U.S. patent application number 16/205445 was filed with the patent office on 2019-10-31 for parenteral formulations for administering macrolide antibiotics.
The applicant listed for this patent is Cempra Pharmaceuticals, Inc.. Invention is credited to Prabhavathi FERNANDES, David E. PEREIRA, Sara WU.
Application Number | 20190328759 16/205445 |
Document ID | / |
Family ID | 49261221 |
Filed Date | 2019-10-31 |
![](/patent/app/20190328759/US20190328759A1-20191031-C00001.png)
![](/patent/app/20190328759/US20190328759A1-20191031-C00002.png)
![](/patent/app/20190328759/US20190328759A1-20191031-C00003.png)
![](/patent/app/20190328759/US20190328759A1-20191031-C00004.png)
![](/patent/app/20190328759/US20190328759A1-20191031-C00005.png)
![](/patent/app/20190328759/US20190328759A1-20191031-C00006.png)
![](/patent/app/20190328759/US20190328759A1-20191031-D00001.png)
![](/patent/app/20190328759/US20190328759A1-20191031-D00002.png)
![](/patent/app/20190328759/US20190328759A1-20191031-D00003.png)
![](/patent/app/20190328759/US20190328759A1-20191031-D00004.png)
![](/patent/app/20190328759/US20190328759A1-20191031-D00005.png)
View All Diagrams
United States Patent
Application |
20190328759 |
Kind Code |
A1 |
PEREIRA; David E. ; et
al. |
October 31, 2019 |
PARENTERAL FORMULATIONS FOR ADMINISTERING MACROLIDE ANTIBIOTICS
Abstract
Pharmaceutical compositions adapted for the parenteral
administration, including intravenous administration, of triazole
containing macrolide antibiotics, and methods for their use in the
treatment of bacterial, protozoal, and other infections are
described herein.
Inventors: |
PEREIRA; David E.; (Apex,
NC) ; WU; Sara; (Cary, NC) ; FERNANDES;
Prabhavathi; (Chapel Hill, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cempra Pharmaceuticals, Inc. |
Chapel Hill |
NC |
US |
|
|
Family ID: |
49261221 |
Appl. No.: |
16/205445 |
Filed: |
November 30, 2018 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14387643 |
Sep 24, 2014 |
10188674 |
|
|
PCT/US13/34179 |
Mar 27, 2013 |
|
|
|
16205445 |
|
|
|
|
61783026 |
Mar 14, 2013 |
|
|
|
61616196 |
Mar 27, 2012 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/22 20130101;
A61P 31/04 20180101; A61K 47/12 20130101; A61P 31/00 20180101; A61K
31/7048 20130101; A61K 9/0019 20130101 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 47/12 20060101 A61K047/12; A61K 47/18 20060101
A61K047/18; A61K 47/22 20060101 A61K047/22; A61K 9/00 20060101
A61K009/00 |
Claims
1. A pharmaceutical composition adapted for parenteral
administration comprising one or more antibiotic compounds and a
formulating agent, wherein the formulating agent is selected from
the group consisting of lactic acid, an amino acid, and
combinations thereof, and pharmaceutically acceptable salts of the
foregoing; and where the one or more antibiotic compounds are of
the formula ##STR00006## and pharmaceutically acceptable salts
thereof, wherein: R.sup.10 is hydrogen, acyl or a prodrug moiety; W
is H, F, Cl, Br, I, or OH; A is CH.sub.2, C(O), C(O)O, C(O)NH,
S(O).sub.2, S(O).sub.2NH, or C(O)NHS(O).sub.2; B is
C.sub.2-C.sub.10 alkenylene or C.sub.1-C.sub.10 alkylene; and C is
hydrogen, hydroxy, acyl, acyloxy, sulfonyl, ureido, or carbamoyl,
or alkyl, alkoxy, heteroalkyl, heteroalkoxy, aryl, arylalkyl,
heteroaryl, or heteroarylalkyl, each of which is optionally
substituted.
2.-39. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Application Ser. No. 61/616,196, filed
Mar. 27, 2012 and U.S. Provisional Application Ser. No. 61/783,026,
filed Mar. 14, 2013, both of which are incorporated by reference
herein.
