U.S. patent application number 14/213532 was filed with the patent office on 2014-09-18 for ceftolozane pharmaceutical compositions.
The applicant listed for this patent is Cubist Pharmaceuticals, Inc.. Invention is credited to Nicole Miller Damour, Joseph Terracciano.
Application Number | 20140274991 14/213532 |
Document ID | / |
Family ID | 51522651 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140274991 |
Kind Code |
A1 |
Damour; Nicole Miller ; et
al. |
September 18, 2014 |
CEFTOLOZANE PHARMACEUTICAL COMPOSITIONS
Abstract
Pharmaceutical compositions can include ceftolozane and an
amount of sodium chloride effective to provide improved ceftolozane
stability.
Inventors: |
Damour; Nicole Miller;
(Belmont, MA) ; Terracciano; Joseph; (Concord,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cubist Pharmaceuticals, Inc. |
Lexington |
MA |
US |
|
|
Family ID: |
51522651 |
Appl. No.: |
14/213532 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61793007 |
Mar 15, 2013 |
|
|
|
61792092 |
Mar 15, 2013 |
|
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Current U.S.
Class: |
514/192 ;
514/207 |
Current CPC
Class: |
A61K 9/19 20130101; A61K
31/431 20130101; A61K 31/431 20130101; A61K 47/02 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/198 20130101; A61K 47/183 20130101; A61K 47/12 20130101;
A61K 31/198 20130101; A61K 31/43 20130101; A61K 31/546 20130101;
A61K 31/545 20130101; A61K 31/546 20130101 |
Class at
Publication: |
514/192 ;
514/207 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 47/02 20060101 A61K047/02; A61K 47/12 20060101
A61K047/12; A61K 31/431 20060101 A61K031/431; A61K 9/19 20060101
A61K009/19; A61K 47/18 20060101 A61K047/18 |
Claims
1. A pharmaceutical composition comprising about 1,000 mg of
ceftolozane active per 189 mg sodium from sodium chloride, and not
more than 0.03% by high performance liquid chromatography (HPLC) of
a RT63 Impurity at a retention time of about 63 minutes observed by
HPLC using a Develosil column ODS-UG-5; 5 micrometers;
250.times.4.6 mm, a mobile phase of sodium perchlorate buffer
solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate
and oven temperature of 45.degree. C., the pharmaceutical
composition obtained by a process comprising the step of
lyophilizing an aqueous solution comprising sodium chloride and
ceftolozane sulfate to obtain a lyophilized ceftolozane
composition, and formulating the pharmaceutical composition from
the lyophilized ceftolozane composition.
2. The pharmaceutical composition of claim 1, wherein the
pharmaceutical composition comprises a total of about 1,000 mg of
ceftolozane active.
3. A pharmaceutical composition obtained by a process comprising
the step of lyophilizing an aqueous solution comprising about 1,000
mg of ceftolozane per 189 mg sodium from sodium chloride, to obtain
a lyophilized ceftolozane composition.
4. The pharmaceutical composition of claim 3, wherein the pH of the
aqueous solution is 6.0 to 7.0 and the aqueous solution further
comprises L-arginine.
5. The pharmaceutical composition of claim 3, wherein
pharmaceutical composition is formulated for parenteral
administration and further comprises citric acid.
6. The pharmaceutical composition of claim 3, wherein the
composition is a unit dosage form in a vial comprising tazobactam
and 189 mg sodium from sodium chloride per 1,000 mg of ceftolozane
active in the form of ceftolozane sulfate.
7. The pharmaceutical composition of claim 3, wherein a. the
aqueous solution further comprises L-arginine and citric acid; b.
the pH of the aqueous solution is 6.0 to 7.0 prior to
lyophilization; and c. the pharmaceutical composition further
comprises tazobactam blended with the lyophilized ceftolozane
composition.
8. A unit dosage form container containing a unit dosage form of a
pharmaceutical composition formulated for parenteral administration
for the treatment of one or more infections selected from the group
consisting of: complicated intra-abdominal infections, complicated
urinary tract infections and pneumonia infections, the
pharmaceutical composition comprising about 1,000 mg ceftolozane
active in the form of ceftolozane sulfate per 189 mg sodium from
sodium chloride.
