CEFTOLOZANE ANTIBIOTIC COMPOSITIONS
This disclosure provides pharmaceutical compositions comprising ceftolozane, pharmaceutical compositions comprising ceftolozane and tazobactam, methods of preparing those compositions, and related methods and uses of these compositions.
1 - 26 . (canceled)
27 . An antibiotic pharmaceutical product comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof, stabilized to reduce the rate of formation of a degradation product from the compound of formula (I), the degradation product selected from the group consisting of compounds of formulae (IV), (V), (VI) and (VII)
the compound of formula (I) being stabilized by obtaining the compound of formula (I) by a process comprising the steps of:
a. lyophilizing an aqueous solution comprising a compound of formula (I) at a pH of about 5-7 in the presence of a means for stabilizing the compound of formula (I) and in the absence of a compound of formula (II)
or a pharmaceutically acceptable salt thereof, to obtain a lyophilized stabilized composition; and
b. combining the lyophilized stabilized composition of step (a) with a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, to obtain the antibiotic pharmaceutical product comprising the compound of formula (I) (or a pharmaceutically acceptable salt thereof) in the same or a separate container from the compound of formula (II) (or a pharmaceutically acceptable salt thereof),
where the lyophilized stabilized composition of step (a) maintains at least about 90% of the compound of formula (I) in the lyophilized stabilized composition from step (a) after 3 days at 70 degrees C. in a sealed container, where the amount of ceftolozane in the lyophilized stabilized composition is determined by HPLC 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.
28 . The antibiotic pharmaceutical product of claim 27 , where the antibiotic pharmaceutical product comprises the compound of formula (II) or a pharmaceutically acceptable salt thereof and the lyophilized stabilized composition in a combination providing a 2:1 weight ratio of the compound of formula (I) to the compound of formula (II) in the antibiotic pharmaceutical product, and wherein the antibiotic pharmaceutical product comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the compound of formula (II), or the pharmaceutically acceptable salt thereof, in the same or separate containers.
29 . The antibiotic pharmaceutical product of claim 27 , wherein a sodium salt of the compound of formula (II) is combined with the lyophilized stabilized compound of formula (I).
30 . The antibiotic pharmaceutical product of claim 27 , comprising less than 0.15% by HPLC of a compound of formula (III)
detectable in the lyophilized stabilized composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.
31 . The antibiotic pharmaceutical product of claim 27 , wherein the lyophilized stabilized composition further comprises one or more compounds selected from the group consisting of a compound of formula (IV), a compound of formula (V), a compound of formula (VI) and a compound of formula (VII).
32 . The antibiotic pharmaceutical product of claim 27 , further characterized by one or more aspects selected from the group consisting of:
a. the compound of formula (II) is a sodium salt;
b. the lyophilized stabilized composition comprises less than 0.15% by HPLC of a compound of formula (III)
detectable in the pharmaceutical composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.; and
c. the lyophilized stabilized composition comprises a total of less than about 1.50% of a compound of formula (IV) as determined by HPLC 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.
33 . An antibiotic pharmaceutical product comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof, stabilized to reduce the rate of formation of a degradation product from the compound of formula (I), the degradation product selected from the group consisting of compounds of formulae (IV), (V), (VI) and (VII)
the compound of formula (I) being stabilized by obtaining the compound of formula (I) by a process comprising the steps of:
a. lyophilizing an aqueous solution comprising a compound of formula (I) at a pH of about 5-7 in the presence of a means for stabilizing the compound of formula (I), to obtain a lyophilized stabilized composition; and
b. combining the lyophilized stabilized composition of step (a) with a composition comprising a compound of formula (II)
or a pharmaceutically acceptable salt thereof, to obtain the antibiotic pharmaceutical product comprising the compound of formula (I) (or a pharmaceutically acceptable salt thereof) in the same or a separate container from the compound of formula (II) (or a pharmaceutically acceptable salt thereof),
where the lyophilized stabilized composition of step (a) maintains at least about 90% of the compound of formula (I) in the lyophilized stabilized composition from step (a) after 3 days at 70 degrees C. in a sealed container, where the amount of ceftolozane in the lyophilized stabilized composition is determined by HPLC 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.
34 . The antibiotic pharmaceutical product of claim 33 , where the antibiotic pharmaceutical product comprises the compound of formula (II) or a pharmaceutically acceptable salt thereof and the lyophilized stabilized composition in a combination providing a 2:1 weight ratio of the compound of formula (I) to the compound of formula (II) in the antibiotic pharmaceutical product, and wherein the antibiotic pharmaceutical product comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the compound of formula (II), or the pharmaceutically acceptable salt thereof, in the same or separate containers.
35 . The antibiotic pharmaceutical product of claim 33 , wherein a sodium salt of the compound of formula (II) is combined with the lyophilized stabilized compound of formula (I).
36 . The antibiotic pharmaceutical product of claim 33 , comprising less than 0.15% by HPLC of a compound of formula (III)
detectable in the lyophilized stabilized composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.
