Ceftolozane-tazobactam pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-2016193221-A1
Application number	US-201615071530-A
Country	US
Kind code	A1
Filing date	Mar 16, 2016
Priority date	Mar 15, 2013
Publication date	Jul 7, 2016
Grant date	—

Abstract

Pharmaceutical compositions are provided in unit dosage forms comprising ceftolozane and tazobactam in separate unit dosage form containers, ceftolozane prepared in the absence of tazobactam, tazobactam prepared in the absence of ceftolozane, and/or compositions where ceftolozane and tazobactam are first combined within a unit dosage form container.

First claim

1 . A unit dosage form package comprising a unit dosage form container enclosing a ceftolozane composition, the unit dosage form package manufactured by a process comprising the steps of:
a. lyophilizing a solution comprising ceftolozane sulfate and about 125 mg to about 500 mg sodium chloride per 1,000 mg of ceftolozane active in the solution to obtain a lyophilized ceftolozane composition prepared in the absence of tazobactam; b. first contacting the lyophilized ceftolozane composition with a tazobactam composition within a unit dosage form container, where the tazobactam composition comprises tazobactam; and c. enclosing the lyophilized ceftolozane composition and the tazobactam composition together within the unit dosage form container.

2 . The unit dosage form of claim 1 , comprising a single container enclosing a total of 1,000 mg of ceftolozane active present as ceftolozane sulfate.

3 . The unit dosage form of claim 2 , comprising a single container enclosing a total of 500 mg tazobactam active present as tazobactam sodium.

4 . The unit dosage form of claim 1 , further comprising L-arginine.

5 . The unit dosage form of claim 1 , wherein the tazobactam composition is obtained by a process comprising the step of lyophilizing a second solution comprising tazobactam acid and sodium bicarbonate to obtain the tazobactam composition prepared in the absence of ceftolozane.

6 . The unit dosage form of claim 1 , comprising a single container enclosing L-arginine, a total of 1,000 mg of ceftolozane active present as ceftolozane sulfate, and a total of 500 mg tazobactam active present as tazobactam sodium.

7 . The unit dosage form of claim 1 , comprising less than about 0.03% of a compound of formula (III):

8 . A unit dosage form package comprising a unit dosage form container enclosing a ceftolozane composition obtained by a process comprising the steps of
a. forming a solution comprising an amount of ceftolozane sulfate providing 1,000 mg of ceftolozane active, 125-500 mg sodium chloride, about 500 mg tazobactam acid, sodium bicarbonate and L-arginine at a pH of about 5-7 within a unit dosage form container b. lyophilizing the solution within the unit dosage form container to obtain a co-lyophilized composition; and c. enclosing the co-lyophilized composition within the unit dosage form container, wherein the co-lyophilized composition further comprises about 0.03%-1.0% of a compound of formula (III) upon lyophilization:

9 . A unit dosage form container 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, L-arginine and about 125 mg to 500 mg of sodium chloride, and tazobactam sodium in an amount providing about 500 mg tazobactam active per 1,000 mg ceftolozane active wherein pharmaceutical composition is obtained by aseptically first combining the tazobactam and ceftolozane within a unit dosage form container, wherein the pharmaceutical composition is obtained by a process further comprising the steps of
a. lyophilizing a first aqueous solution comprising ceftolozane in the absence of tazobactam, the first aqueous solution comprising ceftolozane sulfate at a pH of 5-7 prior to lyophilization to obtain a lyophilized ceftolozane composition, b. lyophilizing a second aqueous solution comprising tazobactam in the absence of ceftolozane, the second aqueous solution comprising sodium bicarbonate prior to lyophilization to obtain a lyophilized tazobactam composition, c. first combining the lyophilized ceftolozane composition with the tazobactam composition within the unit dosage form container.

10 . The unit dosage form of claim 9 , wherein the pharmaceutical composition in the unit dosage form container has less 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.

11 . The unit dosage form of claim 9 , wherein the unit dosage form container contains a total of 1,000 mg of ceftolozane active and a total of 500 mg of tazobactam sodium.

12 . The unit dosage form of claim 9 , wherein the unit dosage form container contains up to about 7% of a Related Substance having the characteristic retention times for peaks 1-11 in Table 1, as identified by high performance liquid chromatography (HPLC) measurements made 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.

13 . The unit dosage form of claim 9 , wherein the unit dosage form container contains up to about 2% of a Related Substance having the characteristic retention times for peaks 1-11 in Table 1, as identified by high performance liquid chromatography (HPLC) measurements made 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.

14 . A unit dosage form package comprising
a. a first sealed container enclosing a ceftolozane composition obtained by a process comprising the steps of lyophilizing a solution comprising ceftolozane sulfate and about 125 mg to about 500 mg sodium chloride per 1,000 mg of ceftolozane active in an aqueous solution with L-arginine to obtain a lyophilized ceftolozane composition prepared in the absence of tazobactam; b. a second sealed container enclosing a tazobactam composition obtained by a process comprising the steps of lyophilizing a solution comprising tazobactam acid and sodium bicarbonate to obtain a lyophilized tazobactam composition prepared in the absence of ceftolozane; c. instructions to contact combine the ceftolozane composition and the tazobactam composition in a fixed dose ratio to provide an injectable antibiotic formulation for the treatment of an infection selected from the group consisting of:
complicated intra-abdominal infections, complicated urinary tract infections and pneumonia infections.

15 . The unit dosage form package of claim 14 , wherein the first container comprises a total amount of 1,000 mg of ceftolozane active, the second container comprises a total amount of 500 mg of tazobactam active.

16 . The unit dosage form package of claim 14 , wherein the instructions recite a fixed dose combination of the ceftolozane composition and the tazobactam composition in a 2:1 ratio of the ceftolozane active to the tazobactam active and formulate the fixed dose combination for intravenous administration for the treatment of a complicated urinary tract infection.

17 . The unit dosage form package of claim 14 , wherein the instructions recite a fixed dose combination of the ceftolozane composition and the tazobactam composition in a 2:1 ratio of the ceftolozane active to the tazobactam active and formulate the fixed dose combination for intravenous administration for the treatment of a complicated intra-abdominal infection.

Assignees

• Merck Sharp & Dohme

Inventors

• Terracciano Joseph
• Damour Nicole Miller
• Jiang Chun
• Fogliato Giovanni
• Donadelli Giuseppe Alessandro
• Resemini Dario

Classifications

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K47/183

  Amino acids, e.g. glycine, EDTA or aspartame · CPC title

• A61K31/545

  Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-A61K-0953.gif] , e.g. cephalosporins, {cefaclor, or cephalexine} · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title