9. The unit dosage form container of claim 8, comprising the
ceftolozane sulfate, tazobactam and the sodium chloride and not
more than 0.03% by high performance liquid chromatography (HPLC) of
a RT63 Impurity at a retention time of about 63 minutes observed by
HPLC using a Develosil column ODS-UG-5; 5 micrometers;
250.times.4.6 mm, a mobile phase of sodium perchlorate buffer
solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate
and oven temperature of 45.degree. C.
10. The unit dosage form container of claim 8 in the form of a bag
or vial.
11. The unit dosage form container of claim 8, containing a total
of about 1,000 mg of ceftolozane active.
12. The unit dosage form container of claim 8, containing a total
of about 2,000 mg of ceftolozane active.
13. The unit dosage form of claim 12 for the treatment of
pneumonia.
14. The unit dosage form container of claim 11 in the form of a bag
or vial.
15. The pharmaceutical composition of claim 3, comprising
ceftolozane sulfate, sodium chloride and further comprising
tazobactam, the pharmaceutical composition comprising not more than
0.03% by high performance liquid chromatography (HPLC) of a RT63
Impurity at a retention time of about 63 minutes observed by HPLC
using a Develosil column ODS-UG-5; 5 micrometers; 250.times.4.6 mm,
a mobile phase of sodium perchlorate buffer solution (pH
2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min flow rate and oven
temperature of 45.degree. C.
16. A method of manufacturing a ceftolozane composition having not
more than 0.03% of a RT63 impurity as measured by high performance
liquid chromatography (HPLC) of a RT63 Impurity at a retention time
of about 63 minutes observed by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C., the
method comprising the step of lyophilizing an aqueous solution
comprising about 1,000 mg of ceftolozane per 189 mg sodium from
sodium chloride, to obtain the ceftolozane composition.
17. The product of the process of claim 16, containing a total of
1,000 mg ceftolozane in a unit dosage form container.
Description
RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Patent
Application No. 61/792,092, filed Mar. 15, 2013, and U.S.
Provisional Patent Application No. 61/793,007, filed Mar. 15, 2013,
both of which are incorporated herein in their entirety.
TECHNICAL FIELD
[0002] This disclosure relates to pharmaceutical compositions
comprising ceftolozane.
BACKGROUND
[0003] Ceftolozane is a cephalosporin antibacterial agent. The
antibacterial activity of ceftolozane is believed to result from
its interaction with penicillin binding proteins (PBPs) to inhibit
the biosynthesis of the bacterial cell wall which acts to stop
bacterial replication. Antibacterial pharmaceutical compositions
can include ceftolozane as a pharmaceutically acceptable salt
formulated for intravenous administration. Ceftolozane sulfate is a
pharmaceutically acceptable ceftolozane salt of formula (I) that
can be formulated for intravenous administration or infusion.
##STR00001##
[0004] 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. A number of safe and effective
injectable cephalosporin pharmaceutical compositions (e.g., as
listed in FIG. 1, Table 1) comprise up to about 85 mg of sodium per
gram of cephalosporin activity (i.e., 0-85 mg sodium per gram of
cephalosporin activity).
[0005] In contrast, ceftolozane sulfate pharmaceutical compositions
with similar levels of sodium (e.g., about 20-75 mg sodium from
sodium chloride per gram of ceftolozane) exhibit undesirable levels
of instability as measured by high pressure liquid chromatography
(HPLC) during stability testing. For example, certain ceftolozane
sulfate pharmaceutical compositions were characterized by at least
1.5-fold greater formation of an additional impurity identified by
a retention time of 63 minutes ("RT63 Impurity") during a stability
study as disclosed herein. In addition, stability testing of
ceftolozane pharmaceutical compositions with lower sodium levels
also resulted in greater reduction in total ceftolozane purity.
[0006] Accordingly, there is a need for improved ceftolozane
sulfate pharmaceutical compositions with greater stability,
including improved pharmaceutical compositions that are not
characterized by the RT63 Impurity after a three month stability
test also described herein.