37 . The antibiotic pharmaceutical product of claim 33 , wherein the lyophilized stabilized composition further comprises one or more compounds selected from the group consisting of a compound of formula (IV), a compound of formula (V), a compound of formula (VI) and a compound of formula (VII).
38 . The antibiotic pharmaceutical product of claim 33 , further characterized by one or more aspects selected from the group consisting of:
a. the compound of formula (II) is a sodium salt;
b. the lyophilized stabilized composition comprises less than 0.15% by HPLC of a compound of formula (III)
detectable in the pharmaceutical composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.; and
c. the lyophilized stabilized composition comprises a total of less than about 1.50% of a compound of formula (IV) as determined by HPLC 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.
39 . An antibiotic pharmaceutical product comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof, stabilized to reduce the rate of formation of a degradation product from the compound of formula (I), the degradation product selected from the group consisting of compounds of formulae (IV), (V), (VI) and (VII)
the compound of formula (I) being stabilized by obtaining the compound of formula (I) by a process comprising the steps of:
a. lyophilizing an aqueous solution comprising a compound of formula (I) in the presence of a means for stabilizing the compound of formula (I) and in the absence of a compound of formula (II)
or a pharmaceutically acceptable salt thereof, to obtain a lyophilized stabilized composition; and
b. combining the lyophilized stabilized composition of step (a) with a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, to obtain the antibiotic pharmaceutical product comprising the compound of formula (I) (or a pharmaceutically acceptable salt thereof) in the same or a separate container from the compound of formula (II) (or a pharmaceutically acceptable salt thereof),
where the lyophilized stabilized composition of step (a) maintains at least about 90% of the compound of formula (I) in the lyophilized stabilized composition from step (a) after 3 days at 70 degrees C. in a sealed container, where the amount of ceftolozane in the lyophilized stabilized composition is determined by HPLC 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.
40 . The antibiotic pharmaceutical product of claim 39 , where the antibiotic pharmaceutical product comprises the compound of formula (II) or a pharmaceutically acceptable salt thereof and the lyophilized stabilized composition in a combination providing a 2:1 weight ratio of the compound of formula (I) to the compound of formula (II) in the antibiotic pharmaceutical product, and wherein the antibiotic pharmaceutical product comprises the compound of formula (I) or the pharmaceutically acceptable salt thereof and the compound of formula (II), or the pharmaceutically acceptable salt thereof, in the same or separate containers.
41 . The antibiotic pharmaceutical product of claim 39 , wherein a sodium salt of the compound of formula (II) is combined with the lyophilized stabilized compound of formula (I).
42 . The antibiotic pharmaceutical product of claim 39 , comprising less than 0.15% by HPLC of a compound of formula (III)
detectable in the lyophilized stabilized composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.
43 . The antibiotic pharmaceutical product of claim 39 , wherein the lyophilized stabilized composition further comprises one or more compounds selected from the group consisting of a compound of formula (IV), a compound of formula (V), a compound of formula (VI) and a compound of formula (VII).
44 . The antibiotic pharmaceutical product of claim 39 , further characterized by one or more aspects selected from the group consisting of:
a. the compound of formula (II) is a sodium salt;
b. the lyophilized stabilized composition comprises less than 0.15% by HPLC of a compound of formula (III)
detectable in the pharmaceutical composition at a retention time relative to the compound of formula (I) of 1.22 by HPLC 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.; and
c. the lyophilized stabilized composition comprises a total of less than about 1.50% of a compound of formula (IV) as determined by HPLC 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.
45 . An antibiotic pharmaceutical product comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof, stabilized to reduce the rate of formation of a degradation product from the compound of formula (I), the degradation product selected from the group consisting of Peak 1, Peak 5, Peak 7 and Peak 9 compounds identified by a high performance liquid chromatography (HPLC) by retention times relative to the compound of formula (I) of about 0.14 (Peak 1), 0.9 (Peak 5), 1.3 (Peak 7) and 1.7 (Peak 9), determined by HPLC 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.;
the compound of formula (I) being stabilized by obtaining the compound of formula (I) by a process comprising the steps of:
a. lyophilizing an aqueous solution comprising a compound of formula (I) at a pH of about 5-7 in the presence of a means for stabilizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, to obtain a lyophilized stabilized composition; and
b. combining the lyophilized stabilized composition of step (a) with a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, to obtain the antibiotic pharmaceutical product comprising the compound of formula (I) (or a pharmaceutically acceptable salt thereof) in the same or a separate container from the compound of formula (II) (or a pharmaceutically acceptable salt thereof),
where the lyophilized stabilized composition of step (a) maintains at least about 90% of the compound of formula (I) in the lyophilized stabilized composition from step (a) after 3 days at 70 degrees C. in a sealed container, where the amount of ceftolozane in the lyophilized stabilized composition is determined by HPLC 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.
46 . The antibiotic pharmaceutical product of claim 45 , wherein the aqueous solution comprising a compound of formula (I) is lyophilized in the absence of a compound of formula (II)