U.S. patent application number 14/522893 was filed with the patent office on 2015-02-12 for tazobactam and ceftolozane antibiotic compositions.
The applicant listed for this patent is CALIXA THERAPEUTICS, INC.. Invention is credited to Giuseppe Alessandro Donadelli, Giovanni Fogliato, Chun Jiang, Dario Resemini.
Application Number | 20150045336 14/522893 |
Document ID | / |
Family ID | 51522651 |
Filed Date | 2015-02-12 |
United States Patent
Application |
20150045336 |
Kind Code |
A1 |
Jiang; Chun ; et
al. |
February 12, 2015 |
TAZOBACTAM AND CEFTOLOZANE ANTIBIOTIC COMPOSITIONS
Abstract
This disclosure provides pharmaceutical compositions comprising
ceftolozane, pharmaceutical compositions comprising ceftolozane and
tazobactam, methods of making those compositions, and related
methods and uses of these compositions.
Inventors: |
Jiang; Chun; (Hillsborough,
CA) ; Fogliato; Giovanni; (Barzana (BG), IT) ;
Donadelli; Giuseppe Alessandro; (Casalpusterlengo (Lodi),
IT) ; Resemini; Dario; (Milan, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CALIXA THERAPEUTICS, INC. |
LEXINGTON |
MA |
US |
|
|
Family ID: |
51522651 |
Appl. No.: |
14/522893 |
Filed: |
October 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14214367 |
Mar 14, 2014 |
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14522893 |
|
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61793007 |
Mar 15, 2013 |
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61792092 |
Mar 15, 2013 |
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Current U.S.
Class: |
514/192 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 31/545 20130101; A61K 31/546 20130101; A61K 47/183 20130101;
A61K 31/43 20130101; A61K 47/02 20130101; A61K 31/198 20130101;
A61K 2300/00 20130101; A61K 31/431 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/431 20130101; A61K 31/546 20130101;
A61K 31/198 20130101; A61K 9/19 20130101 |
Class at
Publication: |
514/192 |
International
Class: |
A61K 9/19 20060101
A61K009/19; A61K 31/546 20060101 A61K031/546; A61K 31/431 20060101
A61K031/431 |
Claims
1. A composition comprising tazobactam combined with ceftolozane
that is lyophilized in the absence of tazobactam.
2. The composition of claim 1, wherein the lyophilized ceftolozane
is ceftolozane sulfate.
3. The composition of claim 1, wherein the lyophilized ceftolozane
is a ceftolozane compound of formula (I) prior to lyophilization:
##STR00007##
4. The composition of claim 3, wherein the lyophilized ceftolozane
is obtained by a process comprising: a. forming a solution
comprising the compound of formula (I) without tazobactam; b.
adjusting the pH of the solution to a pH of about 6.0; and c.
lyophilizing the solution to obtain the lyophilized
ceftolozane.
5. The composition of claim 1, wherein the composition has a pH of
6.0 upon reconstitution with saline.
6. The composition of claim 1, comprising about 30.4%-37.2% by
weight ceftolozane active.
7. The composition of claim 1, comprising about 15.2%-18.6% by
weight tazobactam active.
8. The composition of claim 1, comprising ceftolozane and
tazobactam (as free acid) in a 2:1 weight ratio.
9. The composition of claim 1, comprising
(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-1-methyle-
thoxyimino]acetamido]-3-cephem-4-carboxylic acid) and tazobactam
(as free acid) in a about a 2:1 weight ratio.
10. The composition of claim 1, comprising
(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 tazobactam (as free acid) in a about a 2:1
weight ratio.
11. A ceftolozane/tazobactam composition comprising ceftolozane
combined with tazobactam, wherein the ceftolozane and the
tazobactam are individually freeze-dried prior to combination.
12. The ceftolozane/tazobactam composition of claim 11, wherein the
ceftolozane and the tazobactam are blended to form a
ceftolozane/tazobactam composition comprising about 30.4%-37.2% by
weight ceftolozane active and about 15.2%-18.6% by weight
tazobactam (as free acid).
13. The ceftolozane/tazobactam composition of claim 11, wherein the
ceftolozane is ceftolozane sulfate.
14. The ceftolozane/tazobactam composition of claim 11, wherein the
ceftolozane is obtained by a process comprising freeze-drying an
aqueous solution comprising the ceftolozane in the absence of
tazobactam at a pH of 6.0-7.0.
15. The ceftolozane/tazobactam composition of claim 11, wherein the
composition has a pH of about 6.0 upon reconstitution in
saline.
16. The ceftolozane/tazobactam composition of claim 11 in a unit
dosage form comprising a total of 1000 mg ceftolozane and a total
of 500 mg tazobactam (as free acid) in a unit dosage form.
17. The ceftolozane/tazobactam composition of claim 11, wherein the
lyophilized ceftolozane is a ceftolozane compound of formula (I)
prior to lyophilization: ##STR00008##
18. A ceftolozane/tazobactam composition comprising ceftolozane
combined with tazobactam in a 2:1 weight ratio between the
ceftolozane active and the tazobactam active, wherein the
ceftolozane is obtained from a solution comprising ceftolozane in
the absence of tazobactam.
19. The ceftolozane/tazobactam composition of claim 18, wherein the
ceftolozane in the solution is a ceftolozane compound of formula
(I): ##STR00009##
20. The ceftolozane/tazobactam composition of claim 18, wherein the
ceftolozane is obtained by lyophilizing the solution in the absence
of tazobactam.
21. The ceftolozane/tazobactam composition of claim 20, wherein the
pH of the solution is adjusted to about 6.0 prior to
lyophilization.
22. The ceftolozane/tazobactam composition of claim 18, obtained by
a process comprising the steps of: a. lyophilizing the solution
comprising ceftolozane in the absence of tazobactam to obtain a
lyophilized ceftolozane composition; and b. combining the
lyophilized ceftolozane composition and with tazobactam to form the
pharmaceutical composition.
23. The pharmaceutical composition of claim 22, wherein the
ceftolozane is ceftolozane sulfate.
24. The pharmaceutical composition of claim 22, wherein the
tazobactam is tazobactam sodium.
25. The pharmaceutical composition of claim 22, comprising
lyophilizing the ceftolozane at a pH of about 6.0.
26. The composition of claim 25, comprising forming the solution
with a ceftolozane compound of formula (I): ##STR00010## and
adjusting the pH of the ceftolozane solution to about 6.0 prior to
lyophilization.
27. A pharmaceutical composition obtained by: a. adjusting the pH
of a solution comprising a compound of formula (I) to a pH of about
5.0-7.0 in the absence of tazobactam; ##STR00011## b. freeze-drying
the solution to obtain a ceftolozane composition; and c. combining
the ceftolozane composition and with tazobactam to form the
pharmaceutical composition.
28. (canceled)
29. The pharmaceutical composition of claim 27, wherein the
ceftolozane composition is ceftoloazne sulfate.
30. The pharmaceutical composition of claim 29, wherein the
lyophilized tazobactam is tazobactam sodium.
31. The pharmaceutical composition of claim 29, wherein the
pharmaceutical composition comprises ceftolozane active and
tazobactam active in a 2:1 weight ratio.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/214,367, filed Mar. 14, 2014, which claims priority to U.S.
Provisional Application No. 61/792,092, filed Mar. 15, 2013, and
U.S. Provisional Application No. 61/793,007, filed Mar. 15, 2013.
The contents of these applications are incorporated hereby by
reference in their entireties.
TECHNICAL FIELD
[0002] This disclosure relates to pharmaceutical compositions
comprising ceftolozane, pharmaceutical compositions comprising
tazobactam and ceftolozane, methods of making those compositions,
and related methods and uses thereof.
BACKGROUND
[0003] The cephalosporin
(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 (also referred to as ceftolozane, "CXA-101" or
(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-1-methyle-
thoxyimino]acetamido]-3-cephem-4-carboxylic acid) is an
antibacterial agent. 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. Ceftolozane can be
combined (e.g., mixed) with a .beta.-lactamase inhibitor ("BLI"),
such as tazobactam. Tazobactam is a BLI against Class A and some
Class C .beta.-lactamases, with well-established in vitro and in
vivo efficacy in combination with active .beta.-lactam
antibiotics.
