U.S. patent application number 14/214324 was filed with the patent office on 2014-09-18 for parenteral ceftolozane antibiotic compositions.
The applicant listed for this patent is Cubist Pharmaceuticals, Inc.. Invention is credited to Nicole Miller Damour, John Fred Mohr, Joseph Terracciano, Jacqueline Marie Walsh, Jianxun Zhou.
Application Number | 20140274995 14/214324 |
Document ID | / |
Family ID | 50280243 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140274995 |
Kind Code |
A1 |
Zhou; Jianxun ; et
al. |
September 18, 2014 |
PARENTERAL CEFTOLOZANE ANTIBIOTIC COMPOSITIONS
Abstract
Parenteral pharmaceutical compositions including ceftolozane and
tazobactam can be formulated to provide desired levels of
osmolality, pH and ceftolozane stability.
Inventors: |
Zhou; Jianxun; (Windham,
NH) ; Damour; Nicole Miller; (Belmont, MA) ;
Mohr; John Fred; (Acton, MA) ; Terracciano;
Joseph; (Concord, MA) ; Walsh; Jacqueline Marie;
(Framingham, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cubist Pharmaceuticals, Inc. |
Lexington |
MA |
US |
|
|
Family ID: |
50280243 |
Appl. No.: |
14/214324 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61793007 |
Mar 15, 2013 |
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61792092 |
Mar 15, 2013 |
|
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61882936 |
Sep 26, 2013 |
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61893436 |
Oct 21, 2013 |
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Current U.S.
Class: |
514/192 |
Current CPC
Class: |
A61K 47/36 20130101;
Y02A 50/30 20180101; A61K 9/0019 20130101; A61K 31/546 20130101;
A61P 31/04 20180101; A61K 47/183 20130101; A61K 47/12 20130101;
A61K 31/431 20130101; A61P 43/00 20180101; A61K 47/26 20130101;
A61P 31/00 20180101; Y02A 50/473 20180101; A61K 9/19 20130101; A61K
47/02 20130101; A61P 31/12 20180101; A61K 31/546 20130101; A61K
2300/00 20130101; A61K 31/431 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/192 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 31/431 20060101 A61K031/431 |
Claims
1. A method of treating an infection selected from the group
consisting of Complicated Urinary Tract Infections (cUTI),
Complicated Intra-Abdominal Infections (cIAI) and Hospital-Acquired
Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial
Pneumonia (VABP), the method comprising a. reconstituting a
lyophilized unit dosage form composition comprising the following
components TABLE-US-00026 Nominal Composition Component mg per 1 g
ceftolozane active Ceftolozane Sulfate about 1147 (providing 1,000
mg ceftolozane active) Citric Acid 21 Sodium Chloride 450-500
L-Arginine 500-700 Tazobactam about 537 (providing 500 mg
tazobactam free acid Sodium per 1,000 mg ceftolozane active)
in one or more pharmaceutically acceptable liquid carriers selected
from the group consisting of 0.9% sodium chloride aqueous solution
for injection, 0.45% sodium chloride aqueous solution for
injection, and 5% dextrose for injection and water for injection,
to form a dissolved unit dosage form; b. diluting the dissolved
unit dosage form in one or more pharmaceutically acceptable liquid
carriers selected from the group consisting of 0.9% sodium chloride
aqueous solution for injection, 0.45% sodium chloride aqueous
solution for injection, and 5% dextrose for injection and water for
injection, to form a parenteral pharmaceutical formulation
comprising a therapeutically effective amount of ceftolozane
sulfate and tazobactam, and having an osmolality of about 400-600
mOsm/kg and a pH of about 5-7; and c. intravenously administering
to a patient in need thereof the parenteral pharmaceutical
formulation comprising the therapeutically effective dose of
ceftolozane sulfate and tazobactam; tazobactam in an amount
providing 500 mg of tazobactam acid per 1,000 mg of ceftolozane
active in the parenteral pharmaceutical formulation; 450 to 500 mg
of sodium chloride per 1,000 mg of ceftolozane active in the
parenteral pharmaceutical formulation; and L-arginine.
2. The method of claim 1, further comprising intravenously
administering the parenteral pharmaceutical formulation over a
period of about 1 hour to the patient.
3. The method of claim 1, further comprising administering a second
and a third parenteral pharmaceutical formulation comprising
ceftolozane and tazobactam to a patient in need thereof by
repeating steps (a)-(c) three times a day.
4. The method of claim 1, wherein the infection is a Complicated
Urinary Tract Infections (cUTI) or Complicated Intra-Abdominal
Infections (cIAI).
5. The method of claim 4, wherein the parenteral pharmaceutical
formulation contains a total of 1,000 mg of ceftolozane active
present as ceftolozane sulfate.
6. The method of claim 5, wherein the parenteral pharmaceutical
formulation contains a total of 500 mg of tazobactam acid present
as tazobactam sodium.
7. The method of claim 1, wherein the lyophilized unit dosage form
composition comprises 1,000 mg of ceftolozane active present as
ceftolozane sulfate.
8. The method of claim 1, wherein the lyophilized unit dosage form
composition is obtained by a process comprising the steps of: a.
lyophilizing a first aqueous solution in the absence of tazobactam,
the first aqueous solution comprising ceftolozane, 450 mg to 500 mg
of sodium chloride per 1,000 mg of ceftolozane active, at a pH of
6-7 prior to lyophilization to obtain a first lyophilized
ceftolozane composition, b. lyophilizing a second solution
comprising tazobactam in the absence of ceftolozane to form a
second lyophilized tazobactam composition; and c. blending the
first lyophilized ceftolozane composition and the second
lyophilized tazobactam composition to obtain the antibacterial
composition; and d. packaging a portion of the antibacterial
composition as the lyophilized unit dosage form composition.
9. The method of claim 8, wherein the first aqueous solution
further comprises L-arginine in an amount providing a pH of about
6-7.
10. The method of claim 8, wherein the first aqueous solution
comprises water and the following components: TABLE-US-00027
Nominal Composition Component mg per Vial Ceftolozane Sulfate about
1147 (providing 1,000 mg ceftolozane active) Citric Acid 21 Sodium
Chloride 487 L-Arginine 600 Q.S. for pH adjustment Nitrogen
Q.S.
11. A method of treating a bacterial infection in a subject
comprising administering to a patient in need thereof a parenteral
pharmaceutical antibiotic composition having an osmolality of
400-500 mOsm/kg at a pH of 5-7, the composition comprising a. an
amount of ceftolozane sulfate providing 1,000 mg ceftolozane
active, b. about 450 mg to 500 mg sodium chloride per 1,000 mg
ceftolozane active, and c. an amount of tazobactam sodium providing
500 mg of tazobactam free acid; in a pharmaceutically acceptable
liquid carrier selected from the group consisting of 0.9% sodium
chloride aqueous solution for injection, 5% dextrose for injection
and water for injection.
12. The method of claim 11, wherein the bacterial infection is a
complicated urinary tract infection.
13. The method of claim 11, wherein the bacterial infection is a
complicated intra-abdominal infection.
14. The method of claim 11, wherein the bacterial infection
comprises a bacteria selected from the group consisting of:
Staphylococcus aureus, Escherichia coli, Acinetobacter baumanii,
Haemophilus influenzae, Klebsiella pneumonia, and Pseudomonas
aeruginosa.
15. The method of claim 11, further comprising the steps of a.
reconstituting a unit dosage form of ceftolozane/tazobactam having
the composition: TABLE-US-00028 Nominal Composition Component mg
per Vial Ceftolozane Sulfate about 1147 (providing 1,000 mg
ceftolozane active) Citric Acid 21 Sodium Chloride 487 L-Arginine
600 Q.S. for pH adjustment Tazobactam about 537 (providing 500 mg
tazobactam free acid Sodium per 1,000 mg ceftolozane active)
Nitrogen Q.S.
in a pharmaceutically acceptable liquid carrier to obtain a
reconstituted antibiotic composition; b. intravenously
administering the reconstituted antibiotic composition within the
parenteral pharmaceutical antibiotic composition.
16. The method of claim 15, further comprising repeatedly
intravenously administering separate doses of the parenteral
pharmaceutical antibiotic composition to a patient in need thereof
three times per day.