SUMMARY
[0007] The present disclosure provides ceftolozane pharmaceutical
compositions with improved stability. The invention is based in
part on the surprising discovery that ceftolozane in solid (e.g.,
powder) pharmaceutical compositions comprising about 1000 mg of
ceftolozane active per 189 mg sodium from sodium chloride
demonstrate improved chemical stability and purity compared with
pharmaceutical compositions comprising ceftolozane with
comparatively less sodium chloride. For example, the invention is
based in part on the discovery of the absence of the RT63 Impurity
in HPLC analysis of pharmaceutical compositions comprising about
1,000 mg of ceftolozane and 189 mg sodium from sodium chloride. By
comparison, reducing sodium chloride relative to ceftolozane in
tested compositions resulted in at least 1.5-fold greater impurity
at RT=63 minutes (observed by HPLC using a Develosil column
ODS-UG-5; 5 micrometers; 250.times.4.6 mm, a mobile phase of sodium
perchlorate buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a
1.0 mL/min flow rate and oven temperature of 45.degree. C.). The
ceftolozane formulations with reduced levels of sodium were not as
stable as the ceftolozane formulation containing about 1,000 mg of
ceftolozane per 189 mg sodium from sodium chloride. This includes
preferred ceftolozane formulations containing an amount of
ceftolozane per 189 mg of sodium from sodium chloride effective to
maintain the level of RT63 Impurity below the detection limit
(e.g., 0.03%) measured by HPLC using a Develosil column ODS-UG-5; 5
micrometers; 250.times.4.6 mm, a mobile phase of sodium perchlorate
buffer solution (pH 2.5)/CH.sub.3CN 90:10 (v/v) at a 1.0 mL/min
flow rate and oven temperature of 45.degree. C.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a table (Table 1) of FDA-approved parenteral
cephalosporin antibiotic products, including the amount of sodium
per 1 g of the cephalosporin antibiotic, as provided in the
prescribing information.
[0009] FIG. 2 is a diagram of a lyophilization process that can be
used to obtain a lyophilized ceftolozane composition comprising
sodium chloride.
[0010] FIGS. 3A and 3B are chromatograms of ceftolozane drug
substance obtained according to the analytical method described in
Example 2.
[0011] FIG. 4 is a table (Table 2) of peaks for the ceftolozane
prepared by a lyophilization process obtained by HPLC according to
the analytical method of Example 2.
[0012] FIG. 5 is a table (Table 3a) showing the composition of
various ceftolozane pharmaceutical compositions in which the sodium
chloride concentration is varied.
[0013] FIG. 6 is a table (Table 3b) showing data obtained by HPLC
for the RT 63 impurity as detected in the pharmaceutical
compositions described in FIG. 5 containing ceftolozane.
[0014] FIG. 7 is a table (Table 4) showing the composition of
various additional ceftolozane pharmaceutical compositions in which
the sodium chloride content is varied.
[0015] FIG. 8 is a table (Table 5) showing the total purity of
ceftolozane in the pharmaceutical compositions of FIG. 7, as
measured by HPLC peak area according to the analytical method of
described in Example 2.
[0016] FIG. 9 is a graph showing the total purity of certain
pharmaceutical compositions disclosed in FIG. 7, as measured by
HPLC peak area.
[0017] FIG. 10 is a table (Table 6) showing the composition of
various ceftolozane pharmaceutical compositions in which the sodium
chloride concentration is varied.
[0018] FIG. 11 is a table (Table 7) showing the purity of
Ceftolozane in CXA-201 Compositions with varying amounts of sodium
from sodium chloride at time zero, 1 day, 3 days and 7 days at
60.degree. C.
[0019] FIG. 12 is a table (Table 8) showing purities of ceftolozane
and a control (no excipient) in a lyophilized ceftolozane and
sodium chloride composition at time zero, 1 day, 3 days and 7 days
at 60.degree. C., measured by HPLC.
DETAILED DESCRIPTION
[0020] 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
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.
[0021] Surprisingly, pharmaceutical compositions comprising
ceftolozane sulfate and about 1000 mg ceftolozane active per 189 mg
sodium from sodium chloride exhibited unexpectedly improved
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 (e.g., see Example
3).
[0022] Pharmaceutical compositions comprising ceftolozane can be
formulated to treat infections by parenteral administration
(including subcutaneous, intramuscular, and intravenous)
administration. Pharmaceutical compositions may additionally
comprise excipients, pH adjusting additives (e.g., buffers) and the
like. Non-limiting examples of these additives include citric acid
and L-arginine. For example, L-arginine can be used to adjust pH
and to increase the solubility of ceftolozane; and citric acid can
be used to prevent discoloration of the product, due to its ability
to chelate metal ions. In one particular embodiment, the
pharmaceutical compositions described herein are formulated for
administration by intravenous injection or infusion.