TECHNICAL FIELD
[0002] The invention described herein pertains to pharmaceutical
compositions adapted for the parenteral administration, including
intravenous administration, of triazole containing macrolide
antibiotics, and methods for their use in the treatment of
bacterial, protozoal, and other infections. In particular, the
invention described herein pertains to pharmaceutical compositions
adapted for the parenteral administration, including intravenous
administration of the ketolide antibiotics, such as CEM-101, also
known as solithromycin, and related compounds, and methods for
their use in the treatment of bacterial, protozoal, and other
infections.
BACKGROUND AND SUMMARY OF THE INVENTION
[0003] Macrolide antibiotics, characterized by a large lactone ring
to which are attached one or more deoxy sugars, usually cladinose
and desosamine, are antimicrobial drugs that are active against
aerobic and anaerobic gram positive cocci and are prescribed for
the treatment of a number of infections, including respiratory
tract and soft tissue infections. The macrolides, which belong to
the polyketide class of natural products, function by reversibly
binding to the 50S subunit of the bacterial ribosome, blocking
protein synthesis and preventing bacterial growth and reproduction.
Although this action is primarily bacteriostatic, certain
triazole-containing fluoroketolide macrolides are bactericidal.
Other macrolides may be bactericidal at higher concentrations.
[0004] Ketolides, which are semi-synthetic derivatives of the
14-membered macrolide erythromycin A, belong to the class of drugs
used to treat respiratory tract infections. These drugs are
effective against macrolide-resistant bacteria because of their
ability to bind to two sites on the bacterial ribosome. Even so,
acquired bacterial resistance to macrolides may occur, such as by
post-transcriptional methylation of the 23S bacterial ribosome.
This resistance results in cross-resistance to macrolides,
lincosamides and streptogramins. Although rare, acquired resistance
also can result from the production of drug-inactivating enzymes
such as esterases or kinases, as well as the production of active
ATP-dependent efflux proteins that transport macrolides out of the
cell. A significant fraction of pneumococci are resistant to
currently available antibiotics.
[0005] Erythromycin and the semi-synthetic derivatives azithromycin
and clarithromycin are among the currently approved macrolide
antibiotics. Telithromycin and cethromycin belong to the ketolide
group of antibiotics. Oral administration has been accomplished for
many macrolides and ketolides, including erythromycin,
clarithromycin, telithromycin, and azithromycin. Erythromycin is
also formulated as a lactobionate salt for injection; azithromycin
is also formulated as a citrate salt for injection; and
clarithromycin is available in some countries formulated as a
lactobionate salt for injection. Ketolides, such as telithromycin
and cethromycin have not been approved for parenteral
administration, including IV administration. Unlike the oral
counterparts, the corresponding parenteral administration, such as
intravenous (IV) and intramuscular (IM) administration of known
macrolides and ketolides, especially approved macrolides such as
erythromycin, clarithromycin, telithromycin, and azithromycin, has
been hampered by pharmacologic pain upon administration, and
adverse side effects that may arise from the substantially
different pharmacokinetics and pharmacodynamics accompanying
parenteral administration compared to oral administration. For
example, erythromycin, clarithromycin, and azithromycin have been
reported to be painful when administered parenterally, leading to
limitations on their use, issues with patient compliance, and other
disadvantages.
[0006] Currently, there are no ketolides approved for parenteral
administration, including intravenous administration. Accordingly,
a need exists for alternative parenteral formulations, and methods
for using such parenteral formulations, of ketolides in the
treatment of bacterial, protozoal, and other infections. In
addition, a need exists for parenteral formulations, and methods
for using such parenteral formulations, of ketolides that may be
administered at higher concentrations, and at faster rates.
[0007] It has been unexpectedly discovered that conventional
formulations, such as formulations that include lactobionate salts,
citrate salts, and/or physioloigcal saline, are not readily
adaptable for use with triazole-containing ketolide antibiotics.
Such conventional formulations require undue optimization to
provide compoisions and methods for treating bacterial, protozoal,
and other infections without excessive pain, or other adverse side
effects. In particular, such conventional formulations may not be
administered in high concentrations, or at rapid rates due to pain,
or other adverse side effects.