17. The method of claim 16, wherein each separate parenteral
pharmaceutical antibiotic compositions are administered to the
patient over a 1 hour period.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/792,092, filed Mar. 15, 2013; U.S. Provisional
Application No. 61/793,007, filed Mar. 15, 2013; U.S. Provisional
Application No. 61/882,936, filed Sep. 26, 2013; and U.S.
Provisional Application No. 61/893,436, filed Oct. 21, 2013. The
contents of these applications are incorporated hereby by reference
in their entirety.
TECHNICAL FIELD
[0002] This application discloses parenteral pharmaceutical
compositions comprising ceftolozane.
BACKGROUND
[0003] Increasing resistance to commonly prescribed antimicrobial
agents remains a serious global problem emphasizing the need for
new antimicrobial agents to treat infections caused by
difficult-to-treat pathogens such as Escherichia coli, Klebsiella
pneumoniae, and Pseudomonas aeruginosa. The CDC reports that
antibiotic resistance is one of the most serious health threats
today. The CDC estimates that antibiotic resistant infections
affect over 2 million people in the US annually with an estimated
23,000 people dying as a direct result. There remains an unmet
medical need for new antibiotic therapies to treat gram-negative
pathogens.
[0004] Studies have demonstrated that ceftolozane/tazobactam has a
broad spectrum of activity against Gram-negative bacteria.
Ceftolozane is a cephalosporin antibacterial agent. Ceftolozane is
also referred to as CXA-101, FR264205,
(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, 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). Ceftolozane
sulfate is a pharmaceutically acceptable ceftolozane salt of
formula (I) that can be formulated for intravenous administration
or infusion.
##STR00001##
[0005] 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. CXA-201 refers to a combination of
ceftolozane and the .beta.-lactamase inhibitor ("BLI") tazobactam
with a 2:1 weight ratio between the amount of ceftolozane active
and tazobactam active. Tazobactam is a BLI against Class A and some
Class C .beta.-lactamases. CXA-201 is being evaluated as a
parenteral antibiotic for the treatment of infections caused by
bacterial pathogens such as Escherichia coli, Klebsiella
pneumoniae, and Pseudomonas aeruginosa, including in the treatment
of complicated urinary tract infections and complicated
intra-abdominal infections. Tazobactam potentiates the activity of
ceftolozane against Acinetobacter spp. and common species of
Enterobacteriaceae, including Citrobacter spp., Enterobacter
cloacae, E. coli, K. pneumoniae, Proteus mirabilis, and Serratia
marcescens. These surveillance data demonstrate that 88% to 100% of
these Enterobacteriaceae species are inhibited at <8 .mu.g/mL.
Tazobactam had little impact on the susceptibility of P. aeruginosa
to ceftolozane.
[0006] The stability ceftolozane in certain lyophilized
pharmaceutical compositions initially evaluated for intravenous
administration was improved by lyophilizing a solution of
ceftolozane sulfate with a stabilizing-effective amount of sodium
chloride, sucrose or trehalose (e.g., 125 mg-500 mg of sodium
chloride or about 300 mg of sucrose or about 300 mg of trehalose
per 1,000 mg of ceftolozane active) and an amount of an alkalizing
agent such as L-arginine providing a pH of about 5-7 in the
solution (e.g., about 600 mg L-arginine per 1,000 mg ceftolozane
active).
[0007] For example, an improvement in ceftolozane purity was
observed by high performance liquid chromatography (HPLC) after
stability testing over 7 days at 60 degrees C. (e.g., Examples
below) in ceftolozane compositions obtained by lyophilizing aqueous
solutions of ceftolozane sulfate with stabilizing-effective amounts
of sodium chloride at a pH of 5-7.
[0008] Although increased concentrations of sodium chloride and
L-arginine stabilized lyophilized ceftolozane compositions, these
additional components also raise the osmolality of resulting
pharmaceutical compositions upon reconstitution. Osmolality is a
measure of the number of dissolved particles per unit weight
(mOsm/kg) of a parenteral pharmaceutical composition. This value
can be calculated or determined experimentally by osmometry. Normal
plasma has an osmolality in the range of 285-295 mOsm/kg
(osmolarity range of 300-310 mOsm/L). Agents with an undesirably
high osmolality can cause pain and/or other negative physiologic
disturbances (e.g., excessively high osmolality can cause red blood
cell crenation upon intravenous injection and/or phlebitis while
intravenous administration of agents with excessively low can cause
hemolysis). Accordingly, there is a need for parenteral
formulations of ceftolozane/tazobactam for injection having both a
desired ceftolozane chemical stability and a physiologically and
therapeutically appropriate osmolality (e.g., less than 800
mOsmol/kg and preferably less than 600 mOsmol/kg) and pH (e.g.,
5-7) when prepared in a pharmaceutically acceptable carrier for
administration to a patient in need thereof.
[0009] There remains a need for ceftolozane/tazobactam injectable
pharmaceutical compositions formulated for parenteral
administration that provide desired levels of ceftolozane stability
in an injectable form (e.g., a stabilizing-effective amount of
sodium chloride) comprising a BLI (e.g., tazobactam), while
remaining compatible with relevant biological characteristics
including a providing pharmaceutically acceptable and
therapeutically appropriate levels of pH and osmolality.
SUMMARY
[0010] Parenteral pharmaceutical compositions can be obtained by
dissolving a solid unit dosage form containing ceftolozane in a
stabilized solid form into one or more pharmaceutically acceptable
liquid carriers selected from the group consisting of water for
injection, 0.9% sodium chloride aqueous solution for injection,
0.45% sodium chloride aqueous solution for injection, and 5%
dextrose for injection and water for injection. Ceftolozane can be
stabilized in a solid form (e.g., a lyophilized powder)
pharmaceutical composition by combination with
stabilizing-effective amounts of sodium chloride and L-arginine.
The solid form pharmaceutical composition is preferably formulated
for parenteral administration for the treatment of infections,
comprising a therapeutically effective amount of ceftolozane
sulfate and tazobactam in a ratio of 1,000 mg ceftolozane active
per 500 mg of tazobactam active, in addition to excipients selected
and provided in amounts effective to stabilize ceftolozane in the
solid form pharmaceutical composition. The invention is based in
part on the discovery that therapeutically effective doses of solid
form stabilized ceftolozane compositions can form injectable liquid
pharmaceutical compositions having osmolality levels of about 600
mOsm/kg or less, despite increased levels of
ceftolozane-stabilizing excipients such as sodium chloride and
L-arginine, solid form pharmaceutical compositions can be
reconstituted in isotonic and even certain hypertonic diluents and
carriers.
[0011] A parenteral ceftolozane/tazobactam pharmaceutical
antibiotic composition having an osmolality of less than 800
mOsmol/kg (i.e., 400-500 mOsm/kg) at a pH of about 5-7 includes an
amount of ceftolozane sulfate providing 1,000 mg ceftolozane
active, about 125 mg to 500 mg sodium chloride per 1,000 mg
ceftolozane active, and an amount of tazobactam sodium providing
500 mg of tazobactam per 1,000 mg ceftolozane active at a pH of 5-7
in a pharmaceutically acceptable carrier. The parenteral
pharmaceutical antibiotic composition can have an osmolality of
400-500 mOsm/kg at a pH of 5-7, the composition comprising an
amount of ceftolozane sulfate providing 1,000 mg ceftolozane
active, about 450 mg to 500 mg sodium chloride per 1,000 mg
ceftolozane active, and an amount of tazobactam sodium providing
500 mg of tazobactam free acid, provided in one or more
pharmaceutically acceptable liquid carriers selected from the group
consisting of water for injection, 0.9% sodium chloride aqueous
solution for injection, 0.45% sodium chloride aqueous solution for
injection, and 5% dextrose for injection and water for injection.
The composition can be a solution for injection having a total
volume of about 110 mL and can have one or more of the following
characteristics in any combination: contains a total of about 1,147
mg ceftolozane sulfate; includes L-arginine in an amount effective
to provide a pH of about 5-7, includes about 600 mg of L-arginine
per 1,000 mg of ceftolozane active; includes citric acid (e.g., 21
mg per 1,000 mg of ceftolozane active). The composition also
include a pharmaceutically acceptable carrier that can be 0.9%
sodium chloride aqueous solution for injection, and can be obtained
by dissolving a composition having the vial composition in Table 1a
below.