[0023] Pharmaceutical compositions comprising ceftolozane and
sodium chloride can be obtained by 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). A pharmaceutical composition comprising
ceftolozane can be prepared by adding sodium chloride in a fixed
ratio to ceftolozane in an aqueous solution prior to
lyophilization. For example, the method can comprise the steps of:
(1) forming a solution comprising sodium chloride and ceftolozane
or a salt thereof followed by lyophilizing the solution; and (2)
combining the lyophilized ceftolozane with other components (e.g.,
a .beta.-lactamase inhibitor, such as tazobactam, or a lyophilized
.beta.-lactamase inhibitor, such as a lyophilized tazobactam) to
obtain the pharmaceutical composition. The resulting pharmaceutical
composition can be a powder for reconstitution to obtain an
injectable pharmaceutical composition that can be intravenously
administered to a patient. In yet a further embodiment, the method
comprises adding about 1000 mg of ceftolozane active per 189 mg
sodium from sodium chloride in an aqueous solution, then
lyophilizing the solution to obtain a lyophilized material
comprising sodium chloride and ceftolozane sulfate in a ratio
effective to provide a product with less than 0.03% of the RT63
Impurity as detected by HPLC in Example 2.
[0024] Another embodiment of the invention is a vial containing a
unit dosage form of a pharmaceutical composition formulated for
parenteral administration for the treatment of complicated
intra-abdominal infections or complicated urinary tract infections.
The vial can be obtained by a process comprising the steps of: a)
lyophilizing an aqueous solution comprising about 1000 mg
ceftolozane active in the form of ceftolozane sulfate per 189 mg
sodium from sodium chloride and further comprising citric acid, and
L-arginine to obtain a lyophilized ceftolozane composition; and b)
filling a sufficient quantity of the lyophilized composition into a
vial to obtain a unit dosage form comprising about 1,000 mg of
ceftolozane active in the form of ceftolozane sulfate per 189 mg
sodium from sodium chloride. In one aspect, the pH of the aqueous
solution is 6.0 to 7.0. In another aspect the pharmaceutical
composition is formulated for parenteral administration by
reconstituting the pharmaceutical composition in the vial (e.g.,
with 10 mL of diluent such as water for injection or isotonic
saline) followed by addition of the reconstituted pharmaceutical
composition to a carrier for injection (e.g., about 100 mL of
isotonic saline or other pharmaceutically acceptable carrier for
intravenous administration). Optionally, the vial is also filled
with tazobactam (e.g., a lyophilized tazobactam such as tazobactam
sodium). In yet another aspect, the pharmaceutical composition is a
solid (e.g., amorphous powder, crystal or combination thereof)
obtained from a liquid composition comprising sodium chloride in an
amount providing 189 mg sodium from sodium chloride, 1,000 mg of
ceftolozane active and tazobactam in an amount providing about 500
mg tazobactam acid equivalent per 1,000 mg of ceftolozane active,
the resulting solid pharmaceutical composition being formulated for
parenteral administration and the pH of the aqueous solution is 6.0
to 7.0.
[0025] The pharmaceutical compositions can be administered for the
treatment of infections, such as complicated intra-abdominal
infections, complicated urinary tract infections (cUTIs) and
pneumonia (e.g., community-acquired, hospital-acquired, etc). In
one aspect, provided herein is a method for the treatment of
bacterial infections in a mammal, comprising administering to said
mammal a therapeutically effective amount of a pharmaceutical
composition prepared according to the methods described herein. A
method for the treatment of bacterial infections in a mammal can
comprise administering to said mammal a therapeutically effective
amount of a pharmaceutical composition comprising ceftolozane
sulfate and sodium chloride. Non-limiting examples of bacterial
infections that can be treated by the methods of the invention
include infections caused by: aerobic and facultative gram-positive
microorganisms (e.g., Staphylococcus aureus, Enterococcus faecalis,
Staphylococcus epidermidis, Streptococcus agalactiae, Streptococcus
pneumonia, Streptococcus pyogenes, Viridans group streptococci),
aerobic and facultative gram-negative microorganisms (e.g.,
Acinetobacter baumanii, Escherichia coli, Haemophilus influenza,
Klebsiella pneumonia, Pseudomonas aeruginosa, Citrobacter koseri,
Moraxella catarrhalis, Morganella morganii, Neisseria gonorrhoeae,
Proteus mirabilis, Proteus vulgaris, Serratia marcescens,
Providencia stuartii, Providencia rettgeri, Salmonella enterica),
gram-positive anaerobes (Clostridium perfringens), and
gram-negative anaerobes (e.g., Bacteroides fragilis group (e.g., B.
