U.S. patent application number 14/212781 was filed with the patent office on 2014-09-18 for ceftolozane pharmaceutical compositions.
The applicant listed for this patent is Cubist Pharmaceuticals, Inc.. Invention is credited to Nicole Miller Damour, Joseph Terracciano.
Application Number | 20140274990 14/212781 |
Document ID | / |
Family ID | 51522651 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140274990 |
Kind Code |
A1 |
Terracciano; Joseph ; et
al. |
September 18, 2014 |
CEFTOLOZANE PHARMACEUTICAL COMPOSITIONS
Abstract
Pharmaceutical compositions can include an amount of sodium
chloride effective to stabilize ceftolozane in a lyophilized
formulation.
Inventors: |
Terracciano; Joseph;
(Concord, MA) ; Damour; Nicole Miller; (Belmont,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cubist Pharmaceuticals, Inc. |
Lexington |
MA |
US |
|
|
Family ID: |
51522651 |
Appl. No.: |
14/212781 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61793007 |
Mar 15, 2013 |
|
|
|
61792092 |
Mar 15, 2013 |
|
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Current U.S.
Class: |
514/192 ;
514/202 |
Current CPC
Class: |
A61K 31/431 20130101;
A61K 9/19 20130101; A61K 31/546 20130101; A61K 47/183 20130101;
A61K 31/198 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/198 20130101; A61K 47/02 20130101;
A61K 31/431 20130101; A61K 31/545 20130101; A61K 31/43 20130101;
A61K 31/546 20130101; A61K 47/12 20130101 |
Class at
Publication: |
514/192 ;
514/202 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 31/431 20060101 A61K031/431 |
Claims
1. A pharmaceutical composition comprising stabilized ceftolozane
sulfate obtained by a process comprising lyophilizing an aqueous
solution comprising 125 mg to 500 mg sodium chloride with an amount
of ceftolozane sulfate providing 1,000 mg of ceftolozane active, to
obtain the lyophilized stabilized ceftolozane sulfate
composition.
2. The pharmaceutical composition of claim 1, wherein the
stabilized ceftolozane is obtained by lyophilizing the sodium
chloride and ceftolozane sulfate with L-arginine.
3. The pharmaceutical composition of claim 2, wherein the
stabilized ceftolozane is obtained by lyophilizing an aqueous
solution having a pH of about 6.0 to 7.0.
4. The pharmaceutical composition of claim 1, wherein the
stabilized ceftolozane is obtained by lyophilizing the sodium
chloride and ceftolozane sulfate with L-arginine and citric
acid.
5. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition is formulated for parenteral
administration.
6. The pharmaceutical composition of claim 5, wherein the
composition is a unit dosage form in a vial comprising 125 mg to
500 mg sodium chloride, 1,000 mg of ceftolozane in the form of
ceftolozane sulfate, and L-arginine.
7. The pharmaceutical composition of claim 1, formulated for
parenteral administration.
8. The pharmaceutical composition of claim 1, wherein the pH of the
aqueous solution is 6.0 to 7.0.
9. A unit dosage form container comprising a pharmaceutical
composition of stabilized ceftolozane sulfate, obtained by a
process comprising the step of a. lyophilizing an aqueous solution
comprising 125 mg to 500 mg sodium chloride with an amount of
ceftolozane sulfate providing 1,000 mg of ceftolozane active, to
obtain the lyophilized stabilized ceftolozane sulfate composition;
b. filling the lyophilized stabilized ceftolozane composition into
a unit dosage form container.
10. The unit dosage form container of claim 9, wherein the
stabilized ceftolozane is obtained by lyophilizing the sodium
chloride and ceftolozane sulfate with L-arginine.
11. The unit dosage form container of claim 9, wherein the
stabilized ceftolozane is obtained by lyophilizing the sodium
chloride and ceftolozane sulfate with L-arginine and citric
acid.
12. The unit dosage form container of claim 10, wherein the
stabilized ceftolozane is obtained by lyophilizing an aqueous
solution having a pH of about 6.0 to 7.0.
13. The unit dosage form container of claim 9, wherein
pharmaceutical composition is formulated for parenteral
administration.
14. The unit dosage form container of claim 13, wherein the
composition is a unit dosage form in a vial comprising 125 mg to
500 mg sodium chloride, 1,000 mg of ceftolozane in the form of
ceftolozane sulfate, and L-arginine.
15. The pharmaceutical composition of claim 1, further comprising
tazobactam or a pharmaceutically acceptable salt thereof.
16. The unit dosage form container of claim 9, further comprising
tazobactam sodium.
17. The unit dosage form container of claim 14, further comprising
lyophilized tazobactam sodium.
18. A unit dosage form of a pharmaceutical composition comprising
1,000 mg ceftolozane and 500 mg tazobactam, the pharmaceutical
composition formulated for parenteral administration for the
treatment of complicated intra-abdominal infections or complicated
urinary tract infections, the pharmaceutical composition comprising
ceftolozane sulfate and tazobactam, obtained by a process
comprising the steps of: a. lyophlizing an aqueous solution to
obtain a lyophilized ceftolozane composition, wherein the aqueous
solution comprises water, ceftolozane sulfate, 125-500 mg sodium
chloride per 1,000 mg ceftolozane active in the aqueous solution,
an amount of L-arginine to provide a pH of 6-7 in the solution
prior to lyophilization; b. blending the lyophilized ceftolozane
composition with a lyophilized tazobactam composition in an amount
providing about 500 mg tazobactam free active per 1,000 mg of
ceftolozane active to obtain the unit dosage form.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/792,092, filed Mar. 15, 2013, and U.S.
Provisional Patent Application No. 61/793,007, filed Mar. 15, 2013,
both of which are incorporated herein in their entirety.
TECHNICAL FIELD
[0002] This disclosure relates to pharmaceutical compositions
comprising ceftolozane.
BACKGROUND
[0003] Ceftolozane is a cephalosporin antibacterial agent, also
referred to as CXA-101, FR264205, or by chemical names such as
(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazo-
l-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carb-
oxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
-2-ene-2-carboxylate, and
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethox-
yimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazol-
io}methyl-3-cephem-4-carboxylate.
[0004] The prior art describes a variety of ceftolozane salts. For
example, U.S. Pat. No. 7,129,232 discloses ceftolozane hydrogen
sulfate salt among other salts "with a base or an acid addition
salt such as a salt with an inorganic base, for example, an alkali
metal salt [e.g., sodium salt, potassium salt, etc.], an alkaline
earth metal salt [e.g., calcium salt, magnesium salt, etc.], an
ammonium salt; a salt with an organic base, for example, an organic
amine salt [e.g., trimethylamine salt, triethylamine salt, pyridine
salt, picoline salt, ethanolamine salt, triethanolamine salt,
dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.];
an inorganic acid addition salt [e.g., hydrochloride, hydrobromide,
sulfate, hydrogen sulfate, phosphate, etc.]; an organic carboxylic
or sulfonic acid addition salt [e.g., formate, acetate,
trifluoroacetate, maleate, tartrate, citrate, fumarate,
methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; and a
salt with a basic or acidic amino acid [e.g., arginine, aspartic
acid, glutamic acid, etc.]." Ceftolozane sulfate is a
pharmaceutically acceptable ceftolozane salt of formula (I) that
can be formulated for intravenous administration or infusion.