TABLE-US-00001 TABLE 1a Solid Form Antibacterial Pharmaceutical
Composition Nominal Composition Component mg per Vial Ceftolozane
Sulfate about 1147 (providing 1,000 mg ceftolozane active) Citric
Acid 21 Sodium Chloride 487 L-Arginine 600 Q.S. for pH adjustment
Tazobactam about 537 (providing 500 mg tazobactam free acid Sodium
per 1,000 mg ceftolozane active) Nitrogen Q.S.
A parenteral pharmaceutical antibiotic composition can be obtained
by a process further comprising reconstituting the unit dosage form
in the vial using 0.9% sodium chloride aqueous solution for
injection.
[0012] Methods of treating a bacterial infection in a subject
comprising can include administering to a patient in need thereof a
parenteral pharmaceutical antibiotic composition having an
osmolality of 400-500 mOsm/kg at a pH of 5-7, the composition
comprising an amount of ceftolozane sulfate providing 1,000 mg
ceftolozane active, about 450 mg to 500 mg sodium chloride per
1,000 mg ceftolozane active, and an amount of tazobactam sodium
providing 500 mg of tazobactam free acid; where the parenteral
antibiotic composition also includes a pharmaceutically acceptable
liquid carrier selected from the group consisting of 0.9% sodium
chloride aqueous solution for injection, 5% dextrose for injection
and water for injection. The parenteral pharmaceutical antibiotic
composition can be intravenously administered to treat a bacterial
infection that is a complicated urinary tract infection, a
complicated intra-abdominal infection, and/or is caused by
bacterial pathogens selected from the group consisting of:
Staphylococcus aureus, Escherichia coli, Acinetobacter baumanii,
Haemophilus influenzae, Klebsiella pneumonia, and Pseudomonas
aeruginosa. The method can include treating a bacterial infection
by steps including reconstituting a unit dosage form of
ceftolozane/tazobactam for injection according having the
composition in Table 1 in a pharmaceutically acceptable liquid
carrier to obtain a reconstituted antibiotic composition; and
intravenously administering the reconstituted antibiotic
composition within the parenteral pharmaceutical antibiotic
composition. The method of treatment can also include comprising
repeatedly intravenously administering separate doses of the
parenteral pharmaceutical antibiotic composition to a patient in
need thereof three times per day. Each separate parenteral
pharmaceutical antibiotic compositions can be administered to the
patient over a 1 hour period.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 is a reference HPLC chromatogram showing the peaks of
ceftolozane (CXA-101) and related additional compounds.
[0014] FIG. 2 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 5, wherein the CXA-101 compositions
comprise ceftolozane and sodium chloride.
[0015] FIG. 3 is a plot of the data points from Table 6, showing
the peak area of the composition 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 5, wherein the CXA-101
compositions comprise ceftolozane and sodium chloride.
[0016] FIG. 4 is a plot of the data points from Table 7, showing
the total peak area of the composition with a RRT of 0.43 and the
composition 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 5, wherein the CXA-101 compositions comprise
ceftolozane and sodium chloride.
[0017] FIG. 5 is a plot of the data points from Table 8, showing
the peak area of the composition 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 5, wherein the CXA-101
compositions comprise ceftolozane and sodium chloride.
[0018] FIG. 6 is a plot of the data points from Table 13, 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 5, wherein the CXA-201 compositions comprise
ceftolozane, tazobactam, and sodium chloride.
[0019] FIG. 7 is a plot of the data points from Table 14, showing
the peak area of the composition 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 5, wherein the CXA-201
compositions comprise ceftolozane, tazobactam, and sodium
chloride.
[0020] FIG. 8 is a plot of the data points from Table 15, showing
the total peak area of the composition with a RRT of 0.43 and the
composition 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 5, wherein the CXA-201 compositions comprise
ceftolozane, tazobactam, and sodium chloride.
[0021] FIG. 9 is a plot of the data points from Table 16, showing
the peak area of the composition 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 5, wherein the CXA-201
compositions comprise ceftolozane, tazobactam, and sodium
chloride.
DETAILED DESCRIPTION
[0022] Solid form ceftolozane compositions can be prepared with
components selected and provided in ceftolozane
stabilizing-effective amounts. These solid form compositions can be
dissolved in various pharmaceutically acceptable carriers to obtain
aqueous parenteral pharmaceutical compositions having a suitable pH
and osmolality for intravenous administration.
[0023] In particular, ceftolozane can be stabilized in solid form
compositions (e.g., lyophilized ceftolozane compositions) by
lyophilizing an aqueous solution including a stabilizing effective
amount of sodium chloride (e.g., 125 mg to 500 mg sodium chloride
per 1,000 mg ceftolozane active, preferably 450 mg to 500 mg sodium
chloride per 1,000 mg ceftolozane active) and L-arginine (e.g.,
500-700 mg L-arginine per 1,000 mg of ceftolozane active,
preferably 600 mg L-arginine per 1,000 mg of ceftolozane active).
Unit dosage forms of these lyophilized solid form ceftolozane
compositions containing therapeutically effective doses of
ceftolozane can be blended with tazobactam (e.g., in amounts of
active and excipients providing 1,000 mg of sufficiently stabilized
ceftolozane active and 500 mg tazobactam acid for treatment of
certain urinary tract infections or certain intra-abdominal
infections, or 2,000 mg ceftolozane active and 1,000 mg of
tazobactam acid for certain pneumonia infections). The unit dosage
forms can be dissolved at a pH of about 5-7 to obtain aqueous
parenteral pharmaceutical compositions with an osmolality that is
less than about 600 mOsmol/kg (e.g., about 400-600) upon
reconstitution for intravenous administration to a subject.
Parenteral Pharmaceutical Compositions
[0024] The parenteral pharmaceutical compositions can be obtained
by dissolving and diluting a solid form pharmaceutical compositions
such as the unit dosage form in Table 1 (Example 1). Typically, the
unit dosage form (e.g., a vial or bag) can be dissolved in a small
volume of a pharmaceutically acceptable diluent (e.g., 10-20 mL of
water for injection), withdrawn from the unit dosage form
container, and then diluted to a larger injection volume in the
same or a different pharmaceutically acceptable carrier (e.g., 0.9%
normal aqueous saline for injection) to form the parenteral
pharmaceutical composition. A number of different scenarios can be
used in the preparation of a parenteral pharmaceutical composition
from a unit dosage form, including the use of pharmaceutically
acceptable diluents and carriers independently selected from the
group consisting of: water for injection, 0.9% and 0.45% sodium
chloride aqueous solutions for injection, 5% dextrose for
injection, and combinations thereof (e.g., Example 3). The diluent
and carrier, and composition of the parenteral pharmaceutical
composition can be selected to provide a suitable osmolality, pH,
and a therapeutically effective dose of the pharmaceutically active
component(s) in a liquid parenteral pharmaceutical composition.
Solid Form Pharmaceutical Compositions
[0025] As described herein (e.g., Examples 4a and 4b), adding
stabilizing effective amounts of sodium chloride to compositions
comprising ceftolozane (e.g., 125-500 mg, preferably about 450-500
mg sodium chloride per 1000 mg of ceftolozane) can stabilize
ceftolozane in a solid form of a pharmaceutical composition (e.g.,
a lyophilized powder). Including stabilizing-effective amounts of
sodium chloride can reduce the rate of formation of certain
additional ceftolozane related substances when compared to samples
with a lower sodium chloride concentration. Further, adding about
487 mg sodium chloride per 1000 mg of ceftolozane to a
ceftolozane/tazobactam (e.g., CXA-201) composition can also inhibit
the formation of certain additional compounds. For example, in one
experiment, CXA-201 compositions comprising 125-481 mg sodium
chloride per 1000 mg ceftolozane developed a reduced amount of a
composition having a retention time of 63 minutes ("RT 63'") after
three months at 25.degree. C. (see the HPLC measurements shown in,
Table 11).
