Ceftolozane pharmaceutical compositions

Abstract

Pharmaceutical formulations can include ceftolozane and an alkalizing agent such as L-arginine.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising ceftolozane obtained by a process comprising lyophilizing a solution comprising ceftolozane sulfate, about 450 to 500 mg sodium chloride and L-arginine in an amount effective to provide a pH of 5-7 to the solution, and lyophilizing the solution to obtain pharmaceutical composition comprising stabilized ceftolozane. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition retains at least about 93% of an initial amount of ceftolozane upon lyophilization after 3 days at 70 degrees C. post-lyophilization, as measured 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. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the lyophilized ceftolozane pharmaceutical composition contains 1,000 mg of ceftolozane active. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the L-arginine is present in the solution in an amount of about 500-700 mg L-arginine per 1,000 mg of ceftolozane active. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the solution comprises ceftolozane sulfate, about 480 mg-500 mg sodium chloride per 1,000 mg of ceftolozane active, and about 500-700 mg of L-arginine per 1,000 mg of ceftolozane active. 
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein the lyophilized ceftolozane is obtained by a process comprising lyophilizing a composition comprising about 1,000 mg of ceftolozane active per unit dose form in the pharmaceutical composition. 
     
     
         7 . The pharmaceutical composition of  claim 4 , wherein the lyophilized ceftolozane is obtained by a process comprising lyophilizing a solution consisting essentially of L-arginine, ceftolozane sulfate, sodium chloride and citric acid. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the solution consists of water, ceftolozane sulfate, citric acid, sodium chloride and L-arginine. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition comprises ceftolozane sulfate, citric acid, tazobactam sodium, about 500-700 mg L-arginine per 1,000 mg of ceftolozane active, and sodium chloride. 
     
     
         10 . A pharmaceutical composition comprising ceftolozane, about 450-500 mg of sodium chloride per 1,000 mg of ceftolozane active and about 500-700 mg L-arginine per 1,000 mg of ceftolozane active, wherein the pharmaceutical composition retains at least about 93% of an initial amount of ceftolozane after 3 days at 70 degrees C., as measured 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. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition comprises tazobactam, ceftolozane sulfate, about 480-500 mg of sodium chloride per 1,000 mg of ceftolozane active, and about 600 mg L-arginine per 1,000 mg of ceftolozane active. 
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition comprises 1,000 mg of ceftolozane active. 
     
     
         13 . The pharmaceutical composition of  claim 10 , further comprising citric acid. 
     
     
         14 . The pharmaceutical composition of  claim 10 , wherein the lyophilized ceftolozane composition is obtained by a process comprising lyophilizing a solution comprising of water, ceftolozane sulfate, L-arginine, sodium chloride, and citric acid. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein
 a. the ceftolozane is present as ceftolozane sulfate;   b. the L-arginine is present in an amount providing a pH in the solution of 6-7 prior to lyophilization;   c. the lyophilized ceftolozane composition is obtained by a process comprising lyophilizing a solution consisting essentially of water, ceftolozane sulfate, L-arginine, sodium chloride, and citric acid; and   d. the pharmaceutical composition further comprises tazobactam blended with the lyophilized ceftolozane.   
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the lyophilized ceftolozane composition is obtained by a process comprising lyophilizing a solution comprising:
 a. 200-500 mg sodium chloride per 1,000 mg ceftolozane active; and   b. an amount of L-arginine to provide a pH of about 6-7 prior to lyophilization.   
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the pharmaceutical composition comprises tazobactam sodium in an amount providing about 500 mg tazobactam active per 1,000 mg ceftolozane active. 
     
     
         18 . A unit dosage form of a pharmaceutical composition formulated for parenteral administration for the treatment of complicated intra-abdominal infections or complicated urinary tract infections, the pharmaceutical composition comprising 1,000 mg of ceftolozane active, about 600 mg of L-arginine, citric acid and about 450-500 mg of sodium chloride. 
     
     
         19 . The unit dosage form of  claim 18 , further comprising tazobactam sodium in an amount providing about 500 mg tazobactam active per 1,000 mg ceftolozane active. 
     
     
         20 . The unit dosage form of  claim 19 , wherein the pharmaceutical composition is obtained by
 a. lyophilizing a ceftolozane solution comprising: about 487 mg sodium chloride per 1,000 mg ceftolozane active; an amount of L-arginine to provide a pH of about 6-7 in the solution prior to lyophilization; and about 21 mg citric acid per 1,000 mg ceftolozane active, to obtain a lyophilized ceftolozane composition; and   b. blending the lyophilized ceftolozane composition with tazobactam sodium in an amount providing about 500 mg of tazobactam acid equivalent per 1,000 mg ceftolozane active in the unit dosage form.