Manufacturing beta-lactam combination products

Abstract

This disclosure relates to the manufacture of pharmaceutical compositions comprising an antibiotic compound and a beta-lactamase inhibitor compound when both compounds have a chemical structure that includes a beta-lactam ring, as well as resulting pharmaceutical compositions.

1 . A method of manufacturing an antibacterial pharmaceutical composition comprising ceftolozane and tazbactam in a facility that does not manufacture or house beta-lactam products selected from the group consisting of: penicillins, penems, carbacephems and monobactams, the pharmaceutical composition comprising a therapeutically effective amount of ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active, the method comprising the steps of:
 a. lyophilizing a first aqueous solution comprising ceftolozane sulfate to obtain a lyophilized ceftolozane composition in the absence of tazobactam, penicillins, penems, carbacephems and monobactams;   b. blending the lyophilized ceftolozane composition with a tazobactam composition in the absence of penicillins, penems, carbacephems and monobactams, the tazobactam composition comprising tazobactam prepared and provided in the absence of ceftolozane to obtain the antibacterial pharmaceutical composition.   
     
     
         2 . The method of  claim 1 , further comprising the steps of lyophilizing a second aqueous solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition to obtain the tazobactam composition. 
     
     
         3 . The method of  claim 2 , wherein the second aqueous solution comprises tazobactam acid and sodium bicarbonate. 
     
     
         4 . The method of  claim 3 , wherein the tazobactam composition comprises tazobactam sodium. 
     
     
         5 . The method of  claim 1 , wherein the lyophilized ceftolozane composition is first blended with the tazobactam composition in the absence of contact with a penem, carbacephem, or monobactam. 
     
     
         6 . The method of  claim 1 , wherein the antibacterial pharmaceutical composition comprises less than 1% of a compound of formula (III) detectable at a retention time relative to ceftolozane of 1.22 by high performance liquid chromatography using a Develosil column ODS-UG-5; 5 micrometers; 250×4.6 mm, a mobile phase of sodium perchlorate buffer solution (pH 2.5)/CH 3 CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven temperature of 45° C. 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 6 , further comprising the step of detecting less than about 0.03% of the compound of formula (III) by HPLC in the antibacterial pharmaceutical composition. 
     
     
         8 . The method of  claim 1 , wherein the tazobactam composition is obtained by lyophilizing a second solution in the absence of ceftolozane, the second solution comprising tazobactam to form a second lyophilized tazobactam composition. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutical composition comprises 125-500 mg of sodium chloride per 1000 m of ceftolozane active. 
     
     
         10 . The method of  claim 1 , wherein the first aqueous solution further comprises citric acid. 
     
     
         11 . The method of  claim 1 , wherein
 a. the tazobactam composition is obtained by lyophilizing a second aqueous solution in the absence of ceftolozane, the second aqueous solution comprising tazobactam acid and sodium bicarbonate to form a second lyophilized tazobactam composition;   b. the pharmaceutical composition comprises 125 mg-500 mg of sodium chloride per 1,000 mg of ceftolozane active;   c. the ceftolozane and tazobactam are combined in the absence of any compound belonging to the following classes of beta-lactam containing compounds:   penicillins, penems, carbacephems, and monobactams.   
     
     
         12 . The method of  claim 1 , performed in the absence of any compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams. 
     
     
         13 . The method of  claim 1 , performed in a facility that does not house or manufacture a compound belonging to the following classes of beta-lactam containing compounds: penicillins, penems, carbacephems, and monobactams. 
     
     
         14 . The method of  claim 1 , wherein the first aqueous solution consists essentially of ceftolozane sulfate, water, citric acid, sodium chloride and L-arginine. 
     
     
         15 . The method of  claim 2 , wherein the second aqueous solution consists essentially of tazobactam acid, water, and sodium bicarbonate. 
     
     
         16 . The method of  claim 1 , wherein the antibacterial pharmaceutical composition is a unit dosage form comprising: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                     
                   Nominal Composition 
                 
                     
                     
                   mg per Unit Dosage 
                 
                     
                   Component 
                   form Container 
                 
                     
                     
                 
                     
                 
                 
                 
                 
                 
               
                     
                   Ceftolozane 
                   Ceftolozane 
                   1147 
                 
                     
                   composition 
                   Sulfate 
                 
                     
                     
                   Citric Acid, 
                   21 
                 
                     
                     
                   Anhydrous 
                 
                     
                     
                   Sodium 
                   487 
                 
                     
                     
                   Chloride 
                 
                     
                     
                   L-Arginine 
                   600 
                 
                 
                 
                 
               
                     
                   Tazobactam Sodium 
                   537 
                 
                     
                   Nitrogen 
                   Q.S. 
                 
                     
                     
                 
             
                
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
               
            
             
                
                
                
               
            
           
         
       
     
     
         17 . A facility for manufacturing a pharmaceutical composition formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections, the pharmaceutical composition comprising ceftolozane sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active, the pharmaceutical composition obtained by a process comprising the steps of
 a. lyophilizing a first aqueous solution in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate, 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, to obtain a first lyophilized ceftolozane composition,   b. lyophilizing a second solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition; and   c. blending the first lyophilized ceftolozane composition and the second lyophilized tazobactam composition to obtain the antibacterial composition;   
       wherein the process is performed in the absence of any additional non-cephalosporin beta-lactam compounds. 
     
     
         18 . The method of  claim 17 , wherein the facility is a dedicated facility to the manufacture of pharmaceutical products comprising a fixed dose combination of a cephalosporin and a beta-lactamase inhibitor. 
     
     
         19 . The method of  claim 17 , wherein the facility is a dedicated facility to the manufacture of pharmaceutical products comprising a fixed dose combination of a ceftolozane and a beta-lactamase inhibitor. 
     
     
         20 . The method of  claim 17 , wherein the facility is a dedicated facility to the manufacture of pharmaceutical products comprising a fixed dose combination of a ceftolozane and tazobactam.