fragilis, B. ovatus, B. thetaiotaomicron, and B. vulgates),
Bacteroides distasonis, Prevotella melaninogenica). In certain
embodiments of the methods described herein, bacterial infection is
associated with one or more of the following conditions:
complicated intra-abdominal infections, complicated urinary tract
infections (cUTIs) and pneumonia (e.g., community-acquired, or
nosocomial pneumonia). Community-acquired pneumonia (moderate
severity only) can include infections caused by
piperacillin-resistant, beta-lactamase producing strains of
Haemophilus influenza. Nosocomial pneumonia (moderate to severe)
caused by piperacillin-resistant, beta-lactamase producing strains
of Staphylococcus aureus and by Acinetobacter baumanii, Haemophilus
influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
[0026] 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.
[0027] 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.
[0028] Unless otherwise indicated, as used herein, the phrase
"about 1000 mg ceftolozane" refers to an amount of ceftolozane that
is considered a bioequivalent by the United States Food and Drug
Administration (FDA), i.e. for which 90% CI of the relative mean
Cmax, AUC(0-t) and AUC(0-.infin.) is within 80.00% to 125.00% of
the reference formulation in the fasting state (see: "Guidance for
Industry: Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products--General Considerations" Center for Drug
Evaluation and Research, United States Food and Drug
Administration, 2003).
[0029] As used herein, "189 mg sodium from sodium chloride per 1000
mg of ceftolozane" refers to a ratio of sodium from the sodium
chloride to ceftolozane active. For example, "189 mg sodium from
sodium chloride per 1000 mg of ceftolozane" includes, for example,
94.4 mg sodium from sodium chloride per 500 mg of ceftolozane, as
well as, for example, 47.2 mg sodium from sodium chloride per 250
mg ceftolozane. In addition, "1,000 mg of ceftolozane as
ceftolozane sulfate" refers to an amount of ceftolozane sulfate
effective to provide 1,000 mg of ceftolozane. "189 mg sodium from
sodium chloride" refers to the amount of sodium chloride (e.g., 480
mg) effective to provide 189 mg of sodium. The amount of sodium
from sodium chloride per gram of ceftolozane activity in a
pharmaceutical composition containing ceftolozane sulfate, chloride
and sodium chloride can be calculated using the relevant molecular
weights of ceftolozane, ceftolozane sulfate, sodium chloride and
sodium. For example, a composition comprising about 1,147 mg
ceftolozane sulfate and 189 mg sodium from sodium chloride contains
480 mg sodium chloride per 1,000 mg ceftolozane active.
[0030] As used herein, "1000 mg ceftolozane" refers to an amount of
ceftolozane that is considered a bioequivalent by the United States
Food and Drug Administration (FDA), i.e. for which 90% CI of the
relative mean Cmax, AUC(0-t) and AUC(0-.infin.) is within 80.00% to
125.00% of the reference formulation in the fasting state (see:
"Guidance for Industry: Bioavailability and Bioequivalence Studies
for Orally Administered Drug Products--General Considerations".
Center for Drug Evaluation and Research, United States Food and
Drug Administration, 2003).
[0031] A pharmaceutical composition can comprise ceftolozane in the
form of ceftolozane sulfate and 189 mg sodium from sodium chloride
per 1,000 mg of ceftolozane. The pharmaceutical composition of can
further comprise L-arginine. The pharmaceutical composition can
further comprise citric acid. The pharmaceutical composition can
further comprise a lyophilized composition of the ceftolozane in
the form of ceftolozane sulfate and the sodium from the sodium
chloride. The pharmaceutical composition can also comprise 189 mg
sodium from sodium chloride, 1,000 mg of ceftolozane in the form of
ceftolozane sulfate, and further comprise L-arginine and citric
acid.
Illustrative Examples of Selected Embodiments of the Invention
Example 1
Manufacturing Procedure of Bulk (Tray) Lyophilized Ceftolozane
[0032] There are four main steps in the manufacture of CXA-101 bulk
drug product: dissolution, sterile filtration, bulk lyophilization,
and packaging into Sterbags.RTM.. These four main steps are
composed of a total of 20 minor steps. The CXA-101 bulk drug
product manufacturing process is presented below. [0033] I.