[0026] Methods of Treatment
[0027] The spectrum of activity for ceftolozane/tazobactam includes
many clinically relevant, Gram negative pathogens including members
of the Enterobacteriaceae such as E. coli and K. pneumoniae,
nonfermenters such as P. aeruginosa, Gram-positive pathogens such
as Streptococcus pneumoniae and S. pyogenes, and anaerobic
pathogens such as Bacteroides fragilis (M2.6.2.4). Ceftolozane has
stability to common cephalosporin-resistance mechanisms, including
penicillinases, cephalosporinases, most common class A
.beta.-lactamases, AmpC hyperexpression and efflux mechanisms, and
is little affected by porin deficiency. Ceftolozane/tazobactam
compositions are active against strains of P. aeruginosa that are
resistant to carbapenems, cephalosporins, fluoroquinolones and/or
aminoglycosides, including many MDR isolates. The minimum
inhibitory concentration for 90% of strains (MIC90) for
ceftolozane/tazobactam against a wide array of P. aeruginosa
strains (MIC90 0.5/4 .mu.g/mL) is the lowest among all systemically
administered antipseudomonal antibiotics, except for colistin.
Ceftolozane/tazobactam is active against the majority of
Enterobacteriaceae. The minimum inhibitory concentration (MIC) for
50%/90% of strains (MIC50/90) for E. coli is 0.25/0.5 .mu.g/mL and
for E. coli strains with an ESBL phenotype the MIC50/90 is 0.5/4
.mu.g/mL.
[0028] Non-limiting examples of the 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).
[0029] In one aspect, provided herein is a method for treating a
bacterial infection in a subject in need thereof comprising
intravenously administering to the subject a therapeutically
effective amount of a liquid pharmaceutical formulation comprising
ceftolozane, tazobactam, and 125-500 mg sodium chloride per 1000 mg
ceftolozane active, wherein the liquid pharmaceutical composition
has an osmolality between about 350-900 mOsm/kg (including, e.g.,
400-600 mOsm/kg) and a neutral pH.
[0030] In another aspect, provided herein is a method for treating
a complicated intra-abdominal infection (cIAI) or a complicated
urinary tract infection (cUTI) in a subject in need thereof,
comprising intravenously administering to the subject a liquid
pharmaceutical formulation comprising 1000 mg ceftolozane active,
500 mg of tazobactam active, and 125-500 mg of sodium chloride per
1000 mg ceftolozane active, wherein the liquid pharmaceutical
formulation has an osmolality between about 450 mOsm/kg and 900
mOsm/kg and a neutral pH. In a further embodiment of the methods
provided herein, the liquid pharmaceutical formulation has an
osmolality less than about 600 mOsm/kg.
[0031] In yet another aspect, provided herein is a method for
treating nosocomial pneumonia in a subject in need thereof,
comprising intravenously administering to the subject a liquid
pharmaceutical formulation comprising 2000 mg ceftolozane active,
1000 mg of tazobactam active, and 125-500 mg of sodium chloride per
1,000 mg ceftolozane, wherein the liquid pharmaceutical formulation
has an osmolality between about 450 mOsm/kg and 900 mOsm/kg and a
neutral pH. In a further embodiment of the methods provided herein,
the liquid pharmaceutical formulation has an osmolality between
about 450 mOsm/kg and 600 mOsm/kg.
[0032] In an embodiment of the methods described herein, the liquid
pharmaceutical formulation (e.g., an intravenous infusion solution)
is intravenously administered over a 60 minute period, 3 times per
day (e.g., every 8 hours).
[0033] In another embodiment of the methods described herein, the
method further comprising the steps of reconstituting a solid
composition of ceftolozane, tazobactam, and sodium chloride to
produce an intravenous infusion solution, wherein the solution has
an osmolality between about 600-900 mOsm/kg and more preferably
400-600 mOsm/kg, and administering a therapeutically effective
amount of the solution to said subject.
[0034] In a further embodiment, an infusion solution comprising a
unit dosage form of ceftolozane/tazobactam for injection is
prepared via reconstitution and/or dilution with 0.9% Sodium
Chloride Injection USP and 5% Dextrose Injection USP, which are
both commonly used for reconstituting and diluting parenteral
formulations. Sodium Chloride Injection, USP 0.9%, is a sterile,
nonpyrogenic, isotonic solution. Each milliliter contains 9 mg
sodium chloride in 9 mg injection. In another embodiment, the
infusion solution is prepared via reconstitution and/or dilution
with 0.5% Dextrose Injection, USP solution is sterile and
nonpyrogenic parenteral solution containing dextrose in water for
injection and is intended for intravenous administration. Each 100
mL of 5% Dextrose Injection, USP, contains dextrose, hydrous 5 g in
water for injection. The caloric value is 170 kcal/L. The
osmolality is 252 mOsmol/L (calc.), which is slightly hypotonic.
The solution pH is 4.3 (3.2 to 6.5). In yet another embodiment, the
infusion solution is reconstituted or diluted in part by sterile
water or water for injection (WFI).
[0035] As used herein, a "neutral pH" refers to a pH of about 6.0
to about 8.0. In certain embodiments, a "neutral pH" refers to a pH
that is approximately 7.0. In other embodiments, a "neutral pH"
refers to a pH of about 6.0 to 7.5 or 6.0 to about 7.0. In yet
another embodiment, a "neutral pH" refers to a pH of about 7.4.
[0036] As used herein, "osmolality" refers to the concentration of
particles dissolved in solution expressed as osmoles of solute per
kilogram of solvent. Human blood, for example, has an osmolality of
about 290 mOsm/L, which corresponds to a 290.times.10.sup.3 M
concentration of dissolved particles. Marc Stranz, A Review of pH
and Osmolarity, 6 Int'l J. of Pharm. Compounding 216, 218 (May/June
2002) This value can be calculated or determined experimentally by
osmometry (see, e.g., Example 3). In certain embodiments, the
osmolality is between about 450 mOsm/kg and 900 mOsm/kg. In other
embodiments, the liquid pharmaceutical formulation (e.g., an
intravenous infusion solution) has an osmolality that is between
about 450 mOsm/kg and 600 mOsm/kg. In preferred embodiments, the
liquid pharmaceutical formulation (e.g., an intravenous infusion
solution) has an osmolality that is less than about 600
mOsm/kg.
[0037] Ceftolozane is 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, and is also referred to as "CXA-101,"
FR264205, 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). "Ceftolozane"
includes both ceftolozane free base and salts of ceftolozane, such
as ceftolozane sulfate. Ceftolozane sulfate is a pharmaceutically
acceptable salt of ceftolozane that can be combined with sodium
chloride and other components to obtain an antibiotic composition
suitable for administration by injection or infusion.
[0038] Unless otherwise indicated herein, the phrase "1000 mg
ceftolozane" or "1 g ceftolozane" refers to an amount of
ceftolozane containing the free base equivalent weight of
ceftolozane provided in any suitable salt form. For example, a
composition containing 1000 mg of ceftolozane in the ceftolozane
sulfate solid form will include greater than 1000 mg of material
(e.g., due to at least the additional weight of the sulfate counter
ion). Preferably, a composition containing "1000 mg of ceftolozane"
includes an amount of ceftolozane sulfate comprising 1000 mg of the
ceftolozane molecule in free base equivalent form. For example, as
shown in Table 1, 1147 mg ceftolozane sulfate corresponds to 1000
mg of ceftolozane free base.
[0039] In an embodiment, ceftolozane can be ceftolozane drug
product intermediate (composition) wherein the ceftolozane
composition further comprises excipients, stabilizers, or pH
adjusting additives. For example, the ceftolozane can include
sodium chloride, L-arginine, and citric acid.
[0040] The disclosed pharmaceutical compositions can include 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.
Tazobactam is the most commonly used BLI in the disclosed
pharmaceutical compositions. It is typically used as the free acid,
sodium salt or arginine salt. Tazobactam free acid has the
following structure:
##STR00002##
[0041] "Ceftolozane active" refers to active portion of a salt form
of ceftolozane, i.e., the free base form of ceftolozane.
"Tazobactam active" refers to the active portion of a salt form of
tazobactam, i.e., tazobactam free acid. The disclosed
pharmaceutical compositions commonly have a 2:1 w/w ratio
ceftolozane active to tazobactam active. A unit dosage form of the
disclosed pharmaceutical composition typically has 1000 mg of
ceftolozane active, preferably from ceftolozane sulfate and 500 mg
of tazobactam active, preferably from tazobactam free acid, sodium
salt or arginine salt. Another unit dosage form of the disclosed
pharmaceutical composition has 2000 mg ceftolozane active,
preferably from ceftolozane sulfate and 1000 mg of tazobactam
active, preferably from tazobactam free acid, sodium salt or
arginine salt.
[0042] 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.
[0043] 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, subject, 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.