[0008] It has also been unexpectedly discovered that formulations
of triazole-containing ketolide antibiotics that include one or
more lactic acids, one or more amino acids, or combinations
thereof, including any pharmaceutically acceptable salts of the
foregoing, are useful for the parenteral delivery of such
triazole-containing ketolide antibiotics.
[0009] Illustrative triazole-containing ketolide antibiotics
include compounds described in WO 2004/080391, and related
compounds. Further illustrative triazole-containing ketolide
antibiotics include compounds of the formula:
##STR00001##
and pharmaceutically acceptable salts, solvates, and hydrates
thereof, wherein:
[0010] R.sup.10 is hydrogen, acyl or a prodrug moiety;
[0011] X and Y are taken together with the attached carbon to form
carbonyl;
[0012] V is C(O);
[0013] W is H, F, Cl, Br, I, or OH;
[0014] A is CH.sub.2, C(O), C(O)O, C(O)NH, S(O).sub.2,
S(O).sub.2NH, or C(O)NHS(O).sub.2;
[0015] B is C2-C10 alkenylene, or C1-C10 alkylene, such as
(CH.sub.2).sub.n where n is an integer ranging from 1-10, from 2-6,
or from 3-5; and
[0016] C is hydrogen, hydroxy, acyl, acyloxy, sulfonyl, ureido, or
carbamoyl, or alkyl, alkoxy, heteroalkyl, heteroalkoxy, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, each of which is
optionally substituted.
[0017] Further illustrative triazole-containing ketolide
antibiotics include the fluoroketolide compound solithromycin
(SOL), Chemical Abstracts Registry Number 760981-83-7, and having
the following structure:
##STR00002##
and pharmaceutically acceptable salts, hydrates, solvates, esters,
and prodrugs thereof. SOL is also described in international patent
application, publication number WO 2004/080391. Solithromycin is
also known as CEM-101 and as OP-1068. The preparation of SOL and
related compounds is described in WO 2009/055557. The disclosure of
each of the foregoing publications, and each additional publication
cited herein are incorporated herein by reference.
[0018] Also described herein are solid, solution, and liquid
formulations for such other therapeutic compounds that are
characterized by low solubility and/or low basicity. It has been
surprisingly discovered that the formulations described herein that
include of one or more lactic acids, one or more amino acids, or
combinations thereof, including any pharmaceutically acceptable
salts of the foregoing, are useful for the parenteral delivery of
such low solubility and/or low basicity therapeutic compounds.
[0019] Without being bound by theory, it is believed herein that
the formulations described herein improve the solubility of such
therapeutic compounds, including such therapeutic compounds that
are weakly basic. In another embodiment, described herein are
pharmaceutical compositions comprising lactic acid and
pharmaceutically acceptable salts thereof adapted for the
parenteral administration of low solubility and/or low basicity
therapeutic compounds. In another embodiment, described herein are
pharmaceutical compositions comprising amino acid and
pharmaceutically acceptable salts thereof adapted for the
parenteral administration of low solubility and/or low basicity
therapeutic compounds. In another embodiment, described herein are
pharmaceutical compositions comprising lactic acid and amino acids,
and pharmaceutically acceptable salts thereof, adapted for the
parenteral administration of low solubility and/or low basicity
therapeutic compounds. The solid, liquid, and solution formulations
described herein solve the problems of administering low solubility
and/or weakly basic therapeutic compounds, such as
triazole-containing macrolide antibiotics.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 shows a diagram of the dynamic in vitro apparatus for
evaluating precipitation upon injection of an infusion
solution.
[0021] FIG. 2 shows the traces in the dynamic precipitation model
for the CEM-101/Mannitol/Tartrate Formulation at 3 mg/mL in 0.45%
Saline, infused at the injection rate of 0.3, 1.0, 3.0 and 6.0
mL/min (infusions started at t=1.0 min).
[0022] FIG. 3 shows the traces in the dynamic precipitation model
for the CEM-101/Mannitol/Tartrate Formulation at 3 mg/mL in 5%
Mannitol, infused at the injection rate of 0.3, 1.0, 3.0 and 6.0
mL/min (infusions started at t=1.0 min).