Dissolution [0034] 1. The prescribed amount of WFI is charged into
the dissolution reactor. [0035] 2. A prescribed amount of citric
acid is added. [0036] 3. The solution is cooled at 5.degree. C. to
10.degree. C. [0037] 4. A prescribed amount of CXA-101 drug
substance is added to the solution. [0038] 5. A prescribed amount
of L-arginine is slowly added to the solution. [0039] 6. A check
for complete dissolution is performed. Solution pH is verified to
be in the target range of 6.5 to 7.0. [0040] 7. A prescribed amount
of sodium chloride is added to the solution. [0041] 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. [0042] 9. WFI is
added to bring the net weight to 124.4 kg and the solution is mixed
well. [0043] 10. Samples are withdrawn for testing of final pH.
[0044] II. Sterile filtration [0045] 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. [0046] 12. The line is washed with WFI. [0047] 13. The
washing solution is passed from Step 12 through sterile filtration.
[0048] III. Bulk lyophilization [0049] 14. The washing solution is
loaded onto a separate shelf in the lyophilizer (and later
discarded). [0050] 15. The solution is lyophilized until dry.
[0051] 16. The product shelf is cooled to 20.degree.
C..+-.5.degree. C. [0052] IV. Packaging into Sterbags.RTM. [0053]
17. The lyophilized bulk drug product powder is milled. [0054] 18.
The milled powder is sieved. [0055] 19. The sieved powder is
blended for 30 minutes. [0056] 20. The powder is then discharged
into Sterbags.RTM.
Prefiltration and Sterile-Filtration
[0057] 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.
[0058] 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
[0059] 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.
[0060] 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.
[0061] Sterilize a sufficient quantity of flip-off caps by steam
sterilizer. Then transfer the sterilized flip-off caps into a Grade
A or B area located in an aseptic room.
Filling and Partially Stoppering
[0062] 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.
[0063] Immediately after a vial is filled, partially stopper the
vial with a sterilized stopper. Load the filled and partially
stoppered vials onto the shelves of a lyophilizer aseptically.
Lyophilization to Crimping, Visual Inspection, Labeling and
Packaging
[0064] After all filled and partially stoppered vials are loaded
into a lyophilizer, start the lyophilization program shown in FIG.
2. Freeze the loaded vials at -40.degree. C. and keep until all
vials freeze. Forward the program to primary drying step (shelf
temperature; -20.degree. C., chamber pressure; 100 to 150 mTorr).
Primary drying time should be determined by monitoring the product
temperature. Forward the program to secondary drying step (shelf
temperature; 30.degree. C., chamber pressure; not more than 10
mTorr) after completion of the primary drying step. After all vials
are dried completely, return the chamber pressure to atmospheric
pressure with sterilized nitrogen. Then stopper vials
completely.
[0065] Unload the lyophilized vials from the chamber and crimp with
sterilized flip-off caps.
[0066] Subject all crimped vials to visual inspection and label and
package all passed vials.
Example 2
Analytical HPLC Method
A. Operative Conditions
TABLE-US-00001 [0067] Column Develosil ODS-UG-5; 5 .mu.m, 250
.times. 4.6 mm (Nomura Chemical, Japan) Mobile phase Sodium
Perchlorate Buffer Solution (PH 2.5)/ CH.sub.3CN 90:10 (vlv) Flow
rate 1.0 mL/min Wavelength 254 nm Injection volume 10 .mu.L Oven
Temperature 45.degree. C. Run Time 85 minutes Gradient Profile:
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.
[0068] 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).
[0069] Mobile Phase was then made by mixing Sodium Perchlorate
Buffer Solution (pH 2.5) and acetonitrile in the ratio 90:10
(v/v).
[0070] 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.
[0071] Sample solution: dissolve 20.0 mg, exactly weighed, of
Sample, in 20.0 mL of water (Prepare just before injection into
HPLC system).