[0044] In one embodiment, provided herein is a method for the
treatment of an infection in a subject, where the infection is
caused by Pseudomonas aeruginosa, Serratia marcescens, Escherichia
coli, Klebsiella pneumoniae, Haemophilus influenzae, or
Streptococcus pneumoniae comprising administering to said subject a
therapeutically effective amount of a liquid pharmaceutical
formulation having an osmolality between about 450 mOsm/kg and 900
mOsm/kg and a pH of about 6.0-8.0 comprising approximately 1147 mg
ceftolozane sulfate; approximately 537 mg tazobactam sodium; and
400-500 mg sodium chloride. In one embodiment, the pharmaceutical
composition further comprises 500-650 mg L-arginine and 15-30 mg
anhydrous citric acid.
[0045] In another embodiment, provided herein is a method for the
treatment of urinary tract infection, intra-abdominal infection, or
nosocomial pneumonia in a subject, comprising administering to said
subject a therapeutically effective amount of a liquid
pharmaceutical formulation having an osmolality between about 450
mOsm/kg and 900 mOsm/kg and a pH of about 6.0-8.0 comprising
approximately 1147 mg ceftolozane sulfate; approximately 537 mg
tazobactam sodium; and 400-500 mg sodium chloride. In an
embodiment, the pharmaceutical formulation comprises 487 mg sodium
chloride. In one embodiment, the pharmaceutical formulation further
comprises 500-650 mg L-arginine and 15-30 mg anhydrous citric
acid.
[0046] In one embodiment, provided herein is a method for the
treatment of an infection in a subject, wherein the infection is
caused by Pseudomonas aeruginosa, Serratia marcescens, Escherichia
coli, Klebsiella pneumoniae, Haemophilus influenzae, or
Streptococcus pneumoniae comprising administering to said subject a
therapeutically effective amount of a liquid pharmaceutical
composition having an osmolality between about 450 mOsm/kg and 900
mOsm/kg and a pH of about 6.0-8.0 comprising approximately 1147 mg
ceftolozane sulfate; approximately 537 mg tazobactam sodium;
approximately 487 mg sodium chloride; and approximately 600 mg
L-arginine. In one embodiment, the pharmaceutical formulation
further comprises 15-30 mg anhydrous citric acid.
[0047] In another embodiment, provided herein is a method for the
treatment of urinary tract infection, intra-abdominal infection, or
nosocomial pneumonia in a subject, comprising administering to said
subject a therapeutically effective amount of a liquid
pharmaceutical formulation having an osmolality between about 450
mOsm/kg and 900 mOsm/kg and a pH of about 6.0-8.0 comprising
approximately 1147 mg ceftolozane sulfate; approximately 537 mg
tazobactam sodium; approximately 487 mg sodium chloride; and
approximately 600 mg L-arginine. In one embodiment, the
pharmaceutical formulation further comprises 15-30 mg anhydrous
citric acid.
[0048] Any patent, patent application, publication, or other
disclosure material identified in the specification is hereby
incorporated by reference herein in its entirety. Any material, or
portion thereof, that is said to be incorporated by reference
herein, but which conflicts with existing definitions, statements,
or other disclosure material set forth herein is only incorporated
to the extent that no conflict arises between that incorporated
material and the present disclosure material.
[0049] Unless otherwise indicated, as used herein, the term
"Related Substances" with respect to HPLC detection refers to all
the ceftolozane related process impurities and degradation products
other than ceftolozane separated and detected by HPLC according to
Example 5. Unless otherwise indicated, as used herein, the term "%
Related Substances" refers to the % of the total HPLC peak area
obtained by Example 5 attributed to all the ceftolozane related
process impurities and degradation products other than
ceftolozane.
ILLUSTRATIVE EXAMPLES OF SELECTED EMBODIMENTS OF THE INVENTION
Example 1
Physicochemical and Biological Properties Ceftolozane/Tazobactam
for Injection, 1000 mg/500 mg
[0050] As a product intended for intravenous use, several
properties are important for physiological compatibility. These
include particulate matter, sterility, endotoxin limit, pH, and
osmolality. Particulate matter and sterility are controlled at the
point of manufacture. The drug product is processed aseptically
throughout the entire manufacturing process, inclusive of
ceftolozane, tazobactam sodium, and ceftolozane/tazobactam in-vial
drug product.
[0051] The ceftolozane/tazobactam drug product is controlled to
approximately pH 6, to provide physiological comfort, while still
assuring adequate stability for the drug substances. The
ceftolozane drug product intermediate is controlled during
compounding to pH 6.5.+-.0.5 and is preferably pH 5 to 7. The
tazobactam sodium is preferably at pH 5 to 7.
[0052] Ceftolozane/tazobactam following reconstitution with normal
saline and dilution for infusion also in normal saline (10 mg/mL
ceftolozane; 5 mg/mL tazobactam) is slightly hypertonic, with
osmolality approximately 500 mOsm/kg. However, slightly hypertonic
intravenous infusion solutions are not uncommon as drug products
are commonly prepared and diluted with already-isotonic solutions,
such as normal saline. The generally accepted maximum upper limit
for peripheral intravenous administration is approximately 900
mOsm/kg, though admixtures 600 to 900 mOsm/kg are typically
administered through a central line. Therefore, to be within the
limits of this range, the infusion product is preferably less than
600 mOsm/kg. An example of a unit composition of a dosage for
reconstitution is described in Table 1.
TABLE-US-00002 TABLE 1 Unit Compositions of Ceftolozane/Tazobactam
for Injection, 1000 mg/500 mg Nominal Composition Component
Function mg per Vial Ceftolozane Ceftolozane Active 1147
composition.sup.1) Sulfate Citric Acid, Chelating Agent 21
Anhydrous Sodium Stabilizing Agent 487 Chloride L-Arginine
Alkalizing Agent 600.sup.2) Q.S. for pH adjustment Tazobactam
Sodium.sup.3) Active 537 Nitrogen Processing Aid.sup.(a) Q.S. Total
Weight 2792 .sup.1)Actual amount of Ceftolozane composition will
vary based on the measured potency. Ceftolozane sulfate, 1147 mg,
corresponds to 1000 mg Ceftolozane free base. .sup.2)L-arginine is
added as needed to achieve pH 6.5 .+-. 0.5; 600 mg per vial is
considered a representative total amount. .sup.3)Actual weight of
tazobactam sodium will vary based on the measured potency.
Tazobactam sodium 537 mg, corresponds to 500 mg tazobactam free
acid .sup.4)Nitrogen blanket is applied after powders are dispensed
to the vial and prior to insertion of stopper.
Example 2
Excipients in Ceftolozane Drug Product Intermediate
[0053] The excipients in ceftolozane composition were chosen to
ensure stability and processability of the ceftolozane drug
substance into the drug product. The specific excipients, their
quantities and functions are provided in Table 2. All excipients
are compendial and typical for sterile pharmaceutical dosage forms,
requiring no additional treatment prior to use in the formulation.
The excipients are used in levels within the range established in
other FDA approved products as described in the Inactive
Ingredients Database (IID).
TABLE-US-00003 TABLE 2 Excipients Used in Ceftolozane composition
Concentration Inactive Ingredients Amount, in Infusion Rationale
for Database Component Function mg/Vial Solution, % Inclusion (IID)
Range Citric acid Chelating 21 0.02 Used to prevent 0.0025 to 50%
agent discoloration and degradation Sodium Stabilizing 487 0.49
Used as a stabilizing 0.187 to 45% Chloride agent agent for
ceftolozane sulfate L-arginine Alkalizing 600.sup.(a) Q.S. 0.60
Used to adjust 0.29 to 88% agent for pH ceftolozane solution
adjustment pH .sup.(a)L-arginine is added as needed to achieve pH
6.5 .+-. 0.5; 600 mg per vial is considered a representative total
amount.