[0023] FIG. 4 shows the traces in the dynamic precipitation model
for the CEM-101/Mannitol/Tartrate Formulation at 1 mg/mL in 5%
Mannitol, infused at the injection rate of 0.3, 1.0, 3.0 and 6.0
mL/min (infusions started at t=1.0 min).
[0024] FIG. 5 the traces in the dynamic precipitation model for the
comparison of the 3 mg/mL CEM-101/Mannitol/Tartrate Formulation
(CEM-101) in 5 mM citrate buffer at pH 4 with the 3 mg/mL
CEM-101/Mannitol/Tartrate Formulation (CEM-101) in 0.45% saline at
infusion rates of 1 mL/min (t=1 min), 2 mL/min (t=3 min) and 3
mL/min (t=5 min).
[0025] FIG. 6A and FIG. 6B shows the traces in the dynamic
precipitation model for the evaluation of the 2 mg/mL
CEM-101/Mannitol/Tartrate Formulation (CEM-101) in 0.5% lactate
buffer at pH 4 in 0.5% saline at infusion rates of 1 mL/min (t=1
min), 2 mL/min (t=4 min) and 3 mL/min (t=7 min) and the comparison
with the 2 mg/mL CEM-101/Mannitol/Tartrate Formulation (CEM-101) in
0.45% saline.
[0026] FIG. 7 shows the traces in the dynamic precipitation model
for the evaluation of the 2 mg/mL and the 1 mg/mL
CEM-101/Mannitol/Tartrate Formulation (CEM-101) in 1% lactate
buffer at pH 4 in 0.45% saline at infusion rates of 1 mL/min (t=1
min), 2 mL/min (t=3 min) and 3 mL/min (t=5 min).
[0027] FIG. 8 shows the traces in the dynamic precipitation model
for the evaluation of 3 mL/min (t=6.5 min) of 2 mg/mL SOL in 25 mM
histidine+25 mM glutamic acid+25 mM acetic acid formulation at pH
5.0, each into a 0.5% saline vehicle.
DETAILED DESCRIPTION
[0028] In one illustrative embodiment of the invention, a solid
pharmaceutical composition comprising a drug or other therapeutic
agent that is characterized as having low solubility and/or low
basicity is described. In one aspect, the formulation comprises
lactic acid lactic acid or a pharmaceutically acceptable salt
thereof, or a combination thereof. In one variation, the
formulation comprises one or more amino acids or pharmaceutically
acceptable salts thereof, or a combination thereof. In another
variation, the formulation comprises lactic acid lactic acid or a
pharmaceutically acceptable salt thereof, and one or more amino
acids or pharmaceutically acceptable salts thereof, or a
combination thereof. In another embodiment, the solid formulations
are adapted for parenteral administration, such as intravenous
administration. For example, the solid formulations may be
reconstituted, or dissolved in a pharmaceutically acceptable
vehicle for parenteral administration, such as intravenous
administration.
[0029] In another illustrative embodiment, a solid pharmaceutical
composition comprising a SOL, related compounds, and/or
pharmaceutically acceptable salts thereof, is described. In one
aspect, the formulation comprises lactic acid lactic acid or a
pharmaceutically acceptable salt thereof, or a combination thereof.
In one variation, the formulation comprises one or more amino acids
or pharmaceutically acceptable salts thereof, or a combination
thereof. In another variation, the formulation comprises lactic
acid lactic acid or a pharmaceutically acceptable salt thereof, and
one or more amino acids or pharmaceutically acceptable salts
thereof, or a combination thereof. In another embodiment, the solid
formulations are adapted for parenteral administration, such as
intravenous administration. For example, the solid formulations may
be reconstituted, or dissolved in a pharmaceutically acceptable
vehicle for parenteral administration, such as intravenous
administration.