[0004] Antibiotic pharmaceutical compositions can include a
beta-lactam compound having antibiotic properties (i.e., an
antibiotic compound possessing one or more beta-lactam moieties)
and a BLI, such as tazobactam. Beta-lactam compounds can be
formulated with and/or administered in combination with,
beta-lactamase inhibiting compounds (e.g., tazobactam and salts
thereof) in order to mitigate the effects of bacterial
beta-lactamases. For example, the combination of ceftolozane, and
tazobactam in a 2:1 weight ratio is an antibiotic pharmaceutical
composition ("CXA-201") formulated for parenteral administration.
CXA-201 displays potent antibacterial activity in vitro against
common Gram-negative and selected Gram-positive organisms. CXA-201
is a broad-spectrum antibacterial with in vitro activity against
Enterobacteriaceae including strains expressing extended spectrum
.beta.-lactamases-resistant (MIC.sub.90=1 .mu.g/mL), as well as
Pseudomonas aeruginosa (P. aeruginosa) including multi-drug
resistant strains (MIC.sub.90=2 .mu.g/mL). CXA-201 is a combination
antibacterial with activity against many Gram-negative pathogens
known to cause intrapulmonary infections, including nosocomial
pneumonia caused by P. aeruginosa.
SUMMARY OF THE INVENTION
[0005] Provided herein are pharmaceutical compositions comprising
ceftolozane, methods of making the compositions, and pharmaceutical
compositions prepared using ceftolozane. Also provided herein are
pharmaceutical compositions comprising ceftolozane and tazobactam,
methods of making those compositions, and pharmaceutical
compositions prepared using ceftolozane and tazobactam. Methods of
making and related uses of these combinations are also
provided.
[0006] In one aspect, provided herein is pharmaceutical composition
comprising sodium chloride 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 at a weight ratio of 476:1000 to
500:1000.
[0007] In one particular embodiment, the sodium chloride 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 are at a weight ratio of
476:1000.
[0008] In another particular embodiment, the sodium chloride 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 are at a weight ratio of
480:1000.
[0009] In a further embodiment, the sodium chloride 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 are at a weight ratio of 481:1000
to 500:1000.
[0010] In one particular embodiment, the sodium chloride 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 are at a weight ratio of
481:1000.
[0011] In yet another particular embodiment, the sodium chloride
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 are at a weight ratio of
485:1000.
[0012] In certain embodiments, the pharmaceutical compositions
comprise less than 4% by weight of water.
[0013] In another aspect, provided herein is a pharmaceutical
composition comprising sodium chloride 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 at a molar ratio of 8.14:1 to
8.56:1.
[0014] In one embodiment, provided herein is a pharmaceutical
composition comprising sodium chloride 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 at a molar ratio of 8.23:1 to
8.56:1.
[0015] In another aspect, provided herein is a vial containing an
antibiotic composition for treating an infection, wherein the
antibiotic composition comprises sodium chloride 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 at a weight ratio of 476:1000 to
500:1000.
[0016] In one particular embodiment of the vial, the antibiotic
composition comprises sodium chloride 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 at a weight ratio of 476:1000.
[0017] In another particular embodiment of the vial, the antibiotic
composition comprises sodium chloride 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 at a weight ratio of 480:1000.
[0018] In a further embodiment of the vial, the antibiotic
composition comprises sodium chloride 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 at a weight ratio of 481:1000 to
500:1000.
[0019] In one particular embodiment of the vial, the antibiotic
composition comprises sodium chloride 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 at a weight ratio of 481:1000.
[0020] In yet another particular embodiment of the vial, the
antibiotic composition comprises sodium chloride 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 at a weight ratio of 485:1000.
[0021] In certain embodiments of the vials described above, the
antibiotic compositions comprise less than 4% by weight of
water.
[0022] In other embodiments of the vials, the infections are caused
by bacteria selected from the group consisting of: Staphylococcus
aureus, Escherichia coli, Acinetobacter baumanii, Haemophilus
influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
[0023] In other embodiments of the vials, the infections are
selected from the group consisting of nosocomial pneumonia,
complicated intra-abdominal infections and complicated urinary
tract infections.
[0024] In still another aspect, provided herein is a method of
preparing a composition comprising sodium chloride 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, wherein the method comprises
combining sodium chloride with
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 at a weight ratio of 476:1000 to
500:1000 to form a mixture, followed by lyophilization of the
mixture.
[0025] In one embodiment, the method comprises combining sodium
chloride with
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-
ethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-py-
razolio}methyl-3-cephem-4-carboxylate at a weight ratio of 481:1000
to 500:1000 to form a mixture, followed by lyophilization of the
mixture.
[0026] In a further aspect, provided herein is a method of
preparing a composition comprising sodium chloride 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, wherein the method comprises
combining sodium chloride with
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 at a molar ratio of 8.14:1 to
8.56:1 to form a mixture, followed by lyophilization of the
mixture.
[0027] In one embodiment, the method comprises combining sodium
chloride with
7.beta.-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methyl-
ethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-py-
razolio}methyl-3-cephem-4-carboxylate at a molar ratio of 8.23:1 to
8.56:1 to form a mixture, followed by lyophilization of the
mixture.
[0028] In another aspect, provided herein is a composition formed
by any one of the methods provided herein.
[0029] In yet another aspect, provided herein is a method for the
treatment of a bacterial infection in a mammal, wherein the method
comprises administering to said mammal a therapeutically effective
amount of a pharmaceutical composition provided herein.
[0030] In one embodiment of the treatment method, the bacterial
infection is caused by bacteria selected from the group consisting
of: Staphylococcus aureus, Escherichia coli, Acinetobacter
baumanii, Haemophilus influenzae, Klebsiella pneumonia, and
Pseudomonas aeruginosa.
[0031] In one embodiment of the treatment method, the bacterial
infection is selected from the group consisting of nosocomial
pneumonia, complicated intra-abdominal infections and complicated
urinary tract infections.
BRIEF DESCRIPTION OF THE FIGURES
[0032] FIG. 1 is a graph showing the lyophilization program used in
the manufacturing of the monoproduct for injection.
[0033] FIG. 2 is a flowchart showing the manufacturing process for
a CXA-101 composition for injection.
[0034] FIG. 3 is a flowchart showing the manufacturing steps for a
pharmaceutical composition comprising ceftolozane and sodium
chloride.
[0035] FIG. 4 is a flowchart showing the manufacturing process for
preparing a CXA-201 composition comprising ceftolozane (referred to
as CXA-101), tazobactam, and sodium chloride.
[0036] FIG. 5 is a reference HPLC chromatogram showing the peaks of
ceftolozane (also referred to as CXA-101) and related
impurities.
[0037] FIG. 6 is a plot of the data points from Table 5, showing
the purity of the ceftolozane in CXA-101 compositions at 60.degree.
C. on day 0, day 1, day 3, and day 7, as measured by the HPLC
method described in Example 4, wherein the CXA-101 compositions
comprise ceftolozane and sodium chloride. The amount of the sodium
chloride in the CXA-101 compositions is 481.0 mg sodium chloride
per 1000 mg of ceftolozane (* marks), 190.0 mg sodium chloride per
1000 mg of ceftolozane (filled squares), 125.0 mg sodium chloride
per 1000 mg of ceftolozane (filled diamonds), 75.0 mg sodium
chloride per 1000 mg of ceftolozane (filled triangles), and 50.0 mg
sodium chloride per 1000 mg of ceftolozane (X marks).
[0038] FIG. 7 is a plot of the data points from Table 6, showing
the peak area of the impurity peak 1 in CXA-101 compositions at
60.degree. C. on day 0, day 1, day 3, and day 7, as measured by the
HPLC method described in Example 4, wherein the CXA-101
compositions comprise ceftolozane and sodium chloride. The amount
of the sodium chloride in the CXA-101 compositions is 481.0 mg
sodium chloride per 1000 mg of ceftolozane (* marks), 190.0 mg
sodium chloride per 1000 mg of ceftolozane (filled squares), 125.0
mg sodium chloride per 1000 mg of ceftolozane (filled diamonds),
75.0 mg sodium chloride per 1000 mg of ceftolozane (filled
triangles), and 50.0 mg sodium chloride per 1000 mg of ceftolozane
(X marks).