Example 3
Determining Osmolality of CXA-201Compositions
Example 3a
Osmolality for an Injectable Pharmaceutical Composition Comprising
the Composition of Table 1
[0054] The osmolality data for injectable pharmaceutical
compositions in Table 3a corresponds to the osmolality of unit
dosage forms of ceftolozane/tazobactam for injection formulated by
reconstituting the sample described in Table 1 with various
diluents listed below, then injecting the reconstituted solution
into a 100 mL bag of an injectable pharmaceutically acceptable
carrier. Data for osmolality of the following product
reconstitution scenarios is shown in Table 3a, as determined using
the composition from Table 1 and the corresponding diluent and
injectable carrier as indicated herein. [0055] 5% Dextrose
Injection USP, 100 mL Bag (Baxter) [0056] 0.9% Sodium Chloride
Injection USP, 100 mL Bag (Baxter) [0057] sWFI-D5W: reconstituted
with Sterile WFI then added into 5% Dextrose Injection bag [0058]
NS-D5W: reconstituted with USP Normal Saline then added into 5%
Dextrose Injection bag [0059] sWFI-NS: reconstituted with Sterile
WFI then added into 0.9% Sodium Chloride Injection Bag [0060]
NS-NS: reconstituted with USP Normal Saline then added into 0.9%
Sodium Chloride Injection bag
TABLE-US-00004 [0060] TABLE 3a Osmolality of Ceftolozane Bag
Solution (mOsm/kg) Time Point sWFI - D5W NS - D5W sWFI - NS NS - NS
RT T0 446 470 449 478
Example 3b
Osmolality for Other Injectable Pharmaceutical Compositions
[0061] Additional Ceftolozane and Tazobactam Sodium samples
(described below as #1-#3) were reconstituted as follows: [0062]
Sample#1: Weighed 0.103 g of Tazobactam Sodium and 0.462 g of
CXA-101dissolved in 4 mL of WFI Water and 6 mL of USP Normal
Saline. [0063] Sample#2: Weighed 0.103 g of Tazobactam Sodium and
0.462 g of CXA-101dissolved in 4 mL of WFI Water added 10 mL of USP
Normal Saline. [0064] Sample#3: Weighed 0.103 g of Tazobactam
Sodium dissolved in 1 mL of WFI Water and 0.462 g of
CXA-101dissolved in 1 mL of WFI Water then mixed together added 10
mL of USP Normal Saline. [0065] Tazobactam Sodium (Potency: 97.5%)
[0066] CXA-101 (Potency: 43.3%)
WFI Water
USP Normal Saline
[0067] The osmolality of CXA-101 and Tazobactam Sodium samples
(#1-#3) was then determined using a freezing point depression
Osmometer (available from Advanced Instruments, Inc.).
TABLE-US-00005 TABLE 3b Osmolality of Reconstituted Solutions
CXA-101 Tazobactam Conc. Sodium Osmolality Sample# (mg/mL) Conc.
(mg/mL) WFI Water Saline (mOsm/kg) 1 20.0 10.0 40% (40 mL) 60% (60
mL) 589 2 14.3 7.1 29% (40 mL) 71% (100 mL) 512 3 18.7 8.3 17% (20
mL) 83% (100 mL) 604
[0068] A Unit dosage form composition of Table 1 was reconstituted
with 10 mL of Sterile WFI or USP Normal Saline then added into 100
mL 5% Dextrose Injection (D5W) or 0.9% Sodium Chloride (NS) bags
and the osmolality of the resulting bag solution was determined as
shown in Table 3b.
Example 4a
Sodium Chloride in CXA-101Compositions
[0069] A. Improvement in the Purity of the Ceftolozane in CXA-101
Pharmaceutical Compositions with Varying Amounts of Sodium
Chloride
[0070] A stability study was carried out at 30.degree. C. and
60.degree. C. and analyzed by HPLC. The sodium chloride content in
the CXA-101 compositions is described in Table 4. The HPLC data are
summarized in Tables 5-8. The data are also plotted in FIGS. 6-9 to
show the trends of the purity, and the amounts of the composition
peak 1, the composition with a RRT of 0.43 and the composition peak
3, and the composition peak 7 in the CXA-101 compositions with
respect to NaCl.
TABLE-US-00006 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-00007 TABLE 5 Purity of Ceftolozane in CXA-101
Compositions with Varying Amounts of Sodium Chloride Day A 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-00008 TABLE 6 HPLC Peak Area of Composition 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 %/60.degree. C.
1.31 1.83 1.77 2.5 2.54 INCREASE %/30.degree. C. 0.15 0.27 0.30
0.33
TABLE-US-00009 TABLE 7 HPLC Peak Area of the Composition with a RRT
of 0.43 and Composition 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 %/60.degree. C. 0.76 0.26 0.21 0.71 0.7 INCREASE
%/30.degree. C. 0.04 0.06 0.06 0.06
TABLE-US-00010 TABLE 8 The HPLC Peak Area of Composition 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 %/60.degree. C.
0.18 0.36 0.39 0.54 0.55 INCREASE %/30.degree. C. NC 0.01 0.02
0.05
[0071] Conclusion:
[0072] The stability test demonstrates that high sodium chloride
content enhances stability of CXA-101 Compositions.
[0073] The HPLC measurements on day 3 were used to analyze the
stability of the CXA-101 compositions.
[0074] CXA-101 compositions comprising high amounts of sodium
chloride (e.g., 125-1000 mg sodium chloride per 1000 mg of
ceftolozane) were found to be more chemically stable than CXA-101
compositions comprising low amounts of sodium chloride (e.g., less
than 125 mg sodium chloride per 1000 mg of ceftolozane). Table 5
shows that, by day 3 of heating at 60.degree. C., sample A1, which
has the highest salt concentration, is most stable, i.e., has the
lowest A.sub.t0-t3 of all samples. By day 3, the sample with the
lowest salt concentration, A5, has the highest A.sub.t0-t3
indicating the most degradation. Overall, A5 has degraded 141% more
than A1. Further, Table 5 shows that, by day 3 of heating at
60.degree. C., sample A3, which contains a lower salt concentration
within the limits of the invention at 125 mg, is still
significantly more stable than A4, a composition containing 75.0 mg
of the salt. A3 has a A.sub.t0-t3 of 3.1, while A4 has a
A.sub.t0-t3 of 3.9, meaning that A4 has degraded 26% more than
A3.
B. Long-term Stability Study of CXA-101 Pharmaceutical Compositions
with Varying Amounts of Sodium Chloride
[0075] Another stability study was carried out at 5.degree. C. and
25.degree. C. The sodium chloride content in the CXA-101
compositions is described in Table 9. The amounts of citric acid
and L-arginine in each composition were the same. These samples
were in lyophilized form and were placed on long-term (24-36
months), real time stability programs.
[0076] The composition peak 1 is considered "diagnostic" for
formulation failure because it is the first peak to go out of trend
or specification (1.5%). Thus, the stability of these CXA-101
compositions was also measured by the length of storage until
formulation failure as indicated by the composition peak 1. The
data in Table 9 were extrapolated from the data collected after 4
months. Clearly, based on the amount of the composition peak 1 in
the compositions, the composition with about 480 mg sodium chloride
per 1 gram ceftolozane active was significantly more stable than
the compositions containing 125 mg or 62.5 mg sodium chloride per 1
gram of active ceftolozane (i.e., stability of ceftolozane
compositions: 480>>125 mg>62.5 mg).
TABLE-US-00011 TABLE 9 The Peak 1 Failure Points of CXA-101
Compositions with Varying Amounts of Sodium Chloride Ceftolozane
Peak 1 failure Peak 1 failure active, 1 g+ point at 5.degree. C.
point at 25.degree. C. 480 mg NaCl 245 months 15 months 125 mg NaCl
70 months 5 months 62.5 mg NaCl 25 months 3 months* *Results at 3
months = 1.34%, 4 months = 1.15%
Example 4b
Sodium Chloride in CXA-201 Compositions
[0077] A. Reduction of the Composition at RT=63 minutes in
CXA-201Compositions
[0078] A stability study was carried out at 25.degree. C. and
analyzed by HPLC. CXA-201 compositions comprise ceftolozane and
tazobactam, further comprising high, mid, or low amounts of sodium
chloride (480, 125, or 62.5 mg NaCl per 1000 mg of ceftolozane,
respectively). Comparison of the compositions are listed in Table
10. The amounts of the composition RT 63', as measured by the HPLC
method, are summarized in Table 11.