[0030] In another illustrative embodiment of the invention, a
liquid and/or solution pharmaceutical composition comprising a drug
or other therapeutic agent that is characterized as having low
solubility and/or low basicity is described. In one aspect, the
formulation comprises lactic acid lactic acid or a pharmaceutically
acceptable salt thereof, or a combination thereof. In one
variation, the formulation comprises one or more amino acids or
pharmaceutically acceptable salts thereof, or a combination
thereof. In another variation, the formulation comprises lactic
acid lactic acid or a pharmaceutically acceptable salt thereof, and
one or more amino acids or pharmaceutically acceptable salts
thereof, or a combination thereof. In another embodiment, the
liquid and/or solution formulations further comprises a carrier or
vehicle, such as water.
[0031] In another illustrative embodiment, a liquid and/or solution
pharmaceutical composition comprising a SOL, related compounds,
and/or pharmaceutically acceptable salts thereof, is described. In
one aspect, the formulation comprises lactic acid lactic acid or a
pharmaceutically acceptable salt thereof, or a combination thereof.
In one variation, the formulation comprises one or more amino acids
or pharmaceutically acceptable salts thereof, or a combination
thereof. In another variation, the formulation comprises lactic
acid lactic acid or a pharmaceutically acceptable salt thereof, and
one or more amino acids or pharmaceutically acceptable salts
thereof, or a combination thereof. In another embodiment, the
liquid and/or solution formulations further comprises a carrier or
vehicle, such as water.
[0032] In another embodiment, the formulations described herein
include one or more compounds of the formula:
##STR00003##
and pharmaceutically acceptable salts thereof, wherein:
[0033] R.sup.10 is hydrogen, acyl or a prodrug moiety;
[0034] X and Y are taken together with the attached carbon to form
carbonyl;
[0035] V is C(O);
[0036] W is H, F, Cl, Br, I, or OH;
[0037] A is CH.sub.2, C(O), C(O)O, C(O)NH, S(O).sub.2,
S(O).sub.2NH, or C(O)NHS(O).sub.2;
[0038] B is C.sub.2-C.sub.10 alkenylene, or B is C.sub.1-C.sub.10
alkylene, such as (CH.sub.2).sub.n where n is an integer ranging
from 1-10, from 2-6, from 3-5, from 3-4, or n is 3; and
[0039] C is hydrogen, hydroxy, acyl, acyloxy, sulfonyl, ureido, or
carbamoyl, or alkyl, alkoxy, heteroalkyl, heteroalkoxy, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, each of which is
optionally substituted.
[0040] In another embodiment, R.sup.10 is hydrogen. In another
embodiment, W is H or F. In another embodiment, W is F. In another
embodiment, A is CH.sub.2. In another embodiment, B is
(CH.sub.2).sub.n, where n is an integer ranging from 1-10. In
another embodiment, B is (CH.sub.2).sub.n, where n is an integer
ranging from 2-6. In another embodiment, B is (CH.sub.2).sub.n,
where n is an integer ranging from 3-5. In another embodiment, B is
(CH.sub.2).sub.n, where n is 3. In another embodiment, C is
optionally substituted aryl. In another embodiment, C is aminoaryl.
In another embodiment, C is 3-aminophenyl. It is to be understood
that the selections for each of R.sup.10 X, Y, V, W, A, B, and C
combined in all possible ways area also described herein. For
example, in another embodiment, R.sup.10 is hydrogen, and W is H or
F; and R.sup.10 is hydrogen, W is F, and A is CH.sub.2. In
addition, it is to be understood that pharmaceutically acceptable
salts of any of the foregoing are also described herein.
[0041] In another embodiment, the formulations described herein
include a compound of the formula:
##STR00004##
and pharmaceutically acceptable salts, hydrates, solvates, esters,
and prodrugs thereof. The following acid dissociation constants are
observed for SOL, pKa1=9.44; pKa2=3.5. Such dissociation constants
are illustrative of compounds that may be characterized as having
low basicity.