[0039] FIG. 8 is a plot of the data points from Table 7, showing
the total peak area of the impurity with a RRT of 0.43 and the
impurity peak 3 in CXA-101 compositions at 60.degree. C. on day 0,
day 1, day 3, and day 7, as measured by the HPLC method described
in Example 4, wherein the CXA-101 compositions comprise ceftolozane
and sodium chloride. The amount of the sodium chloride in the
CXA-101 compositions is 481.0 mg sodium chloride per 1000 mg of
ceftolozane (* marks), 190.0 mg sodium chloride per 1000 mg of
ceftolozane (filled squares), 125.0 mg sodium chloride per 1000 mg
of ceftolozane (filled diamonds), 75.0 mg sodium chloride per 1000
mg of ceftolozane (filled triangles), and 50.0 mg sodium chloride
per 1000 mg of ceftolozane (X marks).
[0040] FIG. 9 is a plot of the data points from Table 8, showing
the peak area of the impurity peak 7 in CXA-101 compositions at
60.degree. C. on day 0, day 1, day 3, and day 7, as measured by the
HPLC method described in Example 4, wherein the CXA-101
compositions comprise ceftolozane and sodium chloride. The amount
of the sodium chloride in the CXA-101 compositions is 481.0 mg
sodium chloride per 1000 mg of ceftolozane (* marks), 190.0 mg
sodium chloride per 1000 mg of ceftolozane (filled squares), 125.0
mg sodium chloride per 1000 mg of ceftolozane (filled diamonds),
75.0 mg sodium chloride per 1000 mg of ceftolozane (filled
triangles), and 50.0 mg sodium chloride per 1000 mg of ceftolozane
(X marks).
[0041] FIG. 10 is a plot of the data points from Table 10, showing
the purity of ceftolozane in CXA-201 compositions at 60.degree. C.
on day 0, day 1, day 3, and day 7, as measured by the HPLC method
described in Example 4, wherein the CXA-201 compositions comprise
ceftolozane, tazobactam, and sodium chloride. The amount of the
sodium chloride in the CXA-201 compositions is 481.0 mg sodium
chloride per 1000 mg of ceftolozane (X marks), 125.0 mg sodium
chloride per 1000 mg of ceftolozane (filled diamonds), 75.0 mg
sodium chloride per 1000 mg of ceftolozane (filled squares), and
50.0 mg sodium chloride per 1000 mg of ceftolozane (filled
triangles).
[0042] FIG. 11 is a plot of the data points from Table 11, showing
the peak area of the impurity peak 1 in CXA-201 compositions at
60.degree. C. on day 0, day 1, day 3, and day 7, as measured by the
HPLC method described in Example 4, wherein the CXA-201
compositions comprise ceftolozane, tazobactam, and sodium chloride.
The amount of the sodium chloride in the CXA-201 compositions is
481.0 mg sodium chloride per 1000 mg of ceftolozane (X marks),
125.0 mg sodium chloride per 1000 mg of ceftolozane (filled
diamonds), 75.0 mg sodium chloride per 1000 mg of ceftolozane
(filled squares), and 50.0 mg sodium chloride per 1000 mg of
ceftolozane (filled triangles).
[0043] FIG. 12 is a plot of the data points from Table 12, showing
the total peak area of the impurity with a RRT of 0.43 and the
impurity peak 3 in CXA-201 compositions at 60.degree. C. on day 0,
day 1, day 3, and day 7, as measured by the HPLC method described
in Example 4, wherein the CXA-201 compositions comprise
ceftolozane, tazobactam, and sodium chloride. The amount of the
sodium chloride in the CXA-201 compositions is 481.0 mg sodium
chloride per 1000 mg of ceftolozane (X marks), 125.0 mg sodium
chloride per 1000 mg of ceftolozane (filled diamonds), 75.0 mg
sodium chloride per 1000 mg of ceftolozane (filled squares), and
50.0 mg sodium chloride per 1000 mg of ceftolozane (filled
triangles).
[0044] FIG. 13 is a plot of the data points from Table 13, showing
the peak area of the impurity peak 7 in CXA-201 compositions at
60.degree. C. on day 0, day 1, day 3, and day 7, as measured by the
HPLC method described in Example 4, wherein the CXA-201
compositions comprise ceftolozane, tazobactam, and sodium chloride.
The amount of the sodium chloride in the CXA-201 compositions is
481.0 mg sodium chloride per 1000 mg of ceftolozane (X marks),
125.0 mg sodium chloride per 1000 mg of ceftolozane (filled
diamonds), 75.0 mg sodium chloride per 1000 mg of ceftolozane
(filled squares), and 50.0 mg sodium chloride per 1000 mg of
ceftolozane (filled triangles).
[0045] FIG. 14 is a manufacturing flowchart showing CXA-201
development using a co-lyophilization process, as described
herein.
[0046] FIG. 15 is the formula of the impurity RRT 1.22, which has
been identified to be a degradation product formed by a reaction
between ceftolozane and formylacetic acid, a degradation product of
tazobactam as illustrated in Marunaka et al. (Chem. Pharm. Bull.
1988, Vol. 36 (11), pp. 4478-4487).
DETAILED DESCRIPTION OF THE INVENTION
[0047] Pharmaceutical compositions comprising one or more drug
substances or excipients can be prepared in a variety of ways,
including, for example, blending and lyophilization (also known as
"co-lyophilization"). 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).
[0048] The formulation of pharmaceutical compositions can be
selected to minimize decomposition of the constituent drug
substances and to produce a composition that is stable under a
variety of storage conditions.
[0049] Surprisingly, pharmaceutical compositions comprising
ceftolozane and 125 to 1000 mg sodium chloride per 1000 mg of
ceftolozane have been observed to exhibit better chemical stability
over the course of time and/or in the presence of heat, and less
impurities than those pharmaceutical compositions comprising
ceftolozane and less sodium chloride (i.e., less than 125 mg sodium
chloride per 1000 mg of ceftolozane). In particular embodiments
described herein (see, e.g., Example 5), the pharmaceutical
compositions comprising ceftolozane and 125 to 500 mg sodium
chloride per 1000 mg of ceftolozane have been found to be more
stable than the compositions comprising ceftolozane and less than
125 mg sodium chloride per 1000 mg of ceftolozane.
[0050] It has also been observed that pharmaceutical compositions
comprising ceftolozane, tazobactam, and 125 to 1000 mg sodium
chloride per gram of ceftolozane exhibit better chemical stability
and less impurities than those pharmaceutical compositions
comprising ceftolozane and tazobactam, but less sodium chloride. In
particular embodiments described herein (see, e.g., Example 5), the
pharmaceutical compositions comprising ceftolozane, tazobactam, and
125 to 500 mg sodium chloride per 1000 mg of ceftolozane have been
found to be more stable than the compositions comprising
ceftolozane, tazobactam, and less than 125 mg sodium chloride per
gram of ceftolozane. Accordingly, in one aspect, provided herein is
a pharmaceutical composition comprising ceftolozane and 125 to 1000
mg sodium chloride per 1000 mg of ceftolozane. In another aspect,
the invention is a pharmaceutical composition comprising
ceftolozane and tazobactam, further comprising 125 to 1000 mg
sodium chloride per 1000 mg of ceftolozane. In certain embodiments
of both of these aspects, the pharmaceutical composition comprises
125 to 500 mg sodium chloride per 1000 mg of ceftolozane.
[0051] As used herein, "125 to 1000 mg sodium chloride per 1000 mg
of ceftolozane" refers to a ratio of sodium chloride to
ceftolozane. For example, "125 to 1000 mg sodium chloride per 1000
mg of ceftolozane" includes, for example, 62.5 to 500 mg sodium
chloride per 500 mg of ceftolozane, as well as, for example, 25 to
200 mg sodium chloride per 200 mg ceftolozane, etc.
[0052] In addition, surprisingly, pharmaceutical compositions
comprising ceftolozane and tazobactam prepared by blending these
two compounds, wherein the ceftolozane and tazobactam are
individually lyophilized prior to blending, have been observed to
exhibit beneficial properties, including reduced levels of
impurities. In a particular embodiment described herein (see, e.g.,
Example 3), the pharmaceutical composition prepared by blending
ceftolozane and tazobactam, wherein the ceftolozane and tazobactam
were individually lyophilized prior to blending, lead to a much
lower concentration of the following degradation product:
##STR00001##
[0053] This degradation product, having a Relative Retention Time
(RRT) of 1.22 (relative to ceftolozane using the HPLC method
described in Example 4), which is also referred to as "the Impurity
RRT 1.22", has been identified to be a degradation product formed
by a reaction between ceftolozane and formylacetic acid, a
degradation product of tazobactam as illustrated in Marunaka et al.