TABLE-US-00012 TABLE 10 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-00013 TABLE 11 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 Area Area Area Sample Summary RT %
RT % RT % 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
[0079] Conclusion:
[0080] 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 composition at RT=63 minutes, as measured by HPLC. The
compositions comprising 480 mg NaCl per 1000 mg of ceftolozane had
the least amount of the composition RT 63' after 3 months at
25.degree. C. The amount of the composition RT 63' in the
compositions comprising 125 mg NaCl per 1000 mg of ceftolozane was
1.5-fold or greater than the amount of the composition 63' in the
compositions comprising 480 mg NaCl per 1000 mg of ceftolozane. The
amount of the composition RT 63' in the compositions comprising
62.5 mg NaCl per 1000 mg of ceftolozane was 2-fold or greater than
the amount of the composition RT 63' in the compositions comprising
480 mg NaCl per 1000 mg of ceftolozane. Thus, the CXA-201
compositions comprising high amounts of sodium chloride (e.g.,
125-1000 mg sodium chloride per 1000 mg of ceftolozane) were more
chemically stable than the compositions comprising low amounts of
sodium chloride (e.g., less than 125 mg sodium chloride per 1000 mg
of ceftolozane).
B. Improvement in the Purity of Ceftolozane in CXA-201
Pharmaceutical Compositions with Varying Amounts of Sodium
Chloride
[0081] A stability study was carried out at 30.degree. C. and
60.degree. C. analyzed by HPLC. The sodium chloride content in the
CXA-201 compositions is described in Table 12. The HPLC data at 30
and 60.degree. C. are summarized in Tables 13-16. The data are also
plotted in FIGS. 6-9 to show the trends of the purity, and the
amounts of the composition peak 1, the composition with a RRT of
0.43 and the composition peak 3, and the composition peak 7 in the
CXA-201 compositions with respect to NaCl.
TABLE-US-00014 TABLE 12 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-00015 TABLE 13 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 (2.7) 94.9 (2.9) 94.7 (3.1) 94.6 (3.1) (.DELTA..sub.t0-t3) 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-00016 TABLE 14 The HPLC Peak Area of Composition Peak 1 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-00017 TABLE 15 The Total HPLC Peak Area of the Composition
with a RRT of 0.43 and Composition Peak 3 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-00018 TABLE 16 The HPLC Peak Area of Composition Peak 7 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
[0082] Conclusion:
[0083] The stability data shows that high sodium chloride content
enhances stability of CXA-201 compositions.
[0084] Similarly to CXA-101 compositions, CXA-201 compositions
comprising high amounts of sodium chloride (e.g., 125-1000 mg
sodium chloride per 1000 mg of ceftolozane) were found to be more
chemically stable than CXA-201 compositions comprising low amounts
of sodium chloride (e.g., less than 125 mg sodium chloride per 1000
mg of ceftolozane). Table 10 shows that, by day 3 of heating at
60.degree. C., sample B1 containing the highest salt concentration
is most stable, i.e., has the lowest A of all samples. By day 3,
the sample with the lowest salt concentration, B4, has the highest
.DELTA..sub.t0-t3 indicating the most degradation. Overall, B4 has
degraded 15% more than B1.
Example 5
HPLC Analysis of Compositions Comprising Ceftolozane
[0085] The purity of the ceftolozane in the pharmaceutical
compositions was measured using the analytical HPLC method
described below.
[0086] The stability studies and HPLC methodologies described
herein were used to acquire the data provided in the following
examples.
Analytical HPLC Method
A. Operative Conditions
TABLE-US-00019 [0087] 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 (v/v) Flow
rate 1.0 mL/min Wavelength 254 nm Injection volume 10 .mu.L Oven
Temperature 45.degree. C. Run Time 85 minutes
TABLE-US-00020 TABLE 17 Gradient Profile used in analytical HPLC
method: 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.
[0088] 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).
[0089] Mobile phase was then made by mixing sodium perchlorate
buffer solution (pH 2.5) and acetonitrile in the ratio 90:10
(v/v).
[0090] 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.
[0091] Sample solution: dissolve 20.0 mg, exactly weighed, of the
Sample, in 20.0 mL of water (Prepare just before injection into
HPLC system).
[0092] System suitability solution (1%): take 1.0 mL of the sample
solution (the 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
[0093] 1. Inject blank (water) 2. Inject system suitability
solution and check for tailing factor and theoretical plate number
for the CXA-101 peak: [0094] The tailing factor must not be greater
than 1.5 [0095] 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 the CXA-101 peak. [0096] The tailing factor must not be greater
than 1.5 [0097] 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. 1
or, alternatively, on the basis of the following RRT values listed
in Table 18.
TABLE-US-00021 [0097] TABLE 18 Identities and RRTs of the Products
Related to Ceftolozane Compound RRT Proposed Structure Source Peak
1 3-side chain ~0.14 ##STR00003## Degradation product and process
product Peak 2 ~0.16 Unidentified Process product Peak 3 ~0.4
Unidentified Process product Peak 4 ~0.6 Unidentified Process
product Peak 5 7-Epimer type ~0.9 ##STR00004## Degradation product
and process product Peak 6 ~1.1 NA Process product Peak 7 .DELTA.3
Isomer type ~1.30 ##STR00005## Degradation product and process
product Peak 8 ~1.37 Unidentified Process product Peak 9
Anti-Isomer type ~1.7 ##STR00006## Process product and Degradation
product Peaks 10, 11 ~2.3 Unidentified Process product
E. Calculations
[0098] I. Report for each related substance its amount as expressed
by area percent.
C i = A i .times. 100 A t + A i ##EQU00001## [0099] wherein: [0100]
C.sub.i=Amount of related substance i in the sample, area % [0101]
A.sub.i=Peak area of related substance i in the sample chromatogram
[0102] A.sub.t=Area of CXA-101 peak in the sample chromatogram
[0103] A.sub.t+.SIGMA.A.sub.i=Total peaks area in the sample
chromatogram [0104] Consider as any unspecified compound, 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.
[0105] II. Report the total composition content as expressed by the
following formula:
C T = A i .times. 100 A t + A i ##EQU00002## [0106] wherein: [0107]
C.sub.T=total composition content in the sample, area % [0108]
A.sub.t=area of CXA-101 peak in the sample chromatogram [0109]
.SIGMA.A.sub.i=total peak areas of compositions in the sample
chromatogram
Example 6
Ceftolozane without the Presence of a Stabilizing Agent
[0110] Five samples were prepared, the components of which are
shown in Table 19 below. Each sample contained 1000 mg of
ceftolozane active, 40 mg citric acid monohydrate (equivalent of 36
mg citric acid anhydrous), and the same amount of L-arginine.
Stabilizing reagents in four samples are 480 mg sodium chloride,
300 mg of trehalose, 300 mg of sucrose, and 300 mg of PVP,
respectively. One sample was a control that contained no
stabilizing reagent. The samples were in lyophilized form and
stored at 60.degree. C. for 7 days. The purities of the samples
were monitored by HPLC on day 0, day 1, day 3 and day 7.
TABLE-US-00022 TABLE 19 Comparison between stabilizing reagents
Excipient Treha- Su- NaCl lose crose PVP None Ceftolozane 1000 1000
1000 1000 1000 amount Excipient 480 300 300 300 N/A amount Purity:
t.sub.0 98.42 98.09 98.14 97.89 97.94 60.degree. C./1 d 97.85 96.73
96.97 96.05 96.15 60.degree. C./3 d 97.21 95.36 95.81 94.57 94.53
60.degree. C./7 d 95.65 94.21 94.19 92.78 92.06 Purity .DELTA.
-2.77% -3.88% -3.95% -5.11% -5.88% (0-7 d)
[0111] As shown in Table 19, the sample containing sodium chloride
exhibited the best stability. The purity of ceftolozane in the
sample containing sodium chloride had the slightest purity drop
over 7 days. This experiment further supports the discovery that
sodium chloride provides surprisingly better stabilizing effect
than the other reagents.
[0112] The purity of the ceftolozane in a composition comprising
100 mg ceftolozane was also evaluated with no stabilizing agent
after 3 days at 70.degree. C. by measuring the residual rate. The
residual rate is measured by detecting the amount of ceftolozane in
a sample before and after a stability test using HPLC, and
determining the percentage of ceftolozane lost during the stability
test. The residual rate of ceftolozane without any stabilizing
agent (i.e., 100 mg of ceftolozane) after 3 days at 70.degree. C.
was 51.2%, meaning that the HPLC peak area after the stability test
for ceftolozane (i.e., 3 days at 70 degrees C.) was about 51.2% of
the HPLC peak area for ceftolozane at the start of the stability
test (i.e, at time zero considered to be 100%).