[0042] Several illustrative embodiments of the invention are
described by the following enumerated clauses:
[0043] 1. A pharmaceutical composition adapted for parenteral
administration comprising one or more antibiotic compounds and a
formulating agent, wherein the formulating agent is selected from
the group consisting of lactic acid, an amino acid, and
combinations thereof, and pharmaceutically acceptable salts of the
foregoing; and where the one or more antibiotic compounds are of
the formula
##STR00005##
and pharmaceutically acceptable salts thereof, wherein:
[0044] R.sup.10 is hydrogen, acyl or a prodrug moiety;
[0045] W is H, F, Cl, Br, I, or OH;
[0046] A is CH.sub.2, C(O), C(O)O, C(O)NH, S(O).sub.2,
S(O).sub.2NH, or C(O)NHS(O).sub.2;
[0047] B is C.sub.2-C.sub.10 alkenylene, or C.sub.1-C.sub.10
alkylene; and
[0048] C is hydrogen, hydroxy, acyl, acyloxy, sulfonyl, ureido, or
carbamoyl, or alkyl, alkoxy, heteroalkyl, heteroalkoxy, aryl,
arylalkyl, heteroaryl, or heteroarylalkyl, each of which is
optionally substituted.
[0049] 2. The composition of clause 1 wherein R.sup.10 is
hydrogen.
[0050] 3. The composition of any one of clauses 1 or 2 wherein W is
H or F.
[0051] 4. The composition of any one of clauses 1 to 3 wherein W is
F.
[0052] 5. The composition of any one of clauses 1 to 4 wherein A is
CH.sub.2.
[0053] 6. The composition of any one of clauses 1 to 5 wherein B is
C.sub.1-C.sub.10 alkylene.
[0054] 6.1. The composition of any one of clauses 1 to 5 wherein B
is C.sub.2-C.sub.6 alkylene.
[0055] 6.2. The composition of any one of clauses 1 to 5 wherein B
is C.sub.3-C.sub.6 alkylene.
[0056] 6.3. The composition of any one of clauses 1 to 5 wherein B
is C.sub.3-C.sub.5 alkylene.
[0057] 6.4. The composition of any one of clauses 1 to 5 wherein B
is C.sub.3-C.sub.4 alkylene.
[0058] 6.5. The composition of any one of clauses 1 to 5 wherein B
is C.sub.4 alkylene.
[0059] 6.6. The composition of any one of clauses 1 to 5 wherein B
is C.sub.3 alkylene.
[0060] 6.7 The composition of any one of clauses 1 to 6 wherein B
is (CH.sub.2).sub.n, where n is an integer from 1 to 10.
[0061] 7. The composition of any one of clauses 1 to 6.1 wherein B
is (CH.sub.2).sub.n, where n is an integer from 2 to 6.
[0062] 8. The composition of any one of clauses 1 to 6.3 wherein B
is (CH.sub.2).sub.n, where n is an integer from 3 to 5.
[0063] 8.1 The composition of any one of clauses 1 to 6.4 wherein B
is (CH.sub.2).sub.n, where n is an integer from 3 to 4.
[0064] 9. The composition of any one of clauses 1 to 6.4 wherein B
is (CH.sub.2).sub.3.
[0065] 10. The composition of any one of clauses 1 to 9 wherein C
is optionally substituted aryl.
[0066] 10.1. The composition of any one of clauses 1 to 9 wherein C
is optionally substituted phenyl.
[0067] 11. The composition of any one of clauses 1 to 9 wherein C
is aminoaryl.
[0068] 11.1 The composition of any one of clauses 1 to 9 wherein C
is aminophenyl.
[0069] 12. The composition of any one of clauses 1 to 9 wherein C
is 3-aminophenyl.
[0070] 13. The composition of clause 1 wherein one of the compounds
is solithromycin, or a pharmaceutically acceptable salt
thereof.
[0071] 14. The composition of any one of clauses 1 to 13 wherein
the formulating agent is lactic acid or a pharmaceutically
acceptable salt thereof, or a combination thereof.
[0072] 14.1 The composition of any one of clauses 1 to 13 wherein
the formulating agent is lactic acid or a sodium salt of a lactic
acid, or a combination thereof.
[0073] 15. The composition of clause 14 wherein the lactic acid or
the sodium salt comprises any mixture of L-lactic acid and D-lactic
acid and the sodium salts thereof.
[0074] 16. The composition of clause 14 wherein the lactic acid or
the sodium salt is L-lactic acid or the sodium salt thereof.
