CEFTOLOZANE-TAZOBACTAM PHARMACEUTICAL COMPOSITIONS
Pharmaceutical compositions can include ceftolozane lyophilized in the absence of tazobactam.
1 . An antibacterial 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 prior to lyophilization to obtain a first lyophilized ceftolozane composition,
b. blending the first lyophilized ceftolozane composition with tazobactam to obtain an antibacterial composition comprising less than 0.13% by HPLC 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.
2 . The antibacterial composition of claim 1 , comprising less than 0.03% of the compound of formula (III) detected by HPLC.
3 . The antibacterial composition of claim 1 , wherein the first aqueous solution further comprises L-arginine in an amount effective to adjust the pH of the first aqueous solution to 6-7 prior to lyophilization to obtain a first lyophilized ceftolozane composition.
4 . The antibacterial composition of claim 1 , wherein the antibacterial pharmaceutical composition is obtained by a process further comprising the steps of
a. lyophilizing a second solution comprising tazobactam in the absence of ceftolozane to form a second lyophilized tazobactam composition; and
b. blending the first lyophilized ceftolozane composition and the second lyophilized tazobactam composition to obtain the antibacterial composition.
5 . The antibacterial composition of claim 4 , 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.
6 . The antibacterial composition of claim 4 , wherein the first aqueous solution comprises L-arginine in an amount effective to provide a pH of about 6-7.
7 . The antibacterial composition of claim 4 , wherein the first aqueous solution comprises 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active.
8 . The antibacterial composition of claim 7 , wherein the first aqueous solution further comprises citric acid.
9 . The antibacterial composition of claim 7 , wherein the first aqueous solution consists of ceftolozane sulfate, citric acid, sodium chloride, L-arginine, and water.
10 . 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, 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active, 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.
11 . The unit dosage form of claim 10 , wherein the first aqueous solution consists of ceftolozane sulfate, citric acid, sodium chloride, L-arginine, and water.
12 . The unit dosage form of claim 10 , 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.
13 . The unit dosage form of claim 10 , wherein the first aqueous solution comprises 125 mg to 500 mg of sodium chloride per 1,000 mg of ceftolozane active.
14 . The unit dosage form of claim 13 , wherein the first aqueous solution further comprises citric acid.
15 . The unit dosage form of claim 14 , wherein the first aqueous solution consists of ceftolozane sulfate, citric acid, sodium chloride, L-arginine, and water.
16 . The unit dosage form of claim 10 , comprising a total of 1,000 mg of ceftolozane active.
17 . The unit dosage form of claim 16 , comprising a total of 500 mg of tazobactam active.
18 . The unit dosage form of claim 17 , comprising a total of not more than 0.03% by HPLC 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.
19 . The unit dosage form of claim 15 , comprising a total of 1,000 mg of ceftolozane active and a total of 500 mg of tazobactam active.
20 . The unit dosage form of claim 19 , comprising a total of not more than 0.03% by HPLC 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.
21 . A composition comprising lyophilized ceftolozane and tazobactam in a ratio of 1,000 mg ceftolozane active per 500 mg of tazobactam active, and less than 0.13% by HPLC 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.
22 . The antibacterial composition of claim 1 , wherein the tazobactam active comprises tazobactam sodium.
23 . The antibacterial composition of claim 1 , wherein the tazobactam active comprises crystalline tazobactam.
24 . The antibacterial composition of claim 1 , wherein the tazobactam active comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof
25 . The antibacterial composition of claim 1 , wherein the ceftolozane active comprises ceftolozane sulfate.
26 . The unit dosage form of claim 10 , 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.
27 . The unit dosage form of claim 26 , wherein the ceftolozane comprises ceftolozane sulfate.
28 . The unit dosage form of claim 26 , wherein the tazobactam comprises tazobactam sodium.
29 . The unit dosage form of claim 10 , wherein the unit dosage form is a vial or a bag.
30 . The composition of claim 21 , wherein the composition comprises an amount of a pharmaceutically acceptable salt of ceftolozane providing a total of 1,000 mg of ceftolozane active.