[0113] As shown in Table 19, ceftolozane without without any
stabilizing agent exhibited an overall decrease in purity of 5.88%.
This experiment further supports the need for an additive with a
stabilizing effect on ceftolozane.
Example 7
Manufacturing Procedure of a Lyophilized Pharmaceutical Composition
Comprising Ceftolozane and Sodium Chloride (CXA-101)
[0114] There are four main steps in the manufacture of a CXA-101
pharmaceutical composition: 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 manufacturing process is described below.
I. Dissolution
[0115] 1. A prescribed amount of WFI (e.g., 81 kg WFI) is charged
into a dissolution reactor. 2. A prescribed amount of citric acid
(e.g., 20.7 mg anhydrous citric acid per 1000 mg ceftolozane
active) is added. 3. The solution is cooled to 5.degree. C. to
10.degree. C. 4. A prescribed amount of CXA-101 drug substance
(e.g., 9.462 kg active) is added to the solution. 5. A prescribed
amount of L-arginine (e.g., 587 mg L-arginine per 1000 mg
ceftolozane active) is slowly added to the solution. 6. A check for
complete dissolution is performed. Solution pH is verified to be in
the target range of 6.5 to 7.0. 7. A prescribed amount of sodium
chloride (e.g., 476 mg sodium chloride per 1000 mg ceftolozane
active) is added to the solution. 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. 9. WFI is added to bring the
net weight to 124.4 kg and the solution is mixed well. 10. Samples
are withdrawn for testing of final pH. II. Sterile filtration 11.
The solution is passed through a filter (pore size 0.45 .mu.m)
followed by two more filters (pore size 0.22 .mu.m) onto a shelf on
the Criofarma lyophilizer. 12. The line is washed with WFI. 13. The
washing solution from Step 12 is passed through sterile filtration.
III. Bulk lyophilization 14. The washing solution is loaded onto a
separate shelf on the lyophilizer (and later discarded). 15. The
solution is lyophilized until dry. 16. The product shelf is cooled
to 20.degree. C..+-.5.degree. C. IV. Packaging into Sterbags.RTM.
17. The lyophilized pharmaceutical composition is milled. 18. The
milled powder is sieved. 19. The sieved powder is blended for 30
minutes. 20. The powder is then discharged into Sterbags.RTM.
Example 8
Efficacy Testing of CXA-201
[0116] Ceftolozane/tazobactam, an antibiotic candidate being
developed to treat certain Gram-negative infections, includes
ceftolozane, a cephalosporin that has demonstrated more potent in
vitro activity against Pseudomonas aeruginosa as compared to the
currently available cephalosporins, with tazobactam, a
Beta-lactamase inhibitor. The addition of tazobactam broadens
coverage to include most Extended-spectrum B-lactamase
(ESBL)-producing Escherichia coli (E. coli), Klebsiella pneumoniae,
and other Enterobacteriaceae.
[0117] Ceftolozane/tazobactam is being developed for the potential
treatment of Complicated Urinary Tract Infections (cUTI) and
Complicated Intra-Abdominal Infections (cIAI). In pivotal Phase 3
clinical trials of ceftolozane/tazobactam in cUTI when studied
against levofloxacin and of ceftolozane/tazobactam, in combination
with metronidazole, in cIAI when studied against meropenen,
ceftolozane/tazobactam met its primary endpoints of statistical
non-inferiority. Ceftolozane/tazobactam is also being developed for
the potential treatment of Hospital-Acquired Bacterial Pneumonia
(HABP)/Ventilator-Associated Bacterial Pneumonia (VABP) at a dose
of 3 g every 8 hours.
[0118] CXA201 has strong activity against the most common and
problematic Gram-negative pathogens. The tables below show Per
Pathogen Micro Eradication (ME Population) from treatment of
urinary tract infections in Phase III clinical trials and the per
pathogen response rates for treatment of complicated
intra-abdominal infections in Phase III clinical trials.
TABLE-US-00023 TABLE 20 Per Pathogen Micro Eradication (ME
Population) from treatment of urinary tract infections in Phase III
clinical trials CXA-201 treating cUTI Gram (-) Aerobes 287/323
(88.9%) Enterobacteriaceae 281/316 (88.9%) E. coli 237/262 (91%)
ESBL 27/36 (75%) CTXM14/15 20/27 (74%) K. pneumoniae 21/25 (84%)
ESBL 7/10 (70%) CTXM14/15 5/8 (62.5%) P. aeruginosa 6/7 (85.7%)
TABLE-US-00024 TABLE 21 Per pathogen response rates for treatment
of complicated intra-abdominal infections in Phase III clinical
trials CXA-201 for cAIA (with metronidazole) Gram (-) Aerobes
234/243 (96.3) Enterobacteriaceae ESBL 22/22 (100) CTXM14/15 12/12
(100) E. coli 193/201 (96.0) ESBL 14/14 (100) CTXM14/15 9/9 (100)
K. pneumoniae 28/28 (100) ESBL 6/6 (100) CTXM14/15 4/4 (100) P.
aeruginosa 25/25 (100) AmpC 4/4 (100)
Surveillance data from a large 2011 US surveillance study are
summarized in Table 22 below. Ceftolozane/tazobactam demonstrated
higher in vitro activity than currently available cephalosporins
and piperacillin/tazobactam when tested against Enterobacteriaceae
(Table 22). Ceftolozane/tazobactam was the most active
.beta.-lactam agent tested against P. aeruginosa and was 2 to
8-fold more active than ceftazidime or cefepime. Similar to other
.beta.-lactam compounds tested, ceftolozane/tazobactam exhibited
modest activity against Acinetobacter spp. This data also
demonstrated that, with the exception of K. pneumoniae with an ESBL
phenotype, ceftolozane-tazobactam inhibited >90% of
Enterobacteriaceae at MIC values <8 .mu.g/mL. Notably, 94.6% of
E. coli with an ESBL phenotype were inhibited at <8 .mu.g/mL of
ceftolozane/tazobactam.
TABLE-US-00025 TABLE 22 Activity of Ceftolozane and
Ceftolozane/Tazobactam with that of other .beta.-Lactams and a
.beta.-Lactam-Inhibitor Combination against Recent Gram-Negative US
Surveillance Isolates (2011) MIC /MIC (.mu.g/mL) No. of
Ceftolozane/ Piperacillia- Species isolates Ceftolozane Tazobactam
Ceftazidine Cefepinse Tazobactam Aztreonam E. coli (non-ESBL) 1076
0.25/0.25 0.12/0.25 0.12/0.25 .ltoreq.0.5/.ltoreq.0.5 2/4
.ltoreq.0.12/.ltoreq.0.12 K. pneumoniae (non-ESBL) 551 0.25/0.5
0.25/0.5 0.12/0.5 .ltoreq.0.5/.ltoreq.0.5 4/8
.ltoreq.0.12/.ltoreq.0.12 P. mirabilis 203 0.5/0.5 0.5/0.5
0.06/0.06 .ltoreq.0.5/.ltoreq.0.5 .ltoreq.0.5/1 .sup.
.ltoreq.0.12/.ltoreq.0.12 Enterobactor spp. 525 0.5/16 0.25/8
0.25/>32 .ltoreq.0.5/2 .sup. 2/64 .ltoreq.0.12/>16 Serratia
spp. 287 0.5/1.sup. 0.5/1.sup. 0.12/0.5 .ltoreq.0.5/.ltoreq.0.5 2/4
.ltoreq.0.12/0.5 .sup. Citrobacter spp. 174 0.25/16.sup. 0.25/8
0.25/>32 .ltoreq.0.5/1 .sup. 2/64 .ltoreq.0.12/>16 P.
aeringinosa 973 1/4 1/4 2/32 4/16 8/>64 8/>16 Acinetobacter
spp. 208 16/>32 8/>32 32/>32 16/>16 >64/>64
>16/>16 H. influenzae 51 0.12/0.25 0.12/0.12 0.06/0.12
.ltoreq.0.5/.ltoreq.0.5 .ltoreq.0.5/.ltoreq.0.5
.ltoreq.0.12/.ltoreq.0.12 Ceftolozane/tazobactam M determined at a
fixed concentration of 4 .mu.g/mL tazobactam indicates data missing
or illegible when filed
* * * * *