(Chem. Pharm. Bull. 1988, Vol. 36 (11), pp. 4478-4487).
[0054] In contrast, a much greater amount of this impurity was
found in compositions of ceftolozane and tazobactam, wherein the
compositions were formed through co-lyophilization, i.e., the
ceftolozane and tazobactam were combined and lyophilized together,
as opposed to being individually lyophilized (see, e.g., Example
7).
[0055] Accordingly, in one aspect, provided herein is a
pharmaceutical composition comprising ceftolozane and tazobactam,
wherein the composition has less than 0.1% by weight of the
following compound:
##STR00002##
[0056] In an embodiment, the pharmaceutical composition has less
than 0.05% by weight of the following compound:
##STR00003##
Ceftolozane
[0057] The compound
5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-2-{[(6R,7R)-7-({(2Z)-2-(5-amin-
o-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)--
2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-methyl-1-
H-pyrazolium mono sulfate (also known also as ceftolozane sulfate,
FR264205, "CXA-101") is a cephalosporin compound (shown below), the
synthesis of which is described in U.S. Pat. No. 7,129,232, wherein
the compound is also named
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. As used herein, the term
"ceftolozane" may also refer to "ceftolozane sulfate".
##STR00004##
Pharmaceutical Compositions
[0058] The term "pharmaceutical composition" includes preparations
suitable for administration to mammals, e.g., humans. When the
compounds of the present invention are administered as
pharmaceuticals to mammals, e.g., humans, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1% to
99.9% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0059] The pharmaceutical compositions described herein can be
formulated to have any concentration desired (i.e., any
concentration of tazobactam, or a hydrate or solvate thereof, and
any concentration of ceftolozane). In some embodiments, the
composition is formulated such that it comprises at least a
therapeutically effective amount of both compounds (i.e., a
therapeutically effective amount of the combination of tazobactam,
or a hydrate or solvate thereof, and ceftolozane).
[0060] Pharmaceutical compositions include those suitable for
parenteral (including intravenous) administration, although the
most suitable route will depend on the nature and severity of the
condition being treated. The compositions may be conveniently
presented in unit dosage form, and prepared by any of the methods
well known in the art of pharmacy.
[0061] 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.
[0062] The pharmaceutical compositions disclosed herein can be
prepared via blending. As used herein, blending refers to a process
comprising physically combining ceftolozane and tazobactam, wherein
each of ceftolozane and tazobactam have been individually
lyophilized (i.e., lyophilized in the absence of one another) prior
to being combined.
[0063] In a particular embodiment, the pharmaceutical compositions
described herein are formulated for parenteral administration. In
another particular embodiment, the pharmaceutical compositions
described herein are formulated for administration by intravenous
injection or infusion.
[0064] In one aspect, provided herein is a pharmaceutical
composition comprising tazobactam and ceftolozane.
[0065] In another aspect, provided herein are pharmaceutical
compositions prepared according to the following methods.
[0066] In one embodiment, provided herein is a pharmaceutical
composition comprising sodium chloride 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 at a weight ratio of 476:1000 to
500:1000, or at a molar ratio of 8.14:1 to 8.56:1.
[0067] In another embodiment, provided herein is a pharmaceutical
composition comprising sodium chloride 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 at a weight ratio of 481:1000 to
500:1000, or at a molar ratio of 8.23:1 to 8.56:1.
[0068] In certain particular embodiments, provided herein are
pharmaceutical compositions comprising sodium chloride 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 at a weight ratio of 476:1000, or
480:1000, or 481:1000, or 485:1000.
[0069] In certain embodiments, the pharmaceutical compositions
further comprise tazobactam sodium at a quantity equivalent of 500
mg of tazobactam free acid in a lyophilized powder form per 1000 mg
of ceftolozane (anhydrous, free base equivalent).
[0070] In certain embodiments, the pharmaceutical compositions
comprise less than 4% by weight of water.
[0071] In other embodiments, the pharmaceutical compositions are
reconstituted with sterile saline and/or sterile water for
injection.
[0072] In a further embodiment, provided herein is a vial
containing one of the pharmaceutical compositions described above
for treating an infection. In certain embodiments, the infections
are caused by bacteria selected from the group consisting of:
Staphylococcus aureus, Escherichia coli, Acinetobacter baumanii,
Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas
aeruginosa. In other embodiments, the infections are selected from
the group consisting of nosocomial pneumonia, complicated
intra-abdominal infections and complicated urinary tract
infections.
Methods of Making Pharmaceutical Compositions
[0073] In one aspect, provided herein is a method of preparing a
composition comprising ceftolozane and sodium chloride, comprising
combining sodium chloride with ceftolozane, wherein 125-1000 mg
sodium chloride per 1000 mg of ceftolozane is combined, followed by
lyophilization of the sodium chloride ceftolozane mixture.
[0074] In another aspect, provided herein is a method of preparing
a composition comprising sodium chloride, tazobactam, and
ceftolozane, comprising combining sodium chloride, tazobactam, and
ceftolozane, wherein 125-1000 mg sodium chloride per 1000 mg of
ceftolozane is combined, followed by lyophilization of the mixture
of sodium chloride, tazobactam, and ceftolozane.
[0075] In one embodiment of these methods, 125-500 mg sodium
chloride per 1000 mg of ceftolozane is combined.
[0076] In another embodiment of these methods, the method further
comprises lyophilizing ceftolozane in the absence of tazobactam. In
yet another embodiment of the methods described above, the method
can further comprise lyophilizing tazobactam in the absence of
ceftolozane.
[0077] In a further embodiment of these methods, the method can
comprise the steps of: (1) adding 125 to 1000 mg sodium chloride
per 1000 mg of ceftolozane followed by lyophilizing ceftolozane;
(2) lyophilizing tazobactam; and (3) combining the separately
lyophilized ceftolozane and tazobactam to obtain said
pharmaceutical composition. In yet a further embodiment, the method
comprises adding 125 to 500 mg sodium chloride per 1000 mg of
ceftolozane.
[0078] In another aspect, provided herein is a method of making a
pharmaceutical composition, comprising combining tazobactam and
ceftolozane. In one embodiment, the method further comprises
lyophilizing ceftolozane in the absence of tazobactam. In another
embodiment, the method further comprises lyophilizing tazobactam in
the absence of ceftolozane.
[0079] In a further embodiment, the method comprises the steps of:
(1) lyophilizing ceftolozane; (2) lyophilizing tazobactam; and (3)
combining the separately lyophilized ceftolozane and tazobactam to
obtain said pharmaceutical composition. In one embodiment, the
method further comprises packaging the blended powder into
Sterbags.RTM..
[0080] In one embodiment of the method, and above embodiments, the
molar ratio of tazobactam to ceftolozane in the mixture is in the
range of 1:3 to 3:1. In another embodiment, the molar ratio of
tazobactam to ceftolozane in the mixture is in the range of 1:2 to
2:1. In another embodiment, the molar ratio of tazobactam to
ceftolozane in the mixture is in the range of 1:0.9 to 0.9:1. In a
particular embodiment, the ratio of tazobactam to ceftolozane in
the mixture is about 0.9:1. In another particular embodiment, the
ratio of tazobactam to ceftolozane in the mixture is about 1:2.
Methods of Treatment
[0081] Tazobactam inhibits or decreases the activity of
beta-lactamases (e.g., bacterial beta-lactamases), and can be
combined with beta-lactam compounds (e.g., antibiotics), thereby
broadening the spectrum of the beta-lactam compound and increasing
the beta-lactam compound's efficacy against organisms that produce
beta-lactamase. A compound or a composition possesses efficacy
against an organism if it kills or weakens the organism, or
inhibits or prevents reproduction the organism.
[0082] 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. In
another 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 tazobactam and
ceftolozane. In certain embodiments of the above methods, the
bacterial infection is caused by an extended-spectrum
beta-lactamase-producing organism. In certain embodiments, the
bacterial infection is caused by an antibiotic-resistant
organism.
[0083] In another 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 comprising ceftolozane. In yet another
aspect, the invention 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
comprising both tazobactam and ceftolozane. In certain embodiments
of the above methods, the bacterial infection is caused by an
extended-spectrum beta-lactamase-producing organism. In certain
embodiments, the bacterial infection is caused by an
antibiotic-resistant organism.
