Tazobactam and ceftolozane antibiotic compositions

Abstract

This disclosure provides pharmaceutical compositions comprising ceftolozane, pharmaceutical compositions comprising ceftolozane and tazobactam, methods of making those compositions, and related methods and uses of these compositions.

1 . A composition comprising tazobactam combined with ceftolozane that is lyophilized in the absence of tazobactam. 
     
     
         2 . The composition of  claim 1 , wherein the lyophilized ceftolozane is ceftolozane sulfate. 
     
     
         3 . The composition of  claim 1 , wherein the lyophilized ceftolozane is a ceftolozane compound of formula (I) prior to lyophilization: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The composition of  claim 3 , wherein the lyophilized ceftolozane is obtained by a process comprising:
 a. forming a solution comprising the compound of formula (I) without tazobactam;   b. adjusting the pH of the solution to a pH of about 6.0; and   c. lyophilizing the solution to obtain the lyophilized ceftolozane.   
     
     
         5 . The composition of  claim 1 , wherein the composition has a pH of 6.0 upon reconstitution with saline. 
     
     
         6 . The composition of  claim 1 , comprising about 30.4%-37.2% by weight ceftolozane active. 
     
     
         7 . The composition of  claim 1 , comprising about 15.2%-18.6% by weight tazobactam active. 
     
     
         8 . The composition of  claim 1 , comprising ceftolozane and tazobactam (as free acid) in a 2:1 weight ratio. 
     
     
         9 . The composition of  claim 1 , comprising (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid) and tazobactam (as free acid) in a about a 2:1 weight ratio. 
     
     
         10 . The composition of  claim 1 , comprising (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate and tazobactam (as free acid) in a about a 2:1 weight ratio. 
     
     
         11 . A ceftolozane/tazobactam composition comprising ceftolozane combined with tazobactam, wherein the ceftolozane and the tazobactam are individually freeze-dried prior to combination. 
     
     
         12 . The ceftolozane/tazobactam composition of  claim 11 , wherein the ceftolozane and the tazobactam are blended to form a ceftolozane/tazobactam composition comprising about 30.4%-37.2% by weight ceftolozane active and about 15.2%-18.6% by weight tazobactam (as free acid). 
     
     
         13 . The ceftolozane/tazobactam composition of  claim 11 , wherein the ceftolozane is ceftolozane sulfate. 
     
     
         14 . The ceftolozane/tazobactam composition of  claim 11 , wherein the ceftolozane is obtained by a process comprising freeze-drying an aqueous solution comprising the ceftolozane in the absence of tazobactam at a pH of 6.0-7.0. 
     
     
         15 . The ceftolozane/tazobactam composition of  claim 11 , wherein the composition has a pH of about 6.0 upon reconstitution in saline. 
     
     
         16 . The ceftolozane/tazobactam composition of  claim 11  in a unit dosage form comprising a total of 1000 mg ceftolozane and a total of 500 mg tazobactam (as free acid) in a unit dosage form. 
     
     
         17 . The ceftolozane/tazobactam composition of  claim 11 , wherein the lyophilized ceftolozane is a ceftolozane compound of formula (I) prior to lyophilization: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A ceftolozane/tazobactam composition comprising ceftolozane combined with tazobactam in a 2:1 weight ratio between the ceftolozane active and the tazobactam active, wherein the ceftolozane is obtained from a solution comprising ceftolozane in the absence of tazobactam. 
     
     
         19 . The ceftolozane/tazobactam composition of  claim 18 , wherein the ceftolozane in the solution is a ceftolozane compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
         20 . The ceftolozane/tazobactam composition of  claim 18 , wherein the ceftolozane is obtained by lyophilizing the solution in the absence of tazobactam. 
     
     
         21 . The ceftolozane/tazobactam composition of  claim 20 , wherein the pH of the solution is adjusted to about 6.0 prior to lyophilization. 
     
     
         22 . The ceftolozane/tazobactam composition of  claim 18 , obtained by a process comprising the steps of:
 a. lyophilizing the solution comprising ceftolozane in the absence of tazobactam to obtain a lyophilized ceftolozane composition; and   b. combining the lyophilized ceftolozane composition and with tazobactam to form the pharmaceutical composition.   
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the ceftolozane is ceftolozane sulfate. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the tazobactam is tazobactam sodium. 
     
     
         25 . The pharmaceutical composition of  claim 22 , comprising lyophilizing the ceftolozane at a pH of about 6.0. 
     
     
         26 . The composition of  claim 25 , comprising forming the solution with a ceftolozane compound of formula (I): 
       
         
           
           
               
               
           
         
         and adjusting the pH of the ceftolozane solution to about 6.0 prior to lyophilization. 
       
     
     
         27 . A pharmaceutical composition obtained by:
 a. adjusting the pH of a solution comprising a compound of formula (I) to a pH of about 5.0-7.0 in the absence of tazobactam;   
       
         
           
           
               
               
           
         
         b. freeze-drying the solution to obtain a ceftolozane composition; and 
         c. combining the ceftolozane composition and with tazobactam to form the pharmaceutical composition. 
       
     
     
         28 . (canceled) 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the ceftolozane composition is ceftoloazne sulfate. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the lyophilized tazobactam is tazobactam sodium. 
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition comprises ceftolozane active and tazobactam active in a 2:1 weight ratio.