Ceftolozane-tazobactam pharmaceutical compositions

Abstract

Pharmaceutical compositions can include ceftolozane lyophilized in the absence of tazobactam.

What is claimed is: 
     
         1 . A unit dosage form of a pharmaceutical composition formulated for parenteral administration for the treatment of a complicated intra-abdominal infection or a complicated urinary tract infection, the pharmaceutical composition comprising ceftolozane 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, at a pH of 6-7 prior to lyophilization 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.   
     
     
         2 . The unit dosage form of  claim 1 , wherein the tazobactam in the second solution is tazobactam acid, and wherein the tazobactam acid in the second solution is lyophilized in the presence of sodium bicarbonate to form the second lyophilized tazobactam solution. 
     
     
         3 . The unit dosage form of  claim 1 , comprising a total of 1,000 mg of ceftolozane active. 
     
     
         4 . The unit dosage form of  claim 3 , comprising a total of 500 mg of tazobactam active. 
     
     
         5 . The unit dosage form of  claim 1 , wherein the unit dosage form is obtained by a process further comprising dissolving the antibacterial composition comprising the ceftolozane and the tazobactam with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition in a formulation for intravenous administration. 
     
     
         6 . The unit dosage form of  claim 5 , wherein the ceftolozane comprises ceftolozane sulfate. 
     
     
         7 . The unit dosage form of  claim 5 , wherein the tazobactam comprises tazobactam sodium. 
     
     
         8 . The unit dosage form of  claim 1 , wherein the unit dosage form is a vial or a bag. 
     
     
         9 . A pharmaceutical product comprising:
 a. tazobactam or salts thereof; and   b. a ceftolozane composition obtained by lyophilizing (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-lmethyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-lmethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid), wherein the ceftolozane composition does not contain tazobactam or salts thereof after lyophilization.   
     
     
         10 . The pharmaceutical product of  claim 9 , wherein the tazobactam or salt thereof is lyophilized in the absence of ceftolozane. 
     
     
         11 . The pharmaceutical product of  claim 9 , wherein the ceftolozane in the ceftolozane composition comprises (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-lmethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid). 
     
     
         12 . The pharmaceutical product of  claim 9 , wherein the ceftolozane in the ceftolozane composition comprises (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. 
     
     
         13 . The pharmaceutical product of  claim 9 , wherein the ceftolozane composition comprises ceftolozane sulfate. 
     
     
         14 . The pharmaceutical product of  claim 9 , wherein the ceftolozane composition is obtained by a process comprising freeze-drying an aqueous solution having a pH of about 5.0 to 7.0 comprising the ceftolozane without tazobactam. 
     
     
         15 . The pharmaceutical product of  claim 9 , having a pH of about 6.0. 
     
     
         16 . The pharmaceutical product of  claim 9 , wherein about 30.4%-37.2% by weight of the pharmaceutical composition is ceftolozane sulfate. 
     
     
         17 . The pharmaceutical product of  claim 16 , wherein about 15.2%-18.6% by weight of the pharmaceutical composition is tazobactam (free acid). 
     
     
         18 . The pharmaceutical product of  claim 9 , comprising ceftolozane active and tazobactam active in a 2:1 weight ratio. 
     
     
         19 . The pharmaceutical product of  claim 9 , comprising ceftolozane active and tazobactam active in a molar ratio of 1:0.9 to 0.9:1.0. 
     
     
         20 . The pharmaceutical product of  claim 9 , comprising a total of 1000 mg ceftolozane active and a total of 500 mg tazobactam active in a unit dosage form. 
     
     
         21 . A pharmaceutical composition comprising tazobactam or a salt thereof, and a lyophilized compound obtained from a solution without tazobactam, the solution comprising the compound of formula (I) prior to lyophilization: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the tazobactam or salt thereof is lyophilized in the absence of ceftolozane. 
     
     
         23 . The pharmaceutical composition of  claim 21 , comprising (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-lmethyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-lmethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid). 
     
     
         24 . The pharmaceutical composition of  claim 21 , 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. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the solution is an aqueous solution having a pH of about 5.0 to 7.0 prior to lyophilization. 
     
     
         26 . The pharmaceutical composition of  claim 21 , having a pH of about 6.0. 
     
     
         27 . The pharmaceutical composition of  claim 21 , wherein about 15.2%-18.6% by weight of the pharmaceutical composition is tazobactam (free acid). 
     
     
         28 . The pharmaceutical composition of  claim 21 , comprising a total of 500 mg tazobactam active in a unit dosage form. 
     
     
         29 . A pharmaceutical composition comprising a ceftolozane compound and a tazobactam compound, wherein the pharmaceutical composition is obtained by a process comprising the steps of:
 a. forming a solution comprising a compound of formula (I) without tazobactam   
       
         
           
           
               
               
           
         
         b. obtaining the ceftolozane compound in a powder ceftolozane composition from the solution of step (a); 
         c. combining the powder ceftolozane composition with the tazobactam comprising tazobactam free acid or a salt thereof to form the pharmaceutical composition. 
       
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the solution is freeze dried to obtain the powder ceftolozane composition. 
     
     
         31 . The pharmaceutical composition of  claim 29 , wherein the solution is adjusted to a pH of about 5-7 prior to freeze drying. 
     
     
         32 . The pharmaceutical composition of  claim 29 , wherein the powder ceftolozane composition comprises (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-lmethyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-lmethylethoxyimino]acetamido]-3-cephem-4-carboxylic acid). 
     
     
         33 . The pharmaceutical composition of  claim 29 , wherein the powder ceftolozane composition comprises (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. 
     
     
         34 . The pharmaceutical composition of  claim 29 , wherein the pharmaceutical composition comprises ceftolozane sulfate. 
     
     
         35 . The pharmaceutical composition of  claim 29 , comprising about 30.4%-37.2% by weight ceftolozane active and about 15.2%-18.6% by weight tazobactam (free acid). 
     
     
         36 . The pharmaceutical composition of  claim 29 , wherein the tazobactam compound is obtained by lyophilizing tazobactam acidin the absence of ceftolozane prior to combination of the tazobactam compound with the powder ceftolozane composition. 
     
     
         37 . The pharmaceutical composition of  claim 29 , comprising ceftolozane active and tazobactam active in a 2:1 weight ratio. 
     
     
         38 . The pharmaceutical composition of  claim 29 , comprising ceftolozane active and tazobactam active in a molar ratio of 1:0.9 to 0.9:1.0. 
     
     
         39 . The pharmaceutical composition of  claim 29 , comprising a total of 1000 mg ceftolozane active and a total of 500 mg tazobactam active in a unit dosage form. 
     
     
         40 . The pharmaceutical composition of  claim 9 , wherein the tazobactam is tazobactam sodium. 
     
     
         41 . The pharmaceutical composition of  claim 21 , wherein the tazobactam is tazobactam sodium. 
     
     
         42 . The pharmaceutical composition of  claim 29 , wherein the tazobactam is tazobactam sodium.