[0084] In certain embodiments of both aspects, the pharmaceutical
composition further comprises 125 to 1000 mg sodium chloride per
1000 mg of ceftolozane. In some other embodiments, the
pharmaceutical composition comprises 125 to 500 mg sodium chloride
per 1000 mg of ceftolozane.
[0085] In another 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 comprising tazobactam, ceftolozane,
and less than 0.1% by weight of the following compound:
##STR00005##
[0086] In one embodiment of the treatment method, the
pharmaceutical composition comprises tazobactam, ceftolozane, and
less than 0.05% by weight of the following compound:
##STR00006##
[0087] 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).
[0088] In certain embodiments of the methods described herein, the
bacterial infection resulting from beta-lactamase-producing
organisms are treated or controlled. Non-limiting examples of
beta-lactamase-producing organisms include:
[0089] (1) ESBL (extended-spectrum beta-lactamase)-producing
organisms selected from the group consisting of Enterobacteriaceae
spp.: Escherichia coli, Klebsiella spp. (including K. pneumoniae
and K. oxytoca), Proteus mirabilis, Proteus vulgaris, Enterobacter
spp., Serratia spp., Citrobacter spp., Pseudomonas spp.,
Acinetobacter spp.) and Bacteroides spp.;
[0090] (2) CSBL (conventional-spectrum beta-lactamase)-producing
organisms, known to those of skill in the art; and
[0091] (3) Inducible-AmpC-type beta-lactamases, such as Citrobacter
spp., Serratia spp., Morganella morganii, Proteus vulgaris, and
Enterobacter cloacae.
[0092] In certain embodiments of the methods described herein,
bacterial infection is associated with one or more of the following
conditions:
[0093] Community-acquired pneumonia (moderate severity only) caused
by piperacillin-resistant, beta-lactamase producing strains of
Haemophilus influenza;
[0094] 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.
[0095] Complicated intra-abdominal infections; Complicated urinary
tract infections (cUTIs); Acute Pyelonephritis; Systemic
Inflammatory Response Syndrome (SIRS).
[0096] Also provided herein is the use of tazobactam, and hydrates
and solvates thereof, in combination with ceftolozane, for the
preparation of a medicament for the treatment of bacterial
infection. The bacterial infection can result from either
gram-negative or gram-positive organisms.
[0097] 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 eliminate the disease, condition or disorder. The term
"treat" can also include treatment of a cell in vitro or an animal
model.
[0098] 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.
EXAMPLES
Example 1
Manufacturing Procedure of Mono Product for Injection
1.1. Preparation of the Compound Solution of CXA-101 Lyophilized
Product
[0099] 1) Weigh 30 kg of water for injection into the compounding
vessel;
[0100] 2) Add 100 g of citric acid, anhydrous and 150 g of sodium
bicarbonate into the compounding vessel and dissolve them with
mixing;
[0101] 3) Weigh 5,000 g potency of CXA-101 drug substance and
suspend it with mixing. (Note any generation of carbon
dioxide.)
[0102] 4) Slowly add 1,100 g of sodium bicarbonate and dissolve
CXA-101 with mixing. (Again, note any generation of carbon
dioxide.)
[0103] 5) Add 1,146 g of sodium chloride and 10,000 g of maltose,
dissolve with mixing.
[0104] 6) Purge dissolved carbon dioxide in the solution with
nitrogen until the pH of the solution does not change.
[0105] 7) Adjust the pH of the solution to 6.0.+-.0.1 with
5%-sodium bicarbonate solution.
[0106] 8) Adjust the total weight to 56,850 g (D.sub.20=1.137) with
water for injection.
[0107] 9) Confirm the pH of the compounded solution within the
range 6.0.+-.0.1.
1.2. Prefiltration and Sterile-Filtration
[0108] 10) 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 urn
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.
[0109] 11) 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 urn 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.
1.3. Processing of Vial, Stopper and Flip-Off Cap
[0110] 12) 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.
[0111] 13) 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.
[0112] 14) 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.
1.4. Filling and Partially Stoppering
[0113] 15) 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.
[0114] 16) 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.
1.5. Lyophilization to Crimping, Visual Inspection, Labeling and
Packaging
[0115] 17) After all filled and partially stoppered vials are
loaded into a lyophilizer, start the lyophilization program shown
in FIG. 1. 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.
[0116] 18) Unload the lyophilized vials from the chamber and crimp
with sterilized flip-off caps.
[0117] 19) Subject all crimped vials to visual inspection and label
and package all passed vials.
Example 2
Manufacturing Procedure of Bulk (Tray) Lyophilized Ceftolozane
[0118] 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 flowchart of the CXA-101
bulk drug product manufacturing process is presented in FIG. 3, and
described below.
I. Dissolution
[0119] 1. The prescribed amount of WFI is charged into the
dissolution reactor.
[0120] 2. A prescribed amount of citric acid is added.
[0121] 3. The solution is cooled at 5.degree. C. to 10.degree.
C.
[0122] 4. A prescribed amount of CXA-101 drug substance is added to
the solution.
[0123] 5. A prescribed amount of L-arginine is slowly added to the
solution.
[0124] 6. A check for complete dissolution is performed. Solution
pH is verified to be in the target range of 6.5 to 7.0.
[0125] 7. A prescribed amount of sodium chloride is added to the
solution.
[0126] 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.
[0127] 9. WFI is added to bring the net weight to 124.4 kg and the
solution is mixed well.
[0128] 10. Samples are withdrawn for testing of final pH.
II. Sterile Filtration
[0129] 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.
[0130] 12. The line is washed with WFI.
[0131] 13. The washing solution is passed from Step 12 through
sterile filtration.
III. Bulk Lyophilization
[0132] 14. The washing solution is loaded onto a separate shelf in
the lyophilizer (and later discarded).
[0133] 15. The solution is lyophilized until dry.
[0134] 16. The product shelf is cooled to 20.degree.
C..+-.5.degree. C.
IV. Packaging into Sterbags.RTM.
[0135] 17. The lyophilized bulk drug product powder is milled.
[0136] 18. The milled powder is sieved.
[0137] 19. The sieved powder is blended for 30 minutes.
[0138] 20. The powder is then discharged into Sterbags.RTM.
Example 3
Manufacturing of Combination Product (Tazobactam and CXA-101) by
Blending
A. Sterile Dry Blending of Bulk Lyophilized Ceftolozane and Bulk
Lyophilized Tazobactam
[0139] A low energy drum blender that agitates the material by
tumbling and also moving the bed up and down is used. A
representative process of blending is described as follows. For
CXA-101/tazobactam for injection, the blender was charged with 23.4
kg of CXA-101 bulk product, and 5.4 kg of tazobactam bulk product.
Both the CXA-101 and tazobactam were individually lyophilized
beforehand. The material was blended for 180 minutes. In-process
tests of content assay for both CXA-101 and tazobactam were
performed to assess the homogeneity using the samples of blend
materials taken from three places. The RSD for each of CXA-101 and
tazobactam content assay was no greater than 2% and the RSD for the
ratio of CXA-101/tazobactam was no greater than 2% (See Table
1).
TABLE-US-00001 TABLE 1 In-Process Testing of Blending Samples of a
CXA-201 Composition at Three Places Acceptance Results Limits (ex-
60 120 180 Test pected value) Sampling minute minute minute
Content: 30.4%-37.2% 1 34.24 34.07 34.42 Ceftolozane.sup.1 2 34.62
34.21 34.66 3 34.71 34.60 34.85 Mean .sup.3 34.52 34.30 34.64 RSD %
0.72 0.80 0.63 Content: 15.2%-18.6% 1 17.96 18.20 17.12
Tazobactam.sup.2 2 16.90 18.26 16.51 3 17.27 16.93 17.02 Mean
.sup.3 17.38 17.80 16.89 RSD % 3.10 4.22 1.96 Ratio of 2.00.sup.4 1
1.91 1.87 2.01 Content (w/w) 2 2.05 1.87 2.10 ceftolozane/ 3 2.01
2.04 2.05 tazobactam Mean .sup.3 1.99 1.93 2.05 RSD % 3.69 5.12 2.2
RSD = relative standard deviation .sup.1Theoretical value: 33.96%
Acceptance limits are 90%-110% of the theoretical value.
.sup.2Theoretical value: 16.99% Acceptance limits are 90%-110% of
the theoretical value. .sup.3 Three samples are taken at each time
point at three places to measure the percentage by weight of
ceftolozane and tazobactam. The "Mean" is the average of the
percentages or the weight ratios of Ceftolozane/tazobactam.
