a pH value of about 5 to about 8. 
     
     
         15 . (canceled) 
     
     
         16 . A reconstituted pharmaceutical composition according to  claim 13  showing a reduced number of sub-visible particles. 
     
     
         17 . The reconstituted pharmaceutical composition of  claim 13 , having less than 500 sub-visible particles per vial, the particles having a size greater than 10 μm. 
     
     
         18 . A method of using a pharmaceutical composition comprising:
 a) a pharmaceutically acceptable salt of caspofungin;   b) an additional pH modifier in an amount below 0.3 mole equivalents of said salt of caspofungin; and   c) a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake for the manufacture of a medicament for the prevention and/or treatment of fungal infections or conditions caused by  Candida  sp. and/or by  Aspergillus  sp. and/or by  Pneumocystis jiroveci  in a mammal; the method comprising forming the medicament from the pharmaceutical composition.   
     
     
         19 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable salt of caspofungin, which process comprises the steps of:
 1) dissolving a bulking agent or a combination of bulking agents in water to form a solution;   2) adding a pharmaceutically acceptable salt of caspofungin to the solution and dissolving the salt of caspofungin in the solution;   3) adding an additional pH modifier to the solution in an amount below 0.3 mole equivalents of said salt of caspofungin to form a pH modified solution;   4) filtering the pH modified solution obtained in step 3) to obtain a filtered solution;   5) freezing the filtered solution obtained in step 4) to form a frozen solution; and   6) freeze drying the frozen solution to form the pharmaceutical composition.   
     
     
         20 . (canceled) 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of the caspofungin salt to the additional pH modifier is more than 10:1. 
     
     
         22 . The pharmaceutical composition of  claim 1 , comprising a) about 20 mg/ml to about 60 mg/ml caspofungin calculated as caspofungin base, b) a pharmaceutically acceptable amount of the pH modifier effective to provide a pH value of about 5.5 to about 6.5, c) about 40 mg/ml to about 60 mg/ml of an excipient, the excipient comprising at least one bulking agent, and water. 
     
     
         23 . A method of treating a patient for a fungal infection comprising:
 reconstituting a pharmaceutical composition by combining a lyophilized powder of the pharmaceutical composition with an aqueous solution to form the reconstituted pharmaceutical composition, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of caspofungin, an additional pH modifier in an amount below 0.3 mole equivalents of said salt of caspofungin, and a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake; and   injecting the reconstituted pharmaceutical composition intravenously into a patient.