##STR00001##
[0005] Certain pharmaceutical compositions containing ceftolozane
are useful as antibiotics for the treatment of certain serious
infections, including serious complicated intra-abdominal
infections and complicated urinary tract infections. The
ceftolozane pharmaceutical compositions can be administered as
intravenous antibacterial agents to treat these infection. The
antibacterial activity of ceftolozane is believed to result from
its interaction with penicillin binding proteins (PBPs) to inhibit
the biosynthesis of the bacterial cell wall which acts to stop
bacterial replication. Antibacterial pharmaceutical compositions
can include a therapeutically effective unit dose of a
pharmaceutically acceptable salt of ceftolozane formulated for
intravenous administration.
[0006] As disclosed herein, ceftolozane was unstable in certain
lyophilized pharmaceutical compositions initially evaluated for
intravenous administration. In particular, a decrease in
ceftolozane purity and the formation of multiple additional related
substances were detected in certain initial ceftolozane
pharmaceutical compositions by peaks in high purity liquid
chromatography (HPLC) after stability testing. This testing pointed
to the need to develop novel ceftolozane formulations providing
increased ceftolozane stability. U.S. Pat. No. 7,129,232 discloses
that "auxiliary substances" such as "stabilizing agents . . . and
other commonly used additives" may be included in pharmaceutical
compositions comprising ceftolozane or many other cephalosporin
compounds "if needed." However, the disclosure does not disclose a
reduction in ceftolozane purity in pharmaceutical compositions
containing ceftolozane sulfate, or the formation of additional
related substances observed during stability testing. Nor does this
disclosure provide guidance on the formation of ceftolozane
pharmaceutical compositions to increase ceftolozane purity during
stability testing or control the relative amounts of ceftolozane
related substances detected by HPLC peak formation during stability
testing.
[0007] In view of the above, there is a need for pharmaceutical
preparations containing ceftolozane compounds having improved
ceftolozane stability.
SUMMARY
[0008] The pharmaceutical antibiotic compositions can include
ceftolozane sulfate obtained by a process comprising the steps of
lyophilizing an aqueous solution containing ceftolozane and a
stabilizing amount of sodium chloride, where the stabilizing amount
of sodium chloride is about 125 to 500 mg of sodium chloride
(including, e.g., 480-500 mg) per 1,000 mg ceftolozane active in
the aqueous solution prior to lyophilization. As disclosed in the
Examples herein, high performance liquid chromatography (HPLC)
analysis conducted during stability testing of lyophilized
ceftolozane pharmaceutical compositions comprising between 50 and
481 mg sodium chloride and 1,000 mg of ceftolozane revealed an
improved ceftolozane stability in compositions formed from aqueous
solutions having at least 125 mg sodium chloride. Unexpectedly,
lyophilized ceftolozane compositions having 125 mg or more sodium
chloride relative to the fixed amount of ceftolozane active prior
to lyophilization were about 35-90% more stable than comparable
ceftolozane compositions having less than 125 mg sodium chloride,
as measured by total ceftolozane purity during a 7-day stability
study in Example 3. In addition, lyophilized ceftolozane
compositions having 125 mg or more sodium chloride relative to the
fixed amount of 1,000 mg ceftolozane active in an aqueous solution
prior to lyophilization produced lyophilized compositions having
lower quantities of additional substances identified by peaks 1 and
7 having characteristic retention times measured by HPLC relative
to the retention time of ceftolozane. Unless otherwise indicated,
HPLC measurements reported herein refer to HPLC using a Develosil
column ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of
sodium perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v)
at a 1.0 mL/min flow rate and oven temperature of 45.degree. C.
Using this system, the retention time of peaks 1 and 7 are about
-0.1 and about 1.3 relative to ceftolozane (an "RRT of 0.1 and 1.3,
respectively).
[0009] In particular, sodium chloride stabilized ceftolozane
compositions described in Example 3 were characterized by about
37-94% less of the material of peak 1 and about 38-306% less of the
material of peak 7 (measured by corresponding HPLC peak areas) than
comparable ceftolozane compositions having less than 125 mg sodium
chloride (e.g., see 7-day stability study in Example 3).
[0010] The disclosed sodium chloride stabilized ceftolozane
compositions can be characterized by decrease in ceftolozane total
purity is not greater than 4.06% after storing the pharmaceutical
composition for seven days at 60.degree. C., as determined by HPLC
using a Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm,
a mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C. These sodium chloride stabilized
ceftolozane compositions were characterized by an increase in the
amount of the impurity represented by Peak 1 not greater than 1.83%
after storing the pharmaceutical composition for seven days at
60.degree. C., as determined by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C., where
Peak 1 has a retention time relative to ceftolozane of 0.1.
[0011] Accordingly, preferred pharmaceutical compositions contain
ceftolozane sulfate having an improved stability as a decrease in
the rate of ceftolozane purity and/or a decrease in the rate of
formation of substances characterized by HPLC peaks 1 and 7
identified during a 7-day stability study in Example 3.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIGS. 1A and 1B are chromatograms of CXA-101 ceftolozane
drug substance obtained from the lyophilization process of Example
1. The chromatograms were obtained according to the analytical
method described in Example 2.
[0013] FIG. 2 is a diagram of a lyophilization process for the
ceftolozane obtained according to the process described in Example
1.
[0014] FIG. 3 is a table (Table 1) of peaks for the ceftolozane
prepared by the lyophilization process in Example 1 obtained by
HPLC according to the analytical method of Example 2.
[0015] FIG. 4 is a table (Table 2) showing the composition of
various additional ceftolozane pharmaceutical compositions in which
the sodium chloride content is varied.
[0016] FIG. 5A is a table (Table 3) showing the total purity of
ceftolozane in the pharmaceutical compositions of FIG. 4, as
measured by HPLC peak area according to the analytical method of
described in Example 2.
[0017] FIG. 5B is a graph showing the total purity of certain
pharmaceutical compositions disclosed in FIG. 4, as measured by
HPLC peak area.
[0018] FIG. 6A is a table (Table 4) showing the amount of material
from characteristic peak 1 in the pharmaceutical compositions of
FIG. 4, as measured by HPLC peak area according to the analytical
method of described in Example 2.
[0019] FIG. 6B is a graph showing the amount of material from
characteristic peak 1 in the pharmaceutical compositions of FIG. 4,
as measured by HPLC peak area according to the analytical method of
described in Example 2.
[0020] FIG. 7A is a table (Table 5) showing the amount of material
from characteristic peak 3 in the pharmaceutical compositions of
FIG. 4, as measured by HPLC peak area according to the analytical
method of described in Example 2.