.sup.4Acceptance limits were established based on batch
history.
B. Packaging into Sterbags.RTM.
[0140] The blended powder is then discharged into
Sterbags.RTM..
C. Finished Drug Product
[0141] The flow chart of the fill and finish process for the final
drug product, CXA-101/tazobactam for injection, 1000 mg/500 mg, is
presented in FIG. 4. Glass vials are washed with WFI and
depyrogenated in a Class 100 depyrogenation tunnel at a temperature
of 320.degree. C. Pre-washed and pre-siliconized stoppers are
autoclaved for 40 minutes at 121.degree. C. The bulk drug product
is packaged in a Sterbag.RTM. system comprised of three bags. The
outer bag is cleaned with disinfectant in a Class 10,000 clean
room. The bag system is placed in a pass-through UV box where it is
subjected to UV radiation (>20 .mu.W/cm.sup.2) for 20 minutes to
sterilize the surface of the outer bag. The outer bag is removed
and left in the UV box. The middle bag is placed in a Class A
laminar airflow (LAF) hood. The sterile middle bag is removed under
LAF. The sterile, bottle-shaped inner bag is then placed in a
sterile stainless steel carrier and attached to the filling
machine.
[0142] Sterile bulk CXA-101/tazobactam drug product is filled under
a nitrogen blanket into 30-mL, Type I clear glass vials. The
sterile drug product is gravity-fed into the filling machine under
LAF. Vial fill weights are periodically checked throughout the
filling operation to ensure proper operation of the filling line.
Filling and stoppering operations are performed under Class 100 LAF
conditions. Capping and vial washing are done in the Class 10,000
clean room.
Example 4
Analytical HPLC Method
A. Operative Conditions
TABLE-US-00002 [0143] 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 10 .mu.L volume Oven
45.degree. C. Temperature Run Time 85 minutes
Gradient Profile:
TABLE-US-00003 [0144] 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.
[0145] 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).
[0146] Mobile phase was then made by mixing sodium perchlorate
buffer solution (pH 2.5) and acetonitrile in the ratio 90:10
(v/v).
[0147] 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.
[0148] Sample solution: dissolve 20.0 mg, exactly weighed, of a
sample, in 20.0 mL of water (prepare just before injection into
HPLC system).
[0149] 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
[0150] 1. Inject blank (water) 2. Inject system suitability
solution and check for tailing factor and theoretical plate number
for CXA-101 peak: [0151] The tailing factor must not be greater
than 1.5 [0152] Theoretical plates number must not be less than
10000 3. Inject sample solution 4. Inject system suitability
solution and check for tailing factor and theoretical plate number
for CXA-101 peak.
[0153] The tailing factor must not be greater than 1.5
[0154] 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 FIG. 5
or, alternatively, on the basis of the following RRT values:
TABLE-US-00004 Impurity RRT Peak 1 (P1) ~0.1 Peak 2 (P2) ~0.2 Peak
3 (P3) ~0.4 Peak 4 (P4) ~0.6 Peak 5 (P5) ~0.9 CXA-101 1.0 Peak 6
(P6) ~1.1 Peak 7 (P7) ~1.3 Peak 8 (P8) ~1.4 Peak 9 (P9) ~1.7 Peak s
10, 11 (P10, 11) ~2.3
E. Calculations
I. Report for Each Related Substance its Amount as Expressed by
Area Percent.
[0155] C i = A i .times. 100 A t + A i ##EQU00001##
[0156] wherein:
[0157] C.sub.i=Amount of related substance i in the Sample, area
%
[0158] A.sub.i=Peak area of related substance i in the Sample
chromatogram
[0159] A.sub.t=Area of CXA-101 peak in the Sample chromatogram
[0160] A.sub.t+.SIGMA.A.sub.i=Total peaks area in the Sample
chromatogram
[0161] 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:
[0162] C T = A i .times. 100 A t + A i ##EQU00002##
[0163] wherein:
[0164] C.sub.T=total impurities content in the Sample, area %
[0165] A.sub.t=area of CXA-101 peak in the sample chromatogram
[0166] .SIGMA.A.sub.i=total peak areas of impurities in the sample
chromatogram
Example 5
Stabilizing Effect of Sodium Chloride
[0167] A. Reduction of the Impurity at RT=63 minutes
[0168] A stability study was carried out at 25.degree. C., and
samples were analyzed by HPLC. High, mid, and low salt formulations
contained 480, 125, and 62.5 mg NaCl per 1000 mg of ceftolozane,
respectively. Compositions of blend Drug Product are listed in
Table 2. Test results are summarized in Table 3.
TABLE-US-00005 TABLE 2 Comparison of the CXA-201 Compositions Lot
CXA-101 NaCl Tazobactam C1 10% High Na C2 20% Mid Na C3 20% Low Na
C4 20% Mid Arginate C5 20% Low Arginate
TABLE-US-00006 TABLE 3 RT 63' Peak Area at t = 3 months, 25.degree.
C./60% RH storage 1.sup.st data 2nd data 3rd data collection
collection collection Sample Summary RT Area % RT Area % RT Area %
C1 High salt + 63.90 0.03 63.30 0.08 62.49 0.14 Tazo Na C2 Mid salt
+ 63.78 0.06 63.12 0.12 62.45 0.28 Tazo Na C3 Low salt + 63.75 0.12
63.11 0.14 62.46 0.29 Tazo Na C4 Mid salt + 63.76 0.10 63.16 0.13
62.44 0.28 Tazo Arg C5 Low salt + 63.72 0.08 63.14 0.16 62.46 0.33
Tazo Arg
[0169] Conclusion:
[0170] at the three month time point, the reduced salt formulations
were observed to be not as stable as the full salt formulation; and
trends indicate that reduction in salt causes at least 1.5-fold
greater impurity at RT=63 minutes (HPLC).
B. CXA-101 Peak Trends with NaCl
[0171] A stability study was carried out at 30.degree. C. and
60.degree. C., and samples were analyzed by HPLC. Sodium chloride
content in test samples is described in Table 4. Stability data are
summarized in Tables 5-8. The data are also plotted in FIGS. 6-9 to
show trends of total purity, peak 1, RRT 0.43+peak 3, and peak 7
with respect to NaCl.
TABLE-US-00007 TABLE 4 Sodium Chloride Content in the CXA-101
Compositions Samples NaCl content A1 481.0 mg NaCl per 1000 mg of
ceftolozane A2 190.0 mg NaCl per 1000 mg of ceftolozane A3 125.0 mg
NaCl per 1000 mg of ceftolozane A4 75.0 mg NaCl per 1000 mg of
ceftolozane A5 50.0 mg NaCl per 1000 mg of ceftolozane
TABLE-US-00008 TABLE 5 The Purity of Ceftolozane in CXA-101
Compositions with Varying Amounts of Sodium Chloride Day A1 A2 A3
A4 A5 t0/60.degree. C. 0 96.6 98.0 97.9 97.8 97.7 t0/30.degree. C.
0 98.1 97.8 97.8 97.7 1 day/60.degree. C. 1 95.9 96.9 96.5 95.7
95.5 1 day/30.degree. C. 1 98.2 97.7 97.7 97.6 3 days/60.degree. C.
3 94.9 95.7 94.8 93.9 93.6 (.DELTA..sub.t0-t3) (1.7) (2.3) (3.1)
(3.9) (4.1) 3 day/30.degree. C. 3 98.0 97.5 97.5 97.3 7
days/60.degree. C. 7 93.6 94.0 94.2 92.3 91.9 7 day/30.degree. C. 7
97.8 97.2 97.1 97.0 Total .DELTA./60.degree. C. 3.07 4.06 3.7 5.48
5.83 Total .DELTA./30.degree. C. 0.3 0.6 0.7 0.7
TABLE-US-00009 TABLE 6 The HPLC Peak Area of Impurity Peak 1 in
CXA-101 Compositions with Varying Amounts of Sodium Chloride Day A1
A2 A3 A4 A5 t0/60.degree. C. 0 0.95 0.31 0.3 0.36 0.39
t0/30.degree. C. 0 0.47 0.36 0.36 0.39 1 day/60.degree. C. 1 1.36
0.86 0.94 1.36 1.39 1 day/30.degree. C. 1 0.48 0.40 0.42 0.48 3
days/60.degree. C. 3 1.71 1.31 1.73 2.06 2.1 3 day/30.degree. C. 3
0.53 0.50 0.52 0.58 7 days/60.degree. C. 7 2.26 2.14 2.07 2.86 2.93
7 day/30.degree. C. 7 0.62 0.63 0.66 0.72 INCREASE %/ 1.31 1.83
1.77 2.5 2.54 60.degree. C. INCREASE %/ 0.15 0.27 0.30 0.33
30.degree. C.