[0075] 17. The composition of clause 14 wherein the lactic acid or
the sodium salt is DL-lactic acid or the sodium salt thereof.
[0076] 18. The composition of any one of clauses 1 to 17 wherein
the formulating agent is one or more amino acids, or
pharmaceutically acceptable salts thereof, or a combination
thereof.
[0077] 19. The composition of any one of clauses 1 to 17 wherein
the formulating agent is one or more alpha amino acids, or
pharmaceutically acceptable salts thereof, or a combination
thereof.
[0078] 20. The composition of any one of clauses 1 to 17 wherein
the formulating agent is one or more amino acids selected from the
naturally occurring amino acids and stereoisomers thereof, and
pharmaceutically acceptable salts of the foregoing, and
combinations thereof.
[0079] 21. The composition of any one of clauses 1 to 17 wherein
the formulating agent is one or more amino acids selected from the
naturally occurring amino acids having the natural configuration,
and pharmaceutically acceptable salts thereof, and combinations
thereof.
[0080] 22. The composition of any one of clauses 1 to 17 wherein
the formulating agent is one or more amino acids selected from the
naturally occurring amino acids having the natural configuration
that have side chain functional groups that are ionizable under
physiological conditions, and pharmaceutically acceptable salts
thereof, and combinations thereof.
[0081] 23. The composition of any one of clauses 1 to 17 wherein
the formulating agent is histidine, aspartic acid, glutamic acid,
or pharmaceutically acceptable salts thereof, or combinations
thereof.
[0082] 24. The composition of any one of clauses 1 to 17 wherein
the formulating agent is histidine or a pharmaceutically acceptable
salt thereof, or a combination thereof.
[0083] 25. The composition of any one of clauses 1 to 17 wherein
the formulating agent is aspartic acid or a pharmaceutically
acceptable salt thereof, or a combination thereof.
[0084] 26. The composition of any one of clauses 1 to 17 wherein
the formulating agent is glutamic acid or a pharmaceutically
acceptable salt thereof, or a combination thereof.
[0085] 27. The composition of any one of clauses 1 to 17 wherein
the formulating agent is histidine or a pharmaceutically acceptable
salt thereof, and aspartic acid or a pharmaceutically acceptable
salt thereof, or a combination thereof.
[0086] 28. The composition of any one of clauses 1 to 17 wherein
the formulating agent is histidine or a pharmaceutically acceptable
salt thereof, and glutamic acid or a pharmaceutically acceptable
salt thereof, or a combination thereof.
[0087] 29. The composition of any one of clauses 1 to 17 wherein
the formulating agent is aspartic acid or a pharmaceutically
acceptable salt thereof, and glutamic acid or a pharmaceutically
acceptable salt thereof, or a combination thereof.
[0088] 30. The composition of any one of clauses 1 to 17 wherein
the formulating agent is histidine or a pharmaceutically acceptable
salt thereof, aspartic acid or a pharmaceutically acceptable salt
thereof, and glutamic acid or a pharmaceutically acceptable salt
thereof, or a combination thereof.
[0089] 31. The composition of any one of the preceding clauses
prepared by lyophilizing an aqueous solution thereof.
[0090] 31.1. The composition of any one of clauses 1 to 31 further
comprising a liquid vehicle.
[0091] 31.2. The composition of clause 31.1 wherein the liquid
vehicle comprises water.
[0092] 31.3. The composition of any one of clauses 31.1 to 31.2
wherein the liquid vehicle contains less than about 0.9%
saline.
[0093] 31.4. The composition of any one of clauses 31.1 to 31.3
wherein the liquid vehicle contains less than about 0.45%
saline.
[0094] 31.5. The composition of any one of clauses 31.1 to 31.4
wherein the liquid vehicle is substantially free of sodium
chloride.
[0095] 31.6. The composition of any one of clauses 31.1 to 31.5
wherein the liquid vehicle is substantially free of citric acid or
a salt thereof.
[0096] 31.7. The composition of any one of clauses 31.1 to 31.6
wherein the liquid vehicle comprises mannitol.
[0097] 32. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 3.5 to about
6.
[0098] 32.1. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4 to about 6.