[0021] FIG. 7B is a graph showing the amount of material from
characteristic peak 3 in the pharmaceutical compositions of FIG. 4,
as measured by HPLC peak area according to the analytical method of
described in Example 2.
[0022] FIG. 8A is a table (Table 6) showing the amount of material
from characteristic peak 7 in the pharmaceutical compositions of
FIG. 4, as measured by HPLC peak area according to the analytical
method of described in Example 2.
[0023] FIG. 8B is a graph showing the amount of material from
characteristic peak 7 in the pharmaceutical compositions of FIG. 4,
as measured by HPLC peak area according to the analytical method of
described in Example 2.
[0024] FIG. 9A is a table (Table 7) showing the formulation
composition of the Co-Lyo-Combo Drug Product used in Example
4A.
[0025] FIG. 9B is a table (Table 8) showing impurity concentrations
at time zero, one month and three months at 25.degree. C./60%
relative humidity of the Co-Lyo-Combo Drug Product.
[0026] FIG. 9C is a table (Table 9) showing impurity concentrations
at time zero, one month and three months at 40.degree. C./75%
relative humidity of the Co-Lyo-Combo Drug Product.
[0027] FIG. 10A is a table (Table 10) showing the formulation
composition of the Blend Drug Product used in Example 4B.
[0028] FIG. 10B is a table (Table 11) showing impurity
concentrations at time zero, one month and three months at
25.degree. C./60% relative humidity of the Blend Drug Product used
in Example 4B.
[0029] FIG. 10C is a table (Table 12) showing impurity
concentrations at time zero, one month and three months at
40.degree. C./75% relative humidity of the Blend Drug Product used
in Example 4B.
[0030] FIG. 11 is a table (Table 13) showing the composition of
various ceftolozane pharmaceutical compositions in which the sodium
chloride concentration is varied.
[0031] FIG. 12 is a table (Table 14) showing the purity of
Ceftolozane in CXA-201 Compositions with varying amounts of sodium
from sodium chloride at time zero, 1 day, 3 days and 7 days at at
30.degree. C. and 60.degree. C.
[0032] FIG. 13 is a table (Table 15) showing the HPLC area of
Impurity of Peak 1 in CXA-201 Compositions with varying amounts of
sodium from sodium chloride at time zero, 1 day, 3 days and 7 days
at 30.degree. C. and at 60.degree. C.
[0033] FIG. 14 is a table (Table 16) showing the HPLC area of the
Impurity at RRT 0.43 and Impurity Peak 3 in CXA-201 Compositions
with varying amounts of sodium from sodium chloride at time zero, 1
day, 3 days and 7 days at 30.degree. C. and at 60.degree. C.
[0034] FIG. 15 is a table (Table 17) showing the HPLC area of
Impurity of Peak 7 in CXA-201 Compositions with varying amounts of
sodium from sodium chloride at time zero, 1 day, 3 days and 7 days
at 30.degree. C. and at 60.degree. C.
[0035] FIG. 16 is a table (Table 18) showing the finished drug
product unit composition of ceftolozane/tazolactam.
[0036] FIG. 17 is a table (Table 19) showing the primary container
closure system for the ceftolozane/tazobactam unit product.
DETAILED DESCRIPTION
[0037] Ceftolozane sulfate can be stabilized in lyophilized
pharmaceutical compositions by incorporation of a
stabilizing-effective amount of an inorganic salt stabilizing agent
in a solution that can be lyophilized to obtain a lyophilized
composition containing stabilized ceftolozane. The
stabilizing-effective amount of a sodium chloride inorganic salt
stabilizing agent is preferably 125 mg to 500 mg (preferably about
480-500 mg) of sodium chloride per 1,000 mg of ceftolozane
active.
[0038] In particular, pharmaceutical compositions comprising
ceftolozane and stabilizing amount of sodium chloride can be
obtained by lyophilization of a solution comprising a
stabilizing-effective amount of sodium chloride and ceftolozane
sulfate. Alternatively, they can be obtained by other methods. As
is known to those skilled in the art, lyophilization is a process
of freeze-drying in which water is sublimed from a frozen solution
of one or more solutes. Specific methods of lyophilization are
described in Remington's Pharmaceutical Sciences, Chapter 84, page
1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co.,
Easton, Pa., 1990). A pharmaceutical composition comprising
ceftolozane can be prepared by adding a stabilizing amount of
sodium chloride in a fixed ratio to ceftolozane in an aqueous
solution prior to lyophilization, then lyophilizing the solution to
obtain a lyophilized composition comprising sodium chloride and
ceftolozane.
[0039] In particular, the pharmaceutical antibiotic compositions
can include ceftolozane sulfate obtained by a process comprising
the steps of lyophilizing an aqueous solution containing
ceftolozane and a stabilizing amount of sodium chloride, where the
stabilizing amount of sodium chloride is about 125 to 500 mg
(preferably, 480-500 mg) of sodium chloride per 500 mg ceftolozane
active in the aqueous solution prior to lyophilization. The
pharmaceutical compositions comprising ceftolozane disclosed herein
can be prepared by adding 125 to 500 mg (preferably, 480-500 mg)
sodium chloride per 1000 mg of ceftolozane prior to lyophilization
(or spray drying). For example, the pharmaceutical compositions can
be obtained by a method comprising the steps of adding a
stabilizing amount (e.g., 125 to 500 mg [more preferably, 480-500
mg] sodium chloride per 1000 mg of ceftolozane active) followed by
lyophilizing (or spray drying) the composition comprising the
sodium chloride and ceftolozane. In one aspect (e.g., Example 1),
ceftolozane and a stabilizing amount of sodium chloride can be
dissolved in an aqueous solution that can be lyophilized (or spray
drying) to obtain a ceftolozane pharmaceutical composition.
[0040] The pharmaceutical compositions may comprise other
additional components including stabilizers, pH adjusting additives
(e.g., buffers) and the like. Non-limiting examples of these
additives include sodium chloride, citric acid and L-arginine. For
example, the pharmaceutical antibiotic compositions can include
ceftolozane sulfate obtained by a process comprising the steps of
lyophilizing an aqueous solution containing ceftolozane sulfate
with a stabilizing amount of sodium chloride (e.g., 125 to 500 mg
[more preferably, 480-500 mg] of sodium chloride per 1,000 mg
ceftolozane active), with L-arginine and/or citric acid in the
aqueous solution prior to lyophilization. The use of sodium
chloride results in greater ceftolozane stability, while an amount
of L-arginine can be used that is effective to adjust pH and to
increase the solubility of ceftolozane, and citric acid can be
included in an amount effective to reduce or prevent discoloration
of the product, due to its ability to chelate metal ions. The
aqueous solution can be subsequently lyophilized (or spray dried)
to obtain a stabilized lyophilized ceftolozane sulfate composition
comprising ceftolozane sulfate, sodium chloride, L-arginine and
citric acid.
[0041] The pharmaceutical composition can also be a
Ceftolozane/Tazobactam for Injection Drug Product, 1000 mg/500 mg.