TABLE-US-00010 TABLE 7 The Total HPLC Peak Area of the Impurity
with a RRT of 0.43 and Impurity peak 3 in CXA-101 Compositions with
Varying Amounts of Sodium Chloride Day A1 A2 A3 A4 A5 t0/60.degree.
C. 0 0.28 0.10 0.09 0.10 0.11 t0/30.degree. C. 0 0.15 0.10 0.10
0.11 1 day/60.degree. C. 1 0.37 0.13 0.16 0.35 0.36 1
day/30.degree. C. 1 0.13 0.09 0.09 0.10 3 days/60.degree. C. 3 0.68
0.21 0.31 0.71 0.71 3 day/30.degree. C. 3 0.17 0.13 0.13 0.14 7
days/60.degree. C. 7 1.04 0.36 0.30 0.81 0.81 7 day/30.degree. C. 7
0.19 0.16 0.16 0.17 INCREASE %/ 0.76 0.26 0.21 0.71 0.7 60.degree.
C. INCREASE %/ 0.04 0.06 0.06 0.06 30.degree. C.
TABLE-US-00011 TABLE 8 The HPLC Peak Area of Impurity Peak 7 in
CXA-101 Compositions with Varying Amounts of Sodium Chloride Day A1
A2 A3 A4 A5 t0/60.degree. C. 0 1.31 0.95 0.96 1.01 1.02
t0/30.degree. C. 0 0.69 1.00 1.01 1.02 1 day/60.degree. C. 1 1.37
1.10 1.10 1.23 1.29 1 day/30.degree. C. 1 0.68 0.99 1.01 1.02 3
days/60.degree. C. 3 1.43 1.19 1.27 1.41 1.46 3 day/30.degree. C. 3
0.68 1.03 1.01 1.05 7 days/60.degree. C. 7 1.49 1.31 1.35 1.55 1.57
7 day/30.degree. C. 7 0.68 1.01 1.03 1.07 INCREASE %/ 0.18 0.36
0.39 0.54 0.55 60.degree. C. INCREASE %/ NC 0.01 0.02 0.05
30.degree. C.
[0172] Conclusion:
[0173] the stability test demonstrates that high sodium chloride
content enhances stability of Mono product CXA-101.
C. CXA-201 Peak Trends with NaCl
[0174] A stability study was carried out at 30.degree. C. and
60.degree. C., and samples were analyzed by HPLC. Sodium chloride
content is described in Table 9. Stability data at 60.degree. C.
are summarized in Tables 10-13. The data are also plotted in FIGS.
10-13 to show trends of total purity, peak 1, RRT 0.43+peak 3, and
peak 7 with respect to NaCl.
TABLE-US-00012 TABLE 9 The Sodium Chloride Content in the CXA-201
Compositions Samples NaCl content B1 481.0 mg sodium chloride per
1000 mg of ceftolozane B2 125.0 mg sodium chloride per 1000 mg of
ceftolozane B3 75.0 mg sodium chloride per 1000 mg of ceftolozane
B4 50.0 mg sodium chloride per 1000 mg of ceftolozane
TABLE-US-00013 TABLE 10 The Purity of Ceftolozane in CXA-201
Compositions with Varying Amounts of Sodium Chloride Day B1 B2 B3
B4 t0 0 98.1 97.8 97.8 97.7 1 day/60.degree. C. 1 97.2 96.3 96.2
96.0 1 day/30.degree. C. 1 98.2 97.7 97.6 97.6 3 days/60.degree. C.
3 95.4 94.9 94.7 94.6 (.DELTA..sub.t0-t3) (2.7) (2.9) (3.1) (3.1) 3
day/30.degree. C. 3 98.0 97.5 97.4 97.3 7 days/60.degree. C. 7 92.7
93.8 93.6 93.4 7 day/30.degree. C. 7 97.8 97.2 97.0 96.9 Total
.DELTA./60.degree. C. 5.3 4.0 4.2 4.3 Total .DELTA./30.degree. C.
0.3 0.6 0.8 0.8
TABLE-US-00014 TABLE 11 The HPLC Peak Area of Impurity Peak 1 of
Ceftolozane in CXA-201 Compositions with Varying Amounts of Sodium
Chloride Day B1 B2 B3 B4 t0 0 0.47 0.38 0.38 0.41 1 day/60.degree.
C. 1 1 1.08 1.09 1.14 1 day/30.degree. C. 1 0.48 0.44 0.45 0.49 3
days/60.degree. C. 3 1.85 1.64 1.66 1.71 3 day/30.degree. C. 3 0.53
0.53 0.56 0.61 7 days/60.degree. C. 7 3.3 2.28 2.25 2.29 7
day/30.degree. C. 7 0.62 0.67 0.71 0.77 INCREASE %/60.degree. C.
2.83 1.9 1.87 1.88 INCREASE %/30.degree. C. 0.15 0.29 0.33 0.36
TABLE-US-00015 TABLE 12 The Total HPLC Peak Area of the Impurity
with a RRT of 0.43 and Impurity Peak 3 of Ceftolozane in CXA-201
Compositions with Varying Amounts of Sodium Chloride Day B1 B2 B3
B4 t0 0 0.15 0.12 0.12 0.12 1 day/60.degree. C. 1 0.36 0.35 0.31
0.32 1 day/30.degree. C. 1 0.13 0.12 0.13 0.12 3 days/60.degree. C.
3 0.92 0.67 0.65 0.62 3 days/30.degree. C. 3 0.17 0.16 0.17 0.16 7
days/60.degree. C. 7 1.29 0.78 0.75 0.71 7 days/30.degree. C. 7
0.19 0.19 0.20 0.20 INCREASE %/60.degree. C. 1.14 0.66 0.63 0.59
INCREASE %/30.degree. C. 0.04 0.07 0.08 0.08
TABLE-US-00016 TABLE 13 The HPLC Peak Area of Impurity Peak 7 of
Ceftolozane in CXA-201 Compositions with Varying Amounts of Sodium
Chloride Day B1 B2 B3 B4 t0 0 0.69 1.01 1.01 1.01 1 day/60.degree.
C. 1 0.73 1.12 1.15 1.18 1 day/30.degree. C. 1 0.68 1.00 0.99 0.95
3 days/60.degree. C. 3 0.8 1.24 1.27 1.27 3 days/30.degree. C. 3
0.68 1.00 1.01 1.03 7 days/60.degree. C. 7 0.94 1.32 1.35 1.4 7
days/30.degree. C. 7 0.68 1.02 1.05 1.06 INCREASE %/60.degree. C.
0.25 0.31 0.34 0.39 INCREASE %/30.degree. C. NC 0.01 0.04 0.05
Conclusion:
[0175] the stability data shows that high sodium chloride content
enhances stability of Combination product CXA-201.
Example 6
Manufacturing of Combination Product (Tazobactam and CXA-101) by
Co-Lyophilization
[0176] The co-lyophilization process is illustrated in FIG. 14. The
components of a CXA-201 composition prepared by co-lyophilization
are described in Table 14 below.
TABLE-US-00017 TABLE 14 Components of a CXA-201 Composition
Prepared by Co-lyophilization Component Function Amount
(mg/container) ceftolozane Active pharmaceutical ingredient 1000
(potency) L-arginine Alkalization reagent 587 Citric acid
(anhydrous) Buffer 21 Sodium chloride Stabilizer 476 Tazobactam
(free acid) Active pharmaceutical ingredient 500 Sodium bicarbonate
Alkalization reagent Quantity sufficient.sup.1 for pH 4.8 to 7.0
water Dissolution solvent Not more than 4% by weight.sup.2 Nitrogen
Inert gas Sufficient quantity .sup.1Sodium content is approximately
78 mg/g of tazobactam in drug product after lyophilization.
.sup.2Water is removed during the lyophilization process and is
controlled at no more than 4% by weight.
Example 7
Assessment of Co-Lyophilized Combo Drug Product
A. Preparation of Co-Lyophilized Combo Drug Product
[0177] The Co-Lyo Combo Drug Product was prepared, as described
above in Example 6. The formulation composition of the Combo drug
product is shown in Table 15.