[0072] 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
[0073] 1. Inject Blank (water) [0074] 2. Inject System Suitability
Solution and check for tailing factor and theoretical plate number
for CXA-101 peak: [0075] The tailing factor must not be greater
than 1.5 [0076] Theoretical plates number must not be less than
10000 [0077] 3. Inject Sample Solution [0078] 4. Inject System
Suitability Solution and check for tailing factor and theoretical
plate number for CXA-101 peak. [0079] The tailing factor must not
be greater than 1.5 [0080] Theoretical plates number must not be
less than 10000 [0081] 5. Identify the peaks of Related Substances
in the Sample chromatogram based on the reference chromatogram
reported in FIGS. 3A and 3B or, alternatively, on the basis of the
RRT (Retention Time Relative to CXA-101) values reported in Table 2
(FIG. 4)
E. Calculations
[0081] [0082] I. Report for each related substance its amount as
expressed by area percent.
[0082] C i = A i .times. 100 A t + A i ##EQU00001## [0083] wherein:
[0084] C.sub.i=Amount of related substance i in the Sample, area %
[0085] A.sub.i=Peak area of related substance i in the Sample
chromatogram [0086] A.sub.t=Area of CXA-101 peak in the Sample
chromatogram [0087] A.sub.t+.SIGMA.A.sub.i=Total peaks area in the
Sample chromatogram
[0088] 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. [0089]
II. Report the total impurities content as expressed by the
following formula:
[0089] C T = A i .times. 100 A t + A i ##EQU00002## [0090] wherein:
[0091] C.sub.T=total impurities content in the Sample, area %
[0092] A.sub.t=area of CXA-101 peak in the sample chromatogram
[0093] .SIGMA.A.sub.i=total peak areas of impurities in the sample
chromatogram
Example 3
Increasing the Amount of Sodium Chloride Stabilizes Ceftolozane
Pharmaceutical Compositions
[0094] Multiple stability studies were performed on ceftolozane
sulfate, wherein the effect of varying amounts of sodium chloride
on the stability of ceftolozane was examined.
[0095] The amount of sodium per mg of sodium chloride can be
calculated (as known to one of ordinary skill in the art) based on
the relative molar weight ratio of sodium and sodium chloride
(e.g., 50 mg sodium chloride contains about 20 mg of sodium,
etc).
[0096] The amount of ceftolozane in ceftolozane sulfate can
similarly be calculated based on the respective molecular molar
weights of ceftolozane and ceftolozane sulfate (e.g., 1,147 mg
ceftolozane sulfate contains about 1,000 mg of ceftolozane).
Accordingly, a composition comprising about 1,147 mg ceftolozane
sulfate and 480 mg of sodium chloride also contains 480 mg of
sodium chloride per 1,000 mg of ceftolozane.
A. Reduction of the Impurity at RT=63 Minutes
[0097] A stability study was carried out at 25.degree. C. as
described above. High, mid, and low salt formulations contained
189, 49.2 and 24.6 mg sodium from sodium chloride (480, 125, and
62.5 mg sodium chloride) per 1000 mg ceftolozane active,
respectively. Compositions of blend Drug Product are listed in
Table 3a in FIG. 5. Test results are summarized in Table 3b in FIG.
6.
[0098] Conclusion: 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
[0099] A stability study was carried out at 60.degree. C. as
described above. Sodium chloride content in test samples is
described in Table 4 (FIG. 7). The results are provided in Table 5,
FIG. 8 and the graph in FIG. 9. These results show that less total
impurities were formed in the presence of 189 grams sodium from
sodium chloride (481 grams sodium chloride) than with 74.7, 49.2,
29.5 or 19.7 mg sodium from sodium chloride (190.0, 125.0, 75.0 or
50.0 mg sodium chloride) per gram CXA-201 at 1, 3 and 7 days at
60.degree. C./60% relative humidity.
C. Improvement in the Purity of Ceftolozane in CXA-201
Pharmaceutical Compositions with Varying Amounts of Sodium
Chloride
[0100] A stability study was carried out at 60.degree. C. as
described above. The sodium chloride content in the CXA-201
compositions is described in Table 6 in FIG. 10. The HPLC data at
60.degree. C. are summarized in Table 7 in FIG. 11.
Example 4
Screening of Stabilizing Agents
[0101] Sodium chloride was screened as a stabilizing agent. The
purity of the ceftolozane in a composition comprising 100 mg
ceftolozane and 100 mg of sodium chloride after 3 days at
60.degree. C. was compared to a composition comprising 100 mg
cefolozane comprising no stabilizing agent.
[0102] As shown in Table 8, FIG. 12, the ceftolozane composition
comprising sodium chloride was demonstrated to be more stable than
the ceftolozane composition comprising no stabilizing agent.
* * * * *