It is presented as a combination of two sterile active powders in a
single vial intended for reconstitution and intravenous
infusion.
[0042] The drug product is first prepared by converting ceftolozane
sulfate drug substance to a sterile drug product intermediate (DPI)
powder with excipients citric acid, sodium chloride and L-arginine.
This is commonly done by lyophilization, as described above.
Tazobactam sodium drug substance is presented as a sterile powder
without any excipients. The tazobactam sodium drug substance is
typically lyophilized (or spray dried). The drug product is then
prepared by aseptically filling the two powders (e.g., the two
separately lyophilized drug powders or spray dried powders)
sequentially into a single vial.
[0043] Each vial of ceftolozane/tazobactam for injection contains
approximately 2255 mg ceftolozane sterile DPI powder that contains
1147 mg ceftolozane sulfate, which is equivalent to 1000 mg
ceftolozane free base, as well as approximately 537 mg tazobactam
sodium sterile drug substance, equivalent to 500 mg tazobactam free
acid. At the time of administration, the vial is reconstituted with
10 mL vehicle, 5% Dextrose Injection USP, sterile Water for
Injection or 0.9% Sodium Chloride Injection USP, then the vial
contents further diluted in an infusion bag of 0.9% Sodium Chloride
Injection USP or 5% Dextrose Injection USP, for administration. The
constituents are shown in Table 18, FIG. 16.
[0044] The primary container-closure system is a Type 1 20 mL
molded glass vial with 20 mm neck finish. The vial is sealed by a
20 mm rubber stopper and 20 mm plastic flip-cap seal with aluminum
ferrule. The primary contain-closure system used for the
ceftolozane/tazobactam unit product is summarized in Table 19, FIG.
17.
[0045] In other embodiments, pharmaceutical compositions comprising
ceftolozane can be obtained by methods that include the steps of:
(1) adding a stabilizing amount of sodium chloride to ceftolozane
(or preparing an aqueous solution of sodium chloride and
ceftolozane) optionally followed by co-lyophilizing or spray drying
the ceftolozane and sodium chloride (or aqueous solution thereof);
and (2) combining the product of step (1) with other components.
For example, the product of step (1) can be combined with a
.beta.-lactamase inhibitor, such as tazobactam (CAS#: 89786-04-9),
avibactam (CAS#1192500-31-4), Sulbactam (CAS#68373-14-8) and/or
clavulanate (CAS#58001-44-8). The beta lactamase inhibitor can be
included in a crystalline or amorpous form, such as a lyophilized
tazobactam or crystalline tazobactam (e.g., U.S. Pat. Nos.
8,476,425 and 5,763,603) to obtain the pharmaceutical
composition.
[0046] The stabilizing effect of sodium chloride on ceftolozane can
be measured by high performance liquid chromatography (HPLC)
analysis, for example by detecting the ratio of peak areas obtained
for ceftolozane compared to peaks for other substances. Various
ceftolozane compositions having 50-481 mg of sodium chloride per
1,000 mg ceftolozane active as described in Table 2 (FIG. 4) were
tested for stability as described in Example 3. The stability
testing of lyophilized ceftolozane pharmaceutical compositions
(Example 3) revealed improved ceftolozane stability in compositions
formed from aqueous solutions having at least 125 mg sodium
chloride. Unless otherwise indicated, HPLC measurements reported
herein are obtained using a Develosil column ODS-UG-5; 5
micrometers; 250.times.4.6 mm, a mobile phase of sodium perchlorate
buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min
flow rate and oven temperature of 45.degree. C.
[0047] Unexpectedly, lyophilized ceftolozane compositions having
125 mg more sodium chloride relative to the fixed amount of
ceftolozane prior to lyophilization were about 35-90% more stable
than comparable ceftolozane compositions having less than 125 mg
sodium chloride, as measured by total ceftolozane purity during a
7-day stability study in Example 3. Referring to the data in Table
3 (FIGS. 5A and 5B), the total purity of ceftolozane (measured by
HPLC according to Example 2) was measured by the % decrease in the
ceftolozane HPLC peak during the 7-day stability test. In
particular, samples obtained by lyophilizing compositions
containing 125 mg, 190 mg and 481 mg of sodium chloride per 1,000
mg of ceftolozane active showed a decrease in ceftolozane that was
at least about 35% less than reductions in ceftolozane observed for
formulations containing 50 mg or 75 mg sodium chloride per 1,000 mg
ceftolozane active (e.g., the % decrease in ceftolozane for the
sample containing 75 mg sodium chloride was about 35% greater than
the comparable % decrease in ceftolozane for the sample containing
190 mg sodium chloride). In addition, samples obtained by
lyophilizing compositions containing 125 mg, 190 mg and 481 mg of
sodium chloride per 1,000 mg of ceftolozane active showed a
decrease in ceftolozane that was up to about 90% less than
reductions in ceftolozane observed for forulations containing 50 mg
or 75 mg sodium chloride per (e.g., the % decrease in ceftolozane
for the sample containing 50 mg sodium chloride was about 90%
greater than the comparable % decrease in ceftolozane for the
sample containing 481 mg sodium chloride).
[0048] In addition, lyophilized ceftolozane compositions having 125
mg more sodium chloride relative to the fixed amount of 1,000 mg
ceftolozane active in an aqueous solution prior to lyophilization
produced lyophilized compositions having lower quantities of
additional substances identified by peaks 1 and 7 having
characteristic retention times measured by HPLC (see Table 1, FIG.
3, indicating retention times of about 0.1 for peak 1 and about 1.3
for peak 7 relative to celftolozane measured according to the HPLC
method of Example 2). In particular, these sodium chloride
stabilized ceftolozane compositions were characterized by about
37-94% less of the material of peak 1 and about 38-306% less of the
material of peak 7 (measured by corresponding HPLC peak areas) than
comparable ceftolozane compositions having less than 125 mg sodium
chloride (e.g., see 7-day stability study in Example 3).
[0049] Referring to the data in Table 4 (FIGS. 6A and 6B), the
amount of the composition of peak 1 (measured by HPLC according to
Example 2) was measured by the % increase in the peak 1 HPLC peak
during the 7-day stability test of Example 3. In particular,
samples obtained by lyophilizing compositions containing 125 mg,
190 mg and 481 mg of sodium chloride per 1,000 mg of ceftolozane
active showed at least a 37% reduction in the amount of the peak 1
composition observed for these formulations containing at least 125
mg sodium chloride per 1,000 mg ceftolozane active, compared to the
compositions obtained by lyophilizing 50 mg or 75 mg sodium
chloride per 1,000 mg of ceftolozane active (e.g., the % increase
in peak 1 for the sample containing 75 mg sodium chloride was about
37% greater than the comparable % decrease in ceftolozane for the
sample containing 190 mg sodium chloride). In addition, samples
obtained by lyophilizing compositions containing 125 mg, 190 mg and
481 mg of sodium chloride per 1,000 mg of ceftolozane active showed
up to a 94% reduction in the amount of the peak 1 composition
observed for these formulations containing at least 125 mg sodium
chloride per 1,000 mg ceftolozane active, compared to the
compositions obtained by lyophilizing 50 mg or 75 mg sodium
chloride per 1,000 mg of ceftolozane active (e.g., the % increase
in peak 1 for the sample containing 50 mg sodium chloride was about
94% greater than the comparable % decrease in ceftolozane for the
sample containing 481 mg sodium chloride).