TABLE-US-00018 TABLE 15 Components of the CXA-201 Composition
Prepared by the Co-Lyophilization CXA-201 16.3 g active ceftolozane
Comp. 8.1 g active Tazobactam free ac. 15.5 g L-Arginine 350 mg
Citric acid 7.9 g NaCl 6.1 pH compounded solution
B. Stress Test
[0178] This sample was put into stability study. The following
Tables 16 and 17 are 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 the
HPLC method as described in Example 4.
TABLE-US-00019 TABLE 16 Stability Data of Co-Lyophilized CXA-201
Composition at 25.degree. C./RH = 60% Test items Spec. D.P. T0 T1
25.degree. C. T2 25.degree. C. Related Substances Peak 1
.ltoreq.1.50% 0.31% 0.54% 0.71% Peak 2 .ltoreq.0.40% 0.07% 0.07%
0.09% Peak 3 .ltoreq.0.30% <0.03% <0.03% <0.03% Peak 4
.ltoreq.0.80% 0.08% 0.08% 0.09% Peak 5 .ltoreq.1.00% 0.27% 0.26%
0.29% Peak 6 .ltoreq.0.15% <0.03% <0.03% <0.03% Peak 7
.ltoreq.2.00% 0.64% 0.65% 0.66% Peak 8 .ltoreq.0.15% <0.03%
<0.03% <0.03% Peak 9 .ltoreq.0.60% 0.05% 0.11% 0.10% Peak 10,
11 .ltoreq.0.15% each 0.04% 0.04% 0.04% Peak 12 .ltoreq.2.00%
<0.03% <0.03% <0.03% Others (RRT 0.43) .ltoreq.0.15%
<0.03% <0.03% 0.04% Others (RRT 1.22) .ltoreq.0.15% 0.13%
0.30% 0.38% Others (RRT 2.18) .ltoreq.0.15% 0.03% <0.03% 0.05%
Others (RRT 2.77) .ltoreq.0.15% <0.03% 0.03% 0.03% Sing. Unk.
.ltoreq.0.15% 0.05% 0.07% 0.05% Total .ltoreq.5.00% 1.67% 2.19%
2.77% pH report value 5.5 4.83
TABLE-US-00020 TABLE 17 Stability Data Co-Lyophilized CXA-201
Composition at 40.degree. C./RH = 75% Test items Spec. D.P. T0 T1
40.degree. C. T2 40.degree. C. Related Substances Peak 1
.ltoreq.1.50% 0.31% 1.77% 2.22% Peak 2 .ltoreq.0.40% 0.07% 0.10%
0.16% Peak 3 .ltoreq.0.30% <0.03% <0.03% 0.06% Peak 4
.ltoreq.0.80% 0.08% 0.09% 0.09% Peak 5 .ltoreq.1.00% 0.27% 0.27%
0.30% Peak 6 .ltoreq.0.15% <0.03% <0.03% <0.03% Peak 7
.ltoreq.2.00% 0.64% 0.69% 0.78% Peak 8 .ltoreq.0.15% <0.03%
<0.03% 0.10% Peak 9 .ltoreq.0.60% 0.05% 0.09% 0.09% Peak 10, 11
.ltoreq.0.15% each 0.04% 0.04% 0.05% Peak 12 .ltoreq.2.00%
<0.03% <0.03% <0.03% Others (RRT 0.43) .ltoreq.0.15%
<0.03% 0.09% 0.15% Others (RRT 1.22) .ltoreq.0.15% 0.13% 0.74%
0.97% Others (RRT 2.18) .ltoreq.0.15% 0.03% <0.03% 0.08% Others
(RRT 2.77) .ltoreq.0.15% <0.03% <0.03% 0.04% Sing. Unk.
.ltoreq.0.15% 0.05% 0.11% 0.25% Total .ltoreq.5.00% 1.67% 4.49%
6.32% pH report value 5.5 4.09
C. Conclusion:
[0179] A new impurity having RRT=1.22 was observed in the
co-lyophilized drug product. The impurity was identified as a
degradation product, shown in FIG. 15, which was formed by a
reaction between ceftolozane and formylacetic acid, which was a
degradation product of tazobactam. The stability data at 25.degree.
C. and at 40.degree. C. have shown that the impurity increases over
time.
Example 8
Assessment of Blend Combination Drug Product
A. Preparation of Blend Combination Drug Product
[0180] The blend drug product was prepared, as described above in
Example 3, on lab scale by use of a small blender. The composition
of the blend drug product is shown in Table 18.
TABLE-US-00021 TABLE 18 Components of the Blend Composition
Quantity as active Component Composition components CXA-201 CXA-101
for Injection Ceftolozane 10.8 g Comp. Bulk (25 g) L-Arginine 6.7 g
Citric acid 233 mg Sodium chloride 5.2 g Tazobactam sodium 5.4 g
(as Tazo sterile Bulk (6 g) free acid)
B. Stress Test
[0181] This sample was put into stability study. The following
Tables 19 and 20 are representative examples that summarizes 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 the
HPLC method as described in Example 4.
TABLE-US-00022 TABLE 19 Stability Data of Blend CXA-201 Composition
at 25.degree. C./RH = 60% Test items Specifications T0 T1
25.degree. C. T2 25.degree. C. Related Substances Peak 1
.ltoreq.1.50% 0.61% 0.93% 1.08% Peak 2 .ltoreq.0.40% <0.03%
<0.03% <0.03% Peak 3 .ltoreq.0.30% <0.03% <0.03%
<0.03% Peak 4 .ltoreq.0.80% 0.03% 0.03% 0.04% Peak 5
.ltoreq.1.00% 0.09% 0.12% 0.13% Peak 6 .ltoreq.0.15% <0.03%
<0.03% <0.03% Peak 7 .ltoreq.2.00% 1.28% 1.34% 1.35% Peak 8
.ltoreq.0.15% <0.03% <0.03% <0.03% Peak 9 .ltoreq.0.60%
0.03% <0.03% 0.03% Peak 10, 11 .ltoreq.0.30% <0.03% 0.04%
0.05% Sing. Unk. .ltoreq.0.15% 0.13% 0.13% 0.14% Total
.ltoreq.5.00% 2.49% 3.03% 3.28% Assay CXA-101 Teor. % = 32.6% 32.5%
n.a. n.a. Assay Teor. % = 17.4% 18.2% n.a. n.a. Tazobactam
Tazobactam .ltoreq.4.0% 0.07% 0.12% 0.14% Related Compound A K.F.
.ltoreq.4.0% 2.6% n.a. n.a. pH 5.0-7.0 6.0 5.6 5.1
TABLE-US-00023 TABLE 20 Stability Data of Blend CXA-201 Composition
at 40.degree. C./RH = 75% Test items Specifications T0 T1
40.degree. C. T2 40.degree. C. Related Substances Peak 1
.ltoreq.1.50% 0.61% 1.66% 2.28% Peak 2 .ltoreq.0.40% <0.03%
<0.03% <0.03% Peak 3 .ltoreq.0.30% <0.03% <0.03% 0.04%
Peak 4 .ltoreq.0.80% 0.03% 0.04% 0.05% Peak 5 .ltoreq.1.00% 0.09%
0.13% 0.14% Peak 6 .ltoreq.0.15% <0.03% <0.03% <0.03% Peak
7 .ltoreq.2.00% 1.28% 1.41% 1.46% Peak 8 .ltoreq.0.15% <0.03%
<0.03% <0.03% Peak 9 .ltoreq.0.60% 0.03% <0.03% 0.03% Peak
10, 11 .ltoreq.0.30% <0.03% 0.08% 0.09% Sing. Unk. .ltoreq.0.15%
0.13% 0.14% 0.13% Total .ltoreq.5.00% 2.49% 4.21% 5.27% Assay
CXA-101 Teor. % = 32.6% 32.5% n.a. n.a. Assay Teor. % = 17.4% 18.2%
n.a. n.a Tazobactam Tazobactam .ltoreq.4.0% 0.07% 0.35% 0.54%
Related Compound A K.F. .ltoreq.4.0% 2.6% n.a. n.a. pH 5.0-7.0 6.0
5.0 4.4
C. Conclusion
[0182] The data at both 25.degree. C. and at 40.degree. C. have
shown that the blending process completely inhibits formation of
the impurity RRT=1.22.
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