[0050] Referring to the data in Table 5 (FIGS. 7A and 7B), the
amount of the composition of peak 3 (measured by HPLC according to
Example 2) was measured by the % increase in the peak 1 HPLC peak
during the 7-day stability test of Example 3. In particular,
samples obtained by lyophilizing compositions containing 125 mg and
190 mg of sodium chloride per 1,000 mg of ceftolozane active showed
at least a 269% reduction in the amount of the peak 3 composition
observed for these formulations containing at least 125 mg sodium
chloride per 1,000 mg ceftolozane active, compared to the
compositions obtained by lyophilizing 50 mg or 75 mg sodium
chloride per 1,000 mg of ceftolozane active (e.g., the % increase
in peak 3 for the sample containing 50 mg sodium chloride was about
269% greater than the comparable % decrease in ceftolozane for the
sample containing 190 mg sodium chloride). In addition, samples
obtained by lyophilizing compositions containing 125 mg or 190 mg
of sodium chloride per 1,000 mg of ceftolozane active showed up to
a 333% reduction in the amount of the peak 3 composition observed
for these formulations containing at least 125 mg sodium chloride
per 1,000 mg ceftolozane active, compared to the compositions
obtained by lyophilizing 50 mg or 75 mg sodium chloride per 1,000
mg of ceftolozane active (e.g., the % increase in peak 3 for the
sample containing 75 mg sodium chloride was about 333% greater than
the comparable % decrease in ceftolozane for the sample containing
125 mg sodium chloride). The ceftolozane sample containing 481 mg
of sodium chloride had a higher amount of the composition of peak 3
than the ceftolozane samples containing 50 mg or 75 mg of sodium
chloride.
[0051] Referring to the data in Table 6 (FIGS. 8A and 8B), the
amount of the composition of peak 7 (measured by HPLC according to
Example 2) was measured by the % increase in the peak 7 HPLC peak
during the 7-day stability test of Example 3. In particular,
samples obtained by lyophilizing compositions containing 125 mg,
190 mg and 481 mg of sodium chloride per 1,000 mg of ceftolozane
active showed at least a 38% reduction in the amount of the peak 7
composition observed for these formulations containing at least 125
mg sodium chloride per 1,000 mg ceftolozane active, compared to the
compositions obtained by lyophilizing 50 mg or 75 mg sodium
chloride per 1,000 mg of ceftolozane active (e.g., the % increase
in peak 7 for the sample containing 75 mg sodium chloride was about
38% greater than the comparable % decrease in ceftolozane for the
sample containing 125 mg sodium chloride). In addition, samples
obtained by lyophilizing compositions containing 125 mg, 190 mg and
481 mg of sodium chloride per 1,000 mg of ceftolozane active showed
up to a 306% reduction in the amount of the peak 7 composition
observed for these formulations containing at least 125 mg sodium
chloride per 1,000 mg ceftolozane active, compared to the
compositions obtained by lyophilizing 50 mg or 75 mg sodium
chloride per 1,000 mg of ceftolozane active (e.g., the % increase
in peak 7 for the sample containing 50 mg sodium chloride was about
306% greater than the comparable % decrease in ceftolozane for the
sample containing 481 mg sodium chloride).
[0052] Accordingly, preferred pharmaceutical compositions contain
ceftolozane sulfate having an improved stability as a decrease in
the rate of ceftolozane purity and/or a decrease in the rate of
formation of substances characterized by HPLC peaks 1 and 7
identified during a 7-day stability study in Example 3. The
preferred ceftolozane pharmaceutical compositions comprise a
stabilizing amount of sodium chloride (e.g., 125 to 500 mg of
sodium chloride per 1000 mg of ceftolozane). Certain preferred
compositions demonstrate improved ceftolozane purity (e.g., Table 3
in FIG. 5A) and chemical stability (e.g., with respect to the
composition of HPLC peak 1 in Table 4, FIG. 6A) compared
pharmaceutical compositions comprising ceftolozane with
comparatively less sodium chloride.
[0053] Pharmaceutical compositions comprising ceftolozane can be
formulated to treat infections by parenteral administration
(including subcutaneous, intramuscular, and intravenous)
administration. Pharmaceutical compositions may additionally
comprise excipients, stabilizers, pH adjusting additives (e.g.,
buffers) and the like. Non-limiting examples of these additives
include sodium chloride, citric acid and L-arginine. For example,
the use of sodium chloride results in greater stability; L-arginine
is used to adjust pH and to increase the solubility of ceftolozane;
and citric acid is used to prevent discoloration of the product,
due to its ability to chelate metal ions. In one particular
embodiment, the pharmaceutical compositions described herein are
formulated for administration by intravenous injection or infusion.
Pharmaceutical antibiotic compositions can include ceftolozane
sulfate and stabilizing amount of sodium chloride (e.g., 125 to 500
mg of sodium chloride per 1,000 mg ceftolozane active) in a
lyophilized unit dosage form (e.g., powder in a vial). The unit
dosage form can be dissolved with a pharmaceutically acceptable
carrier, and then intravenously administered. In another aspect,
pharmaceutical antibiotic compositions can include ceftolozane
sulfate obtained by a process comprising the steps of lyophilizing
an aqueous solution containing ceftolozane and a stabilizing amount
of sodium chloride, where the stabilizing amount of sodium chloride
is about 125 to 500 mg of sodium chloride per 1,000 mg ceftolozane
active in the aqueous solution prior to lyophilization.
[0054] In one aspect, provided herein is a method for the treatment
of bacterial infections in a mammal, comprising administering to
said mammal a therapeutically effective amount of a pharmaceutical
composition prepared according to the methods described herein. A
method for the treatment of bacterial infections in a mammal can
comprise administering to said mammal a therapeutically effective
amount of a pharmaceutical composition comprising ceftolozane
sulfate and sodium chloride. Non-limiting examples of bacterial
infections that can be treated by the methods of the invention
include infections caused by: aerobic and facultative gram-positive
microorganisms (e.g., Staphylococcus aureus, Enterococcus faecalis,
Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus
pneumonia, Streptococcus pyogenes, Viridans group streptococci),
aerobic and facultative gram-negative microorganisms (e.g.,
Acinetobacter baumanii, Escherichia coli, Haemophilus influenza,
Klebsiella pneumonia, Pseudomonas aeruginosa, Citrobacter koseri,
Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae,
Proteus mirabilis, Proteus vulgaris, Serratia marcescens,
Providencia stuartii, Providencia rettgeri, Salmonella enterica),
gram-positive anaerobes (Clostridium perfringens), and
gram-negative anaerobes (e.g., Bacteroides fragilis group (e.g., B.
fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgates),
Bacteroides distasonis, Prevotella melaminogenica). In certain
embodiments of the methods described herein, bacterial infection is
associated with one or more of the following conditions:
complicated intra-abdominal infections, complicated urinary tract
infections (cUTIs) and pneumonia (e.g., community-acquired, or
nosocomial pneumonia). Community-acquired pneumonia (moderate
severity only) can include infections caused by
piperacillin-resistant, beta-lactamase producing strains of
Haemophilus influenza. Nosocomial pneumonia (moderate to severe)
caused by piperacillin-resistant, beta-lactamase producing strains
of Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus
influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
[0055] As used herein, "treating", "treat" or "treatment" describes
the management and care of a patient for the purpose of combating a
disease, condition, or disorder and includes the administration of
a pharmaceutical composition of the present invention to alleviate
the symptoms or complications of a disease, condition or disorder,
or to reduce the extent of the disease, condition or disorder. The
term "treat" can also include treatment of a cell in vitro or an
animal model.
[0056] By a "therapeutically effective amount" of a compound of the
invention is meant a sufficient amount of the compound to treat the
disorder (e.g., bacterial infection). The specific therapeutically
effective amount that is required for the treatment of any
particular patient or organism (e.g., a mammal) will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound or
composition employed; the specific composition employed; the age,
body weight, general health, sex and diet of the patient; the time
of administration, route of administration, and rate of excretion
of the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and like factors well known in the medical arts
(see, for example, Goodman and Gilman's, "The Pharmacological Basis
of Therapeutics", Tenth Edition, A. Gilman, J. Hardman and L.
Limbird, eds., McGraw-Hill Press, 155-173, 2001, which is
incorporated herein by reference in its entirety). The
therapeutically effective amount for a given situation can be
readily determined by routine experimentation and is within the
skill and judgment of the ordinary clinician.
[0057] As used herein, "125-500 mg sodium chloride per 1000 mg of
ceftolozane" refers to a ratio of sodium chloride to ceftolozane
active. The phrase "125-500 mg sodium chloride per 1000 mg of
ceftolozane" includes "62.5 to 250 mg sodium chloride per 500 mg of
ceftolozane active" and other similar weight ratios. In addition,
"1,000 mg of ceftolozane as ceftolozane sulfate" refers to an
amount of ceftolozane sulfate effective to provide 1,000 mg of
ceftolozane. The amount of sodium per gram of ceftolozane activity
in a pharmaceutical composition containing ceftolozane sulfate and
sodium chloride can be calculated using the relevant molecular
weights of ceftolozane, ceftolozane sulfate, sodium chloride and
sodium.
[0058] As used herein, "1000 mg ceftolozane" refers to an amount of
ceftolozane that is considered a bioequivalent by the United States
Food and Drug Administration (FDA), i.e. for which 90% CI of the
relative mean Cmax, AUC(0-t) and AUC(0-.infin.) is within 80.00% to
125.00% of the reference formulation in the fasting state (see:
"Guidance for Industry: Bioavailability and Bioequivalence Studies
for Orally Administered Drug Products--General Considerations".
Center for Drug Evaluation and Research, United States Food and
Drug Administration, 2003).
[0059] "Ceftolozane active" refers to the active portion of a salt
form of ceftolozane, i.e., the free base form of ceftolozane.
[0060] In another aspect, the disclosed sodium chloride stabilized
ceftolozane compositions can be characterized by decrease in
ceftolozane total purity is not greater than 3.7% after storing the
pharmaceutical composition for seven days at 60.degree. C., as
determined by HPLC using a Develosil column ODS-UG-5; 5
micrometers; 250.times.4.6 mm, a mobile phase of sodium perchlorate
buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min
flow rate and oven temperature of 45.degree. C. In another aspect,
the disclosed sodium chloride stabilized ceftolozane compositions
can be characterized by decrease in ceftolozane total purity is not
greater than 4.2% after storing the pharmaceutical composition for
seven days at 60.degree. C., as determined by HPLC using a
Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a
mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C. In another aspect, the disclosed
sodium chloride stabilized ceftolozane compositions can be
characterized by decrease in ceftolozane total purity is not
greater than 4.5% after storing the pharmaceutical composition for
seven days at 60.degree. C., as determined by HPLC using a
Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a
mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C. In another aspect, the disclosed
sodium chloride stabilized ceftolozane compositions can be
characterized by decrease in ceftolozane total purity is not
greater than 5.0% after storing the pharmaceutical composition for
seven days at 60.degree. C., as determined by HPLC using a
Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a
mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C.
[0061] In another aspect, the disclosed sodium chloride stabilized
ceftolozane compositions were characterized by an increase in the
amount of the impurity represented by Peak 1 not greater than 1.8%
after storing the pharmaceutical composition for seven days at
60.degree. C., as determined by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C., where
Peak 1 has a retention time relative to ceftolozane of 0.1. In
another aspect, the disclosed sodium chloride stabilized
ceftolozane compositions were characterized by an increase in the
amount of the impurity represented by Peak 1 not greater than 2.0%
after storing the pharmaceutical composition for seven days at
60.degree. C., as determined by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C., where
Peak 1 has a retention time relative to ceftolozane of 0.1. In
another aspect, the disclosed sodium chloride stabilized
ceftolozane compositions were characterized by an increase in the
amount of the impurity represented by Peak 1 not greater than 2.2%
after storing the pharmaceutical composition for seven days at
60.degree. C., as determined by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C., where
Peak 1 has a retention time relative to ceftolozane of 0.1.
Illustrative Examples of Selected Embodiments of the Invention
Example 1
Manufacturing Procedure of Bulk (Tray) Lyophilized Ceftolozane
[0062] There are four main steps in the manufacture of CXA-101 bulk
drug product: dissolution, sterile filtration, bulk lyophilization,
and packaging into Sterbags.RTM.. These four main steps are
composed of a total of 20 minor steps. The CXA-101 bulk drug
product manufacturing process is presented below.
I. Dissolution
[0063] 1. The prescribed amount of water for injection ("WFI") is
charged into the dissolution reactor.
[0064] 2. A prescribed amount of citric acid is added.
[0065] 3. The solution is cooled at 5.degree. C. to 10.degree.
C.
[0066] 4. A prescribed amount of CXA-101 drug substance is added to
the solution.
[0067] 5. A prescribed amount of L-arginine is slowly added to the
solution.
[0068] 6. A check for complete dissolution is performed. Solution
pH is verified to be in the target range of 6.5 to 7.0.
[0069] 7. A prescribed amount of sodium chloride is added to the
solution, wherein the preferred amount of sodium chloride is
125-500 mg of sodium chloride per 1000 mg of ceftolozane
active.
[0070] 8. A check for complete dissolution is performed. Solution
pH is verified to be in the target range of 6.0 to 7.0. If the pH
is out of this range adjust with either L-Arginine or citric
acid.
[0071] 9. WFI is added to bring the net weight to 124.4 kg and the
solution is mixed well.
[0072] 10. Samples are withdrawn for testing of final pH.
II. Sterile Filtration
[0073] 11. The solution is passed through the filter (pore size
0.45 .mu.m) followed by double filters (pore size 0.22 .mu.m) onto
a shelf on the Criofarma lyophilizer.
[0074] 12. The line is washed with WFI.
[0075] 13. The washing solution is passed from Step 12 through
sterile filtration.
III. Bulk Lyophilization
[0076] 14. The washing solution is loaded onto a separate shelf in
the lyophilizer (and later discarded).
[0077] 15. The solution is lyophilized until dry.
[0078] 16. The product shelf is cooled to 20.degree.
C..+-.5.degree. C.
IV. Packaging into Sterbags.RTM.
[0079] 17. The lyophilized bulk drug product powder is milled.
[0080] 18. The milled powder is sieved.
[0081] 19. The sieved powder is blended for 30 minutes.
[0082] 20. The powder is then discharged into Sterbags.RTM.
Prefiltration and Sterile-Filtration
[0083] Filtrate the compounded solution with a sterile tilter-set
which consists of a 0.2 um polyvinylidene fluoride membrane filter
(Durapore.RTM., Millipore) and a 0.1 um polyvinylidene fluoride
membrane filter (Durapore.RTM., Millipore) connected in tandem.
Confirm the integrity of each filter before and after the
filtration. Take approximately 100 mL of the filtrate in order to
check bioburden.
[0084] Filter the prefiltered compounded solution through a sterile
filter-set which consists of a 0.2 um polyvinylidene fluoride
membrane filter and a 0.1 um polyvinylidene fluoride membrane
filter connected in tandem, and introduce the final filtrate into
an aseptic room. Confirm the integrity of each filter before and
after the filtration.
Processing of Vial, Stopper and Flip-Off Cap
[0085] Wash a sufficient quantity of 28 mL vials with water for
injection and sterilize the washed vials by a dry-heat sterilizer.
Then transfer the sterilized vials into a Grade A area located in
an aseptic room.
[0086] Wash a sufficient quantity of stoppers with, water for
injection. Sterilize and dry the washed stoppers by steam
sterilizer. Then transfer the sterilized stoppers into a Grade A
area located in an aseptic room.
[0087] Sterilize a sufficient quantity of flip-off caps by steam
sterilizer. Then transfer the sterilized flip-off caps into a Grade
A or B area located in an aseptic room.
Filling and Partially Stoppering
[0088] Adjust the fill weight of the filtered compounded solution
to 11.37 g (corresponds to 10 mL of the compounded solution), then
start filling operation. Check the filled weight in sufficient
frequency and confirm it is in target range (11.37 g.+-.1%, 11.26
to 11.43 g). When deviation from the control range (11.37 g.+-.2%,
11.14 to 11.59 g) is occurred, re-adjust the filling weight.
[0089] Immediately after a vial is filled, partially stopper the
vial with a sterilized stopper. Load the filled and partially
stoppered vials onto the shelves of a lyophilizer aseptically.
Lyophilization to Crimping, Visual Inspection, Labeling and
Packaging
[0090] After all filled and partially stoppered vials are loaded
into a lyophilizer, start the lyophilization program shown in FIG.
2. Freeze the loaded vials at -40.degree. C. and keep until all
vials freeze. Forward the program to primary drying step (shelf
temperature; -20.degree. C., chamber pressure; 100 to 150 mTorr).
Primary drying time should be determined by monitoring the product
temperature. Forward the program to secondary drying step (shelf
temperature; 30.degree. C., chamber pressure; not more than 10
mTorr) after completion of the primary drying step. After all vials
are dried completely, return the chamber pressure to atmospheric
pressure with sterilized nitrogen. Then stopper vials
completely.
[0091] Unload the lyophilized vials from the chamber and crimp with
sterilized flip-off caps.
[0092] Subject all crimped vials to visual inspection and label and
package all passed vials.
Example 2
Analytical HPLC Method
A. Operative Conditions
TABLE-US-00001 [0093] Column Develosil ODS-UG-5; 5 .mu.m, 250
.times. 4.6 mm (Nomura Chemical, Japan) Mobile phase Sodium
Perchlorate Buffer Solution (PH 2.5)/CH.sub.3CN 90:10 (vlv) Flow
rate 1.0 mL/min Wavelength 254 nm Injection volume 10 .mu.L Oven
Temperature 45.degree. C. Run Time 85 minutes
Gradient Profile:
TABLE-US-00002 [0094] Time (min) A % B % 0 75 25 30 70 30 60 0 100
85 0 100 85.1 75 25 110 75 25
B. Mobile Phase Preparation.
[0095] Sodium Perchlorate Buffer Solution was made by dissolving
14.05 g of sodium perchlorate Monohydrate in 1000.0 mL of water
followed by adjusting pH to 2.5 with diluted perchloric acid (1 in
20).
[0096] Mobile Phase was then made by mixing Sodium Perchlorate
Buffer Solution (pH 2.5) and acetonitrile in the ratio 90:10
(v/v).
[0097] Sodium Acetate Buffer Solution pH 5.5 (Diluent) was made by
dissolving 1.36 g of sodium acetate trihydrate in 1000.0 mL of
water followed by adjusting to pH 5.5 with diluted acetic acid (1
in 10).
C. Sample Preparation.
[0098] Sample solution: dissolve 20.0 mg, exactly weighed, of
Sample, in 20.0 mL of water (Prepare just before injection into
HPLC system).
[0099] System Suitability Solution (1%): take 1.0 mL of the Sample
Solution (use first sample if more are present) and transfer into a
100.0 mL volumetric flask, dilute with water to volume and mix.
D. HPLC Analysis Procedure
[0100] 1. Inject Blank (water) 2. Inject System Suitability
Solution and check for tailing factor and theoretical plate number
for CXA-101 peak: [0101] The tailing factor must not be greater
than 1.5 [0102] Theoretical plates number must not be less than
10000
3. Inject Sample Solution
[0103] 4. Inject System Suitability Solution and check for tailing
factor and theoretical plate number for CXA-101 peak. [0104] The
tailing factor must not be greater than 1.5 [0105] Theoretical
plates number must not be less than 10000 5. Identify the peaks of
Related Substances in the Sample chromatogram based on the
reference chromatogram reported in FIGS. 1A and 1B or,
alternatively, on the basis of the RRT values reported in Table 1
(FIG. 3), with a retention time of about 0.14 relative to
ceftolozane is believed to have the chemical structure of formula
(II):
##STR00002##
[0105] E. Calculations
[0106] I. Report for each related substance its amount as expressed
by area percent.
C i = A i .times. 100 A t + A i ##EQU00001##
[0107] wherein:
[0108] C.sub.i=Amount of related substance i in the Sample, area
%
[0109] A.sub.i=Peak area of related substance i in the Sample
chromatogram
[0110] A.sub.t=Area of CXA-101 peak in the Sample chromatogram
[0111] A.sub.t+.SIGMA. A.sub.i=Total peaks area in the Sample
chromatogram
[0112] Consider as any Unspecified Impurity, each peak in the
chromatogram except CXA-101, peaks from 1 to 11 and every peak
present in the blank chromatogram and report the largest.
II. Report the total impurities content as expressed by the
following formula:
C T = A i .times. 100 A t + A i ##EQU00002##
[0113] wherein:
[0114] C.sub.T=total impurities content in the Sample, area %
[0115] A.sub.t=area of CXA-101 peak in the sample chromatogram
[0116] .SIGMA. A.sub.i=total peak areas of impurities in the sample
chromatogram
Example 3
The Amount of Sodium Chloride can be Selected to Stabilize
Ceftolozane in Pharmaceutical Compositions
[0117] Multiple stability studies were performed on ceftolozane
sulfate, wherein the effect of varying amounts of sodium chloride
on the stability of ceftolozane was examined.
[0118] The amount of sodium per mg of sodium chloride can be
calculated (as known to one of ordinary skill in the art) based on
the relative molar weight ratio of sodium and sodium chloride
(e.g., 50 mg sodium chloride contains about 20 mg of sodium,
etc).
[0119] The amount of ceftolozane in ceftolozane sulfate can
similarly be calculated based on the respective molecular molar
weights of ceftolozane and ceftolozane sulfate (e.g., 1,147 mg
ceftolozane sulfate contains about 1,000 mg of ceftolozane).
Accordingly, a composition comprising about 1,147 mg ceftolozane
sulfate and 480 mg of sodium chloride also contains 480 mg of
sodium chloride per 1,000 mg of ceftolozane.
[0120] A. CXA-101 Purity Increases in Compositions Having at Least
about 125 Mg NaCl/1,000 Mg Ceftolozane Active
[0121] A stability study was carried out at 60.degree. C. as
described herein. Sodium chloride content in test samples is
described in Table 2 (FIG. 4). The samples were formulated with
481, 190, 125, 75, and 50 mg sodium chloride per 1 g of ceftolozane
active.
[0122] FIG. 5A is Table 3 with data for total purity of ceftolozane
measured by HPLC during the 7-day stability test using the HPLC
method in Example 2, with the data plotted in the graph of FIG.
5B.
[0123] B. The Amount of Substances Identified by HPLC Peaks 1 and 7
Decreases in Compositions Having at Least about 125 Mg NaCl/1,000
Mg Ceftolozane Active
[0124] A stability study was carried out at and 60.degree. C. as
described herein. Sodium chloride content in test samples is
described in Table 2 (FIG. 4). The samples were formulated with
481, 190, 125, 75, and 50 mg sodium chloride per 1 g of ceftolozane
active.
[0125] Stability data for amounts of additional substances in the
ceftolozane compositions from Table 2 (FIG. 4) as measured by peaks
1, 3 and 7 by HPLC (according to Example 2) are summarized in
Tables 4-6, FIGS. 6A, 7A and 8A. The data are also plotted in FIGS.
6B, 7B, and 8B to show trends of total purity, peak 1, RRT
0.43+peak 3, and peak 7 with respect to sodium chloride (NaCl),
respectively. FIG. 5A is Table 3 with total purity of ceftolozane
measured by HPLC during the 7-day stability test, with the data
plotted in the graph of FIG. 5B.
Example 4
The Amount of Sodium Chloride can be Selected to Stabilize
Ceftolozane in Pharmaceutical Compositions Comprising Ceftolozane
and Tazobactam
[0126] A. Stabilized Ceftolozane Compositions Co-Lyophilized with
Tazobactam
[0127] A composition comprising ceftolozane, sodium chloride and
tazobactam was prepared by co-lyophilizing a stabilizing amount of
sodium chloride, ceftolozane sulfate and tazobactam acid in amounts
described in Table 7 (FIG. 9A) together in an aqueous solution to
obtain a stabilized ceftolozane lyophilized composition
("Co-Lyophilized Combo Drug Product"). The components of the
composition that was lyophilized to obtain the Co-Lyophilized Combo
Drug Product is shown in Table 7 (FIG. 9A). Notably, this
composition included about 484 mg of sodium chloride per 1,000 mg
ceftolozane active provided as ceftolozane sulfate, and a weight
ratio of about 2:1 between the CXA101 and tazobactam acid.
[0128] The results of a stability study of the Co-Lyophilized Combo
Drug Product are shown in Table 8 (FIG. 9B) and Table 9 (FIG. 9C)
as representative examples that summarize the results at 25.degree.
C./RH=60% and 40.degree. C./RH=75% after one month (T1) and three
months (T2). Samples were analyzed using a HPLC method as described
in Example 2.
[0129] Referring to the data in Tables 8 and 9, the Co-Lyophilized
Combo Drug Product was characterized by amounts of the substances
corresponding to HPLC peaks 1-12 that were less than the applicable
drug product specification, indicating stabilization of the
ceftolozane in the presence of about 484 mg of sodium chloride per
1,000 mg of ceftolozane active.
[0130] B. Stabilized Ceftolozane Compositions Lyophilized without
Tazobactam
[0131] A composition comprising ceftolozane, and a stabilizing
amount of sodium chloride was lyophilized, and then blended with a
separately lyophilized composition of tazobactam. The stabilized
ceftolozane composition was formed by lyophilizing an aqueous
solution of the "CXA-101 for Injection Bulk" row of Table 10 (FIG.
10A), which was then blended with 5.4 g tazobactam free acid to
form a pharmaceutical composition containing ceftolozane, sodium
chloride and tazobactam components ("Blend Combo Drug Product").
Notably, this composition included about 481 mg of sodium chloride
per 1,000 mg ceftolozane active provided as ceftolozane sulfate,
and a weight ratio of about 2:1 between the CXA101 and tazobactam
acid.
[0132] The results of a stability study of the Blend Combo Drug
Product are shown in Table 11 (FIG. 10B) and Table 12 (FIG. 10C) as
representative examples that summarize the results at 25.degree.
C./RH=60% and 40.degree. C./RH=75% after one month (T1) and three
months (T2). Samples were analyzed using a HPLC method as described
in Example 2.
[0133] Referring to the data in tables 11 and 12, the Blend Combo
Drug Product was characterized by amounts of the substances
corresponding to HPLC peaks 1-12 that were less than the applicable
drug product specification, indicating stabilization of the
ceftolozane in the presence of about 481 mg of sodium chloride per
1,000 mg of ceftolozane active.
Example 5
Improvement in the Purity of Ceftolozane CXA-201 Pharmaceutical
Compositions with Varying Amounts of Sodium Chloride
[0134] A stability study was carried out at 60.degree. c. as
described in Example 3. The sodium chloride content in the CXA-201
compositions is described in Table 13, FIG. 11. The HPLC data at
60.degree. C. are summarized in Table 14-17, FIGS. 12-15.
* * * * *