[0099] 32.2. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4 to about
5.5.
[0100] 32.3. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4.2 to about
5.5.
[0101] 32.4. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4 to about 5.
[0102] 32.5. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4.2 to about
5.
[0103] 32.6. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH in the range from about 4.2 to about
4.5.
[0104] 32.7. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH of about 4.5.
[0105] 32.8. The composition of any one of clauses 1 to 17 wherein
the formulation has a pH of about 4.2.
[0106] 33. A kit comprising a composition of any one of clauses 1
to 32.8, and instructions for the preparation of a pharmaceutically
acceptable infusion solution thereof.
[0107] 34. A method for treating a patient having a bacterial
infection, the method comprising the step of parenterally
administering to the patient a therapeutically effective amount of
a composition of any one of clauses 1 to 32.8.
[0108] 35. The method of clause 34 wherein the administering step
is performed by intravenous injection.
[0109] In reciting the foregoing collection of clauses, it is to be
understood that all possible combinations of features, and all
possible subgenera and subcombinations are described.
[0110] As used herein, the term "alkyl" includes a chain of carbon
atoms, which is optionally branched. As used herein, the term
"alkenyl" and "alkynyl" includes a chain of carbon atoms, which is
optionally branched, and includes at least one double bond or
triple bond, respectively. It is to be understood that alkynyl may
also include one or more double bonds. It is to be further
understood that in certain embodiments, alkyl is advantageously of
limited length, including C.sub.1-C.sub.24, C.sub.1-C.sub.12,
C.sub.1-C.sub.8, C.sub.1-C.sub.6, and C.sub.1-C.sub.4. It is to be
further understood that in certain embodiments alkenyl and/or
alkynyl may each be advantageously of limited length, including
C.sub.2-C.sub.24, C.sub.2-C.sub.12, C.sub.2-C.sub.8,
C.sub.2-C.sub.6, and C.sub.2-C.sub.4. It is appreciated herein that
shorter alkyl, alkenyl, and/or alkynyl groups may add less
lipophilicity to the compound and accordingly will have different
pharmacokinetic behavior. Illustrative alkyl groups are, but not
limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl,
hexyl, heptyl, octyl and the like.
[0111] As used herein, the term "cycloalkyl" includes a chain of
carbon atoms, which is optionally branched, where at least a
portion of the chain in cyclic. It is to be understood that
cycloalkylalkyl is a subset of cycloalkyl. It is to be understood
that cycloalkyl may be polycyclic. Illustrative cycloalkyl include,
but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl,
2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like.
As used herein, the term "cycloalkenyl" includes a chain of carbon
atoms, which is optionally branched, and includes at least one
double bond, where at least a portion of the chain in cyclic. It is
to be understood that the one or more double bonds may be in the
cyclic portion of cycloalkenyl and/or the non-cyclic portion of
cycloalkenyl. It is to be understood that cycloalkenylalkyl and
cycloalkylalkenyl are each subsets of cycloalkenyl. It is to be
understood that cycloalkyl may be polycyclic. Illustrative
cycloalkenyl include, but are not limited to, cyclopentenyl,
cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It is to
be further understood that chain forming cycloalkyl and/or
cycloalkenyl is advantageously of limited length, including
C.sub.3-C.sub.24, C.sub.3-C.sub.12, C.sub.3-C.sub.8,
C.sub.3-C.sub.6, and C.sub.5-C.sub.6. It is appreciated herein that
shorter alkyl and/or alkenyl chains forming cycloalkyl and/or
cycloalkenyl, respectively, may add less lipophilicity to the
compound and accordingly will have different pharmacokinetic
behavior.
[0112] As used herein, the term "heteroalkyl" includes a chain of
atoms that includes both carbon and at least one heteroatom, and is
optionally branched. Illustrative heteroatoms include nitrogen,
oxygen, and sulfur. In certain variations, illustrative heteroatoms
also include phosphorus, and selenium. As used herein, the term
"cycloheteroalkyl" including heterocyclyl and heterocycle, includes
a chain of atoms that includes both carbon and at least one
heteroatom, such as heteroalkyl, and is optionally branched, where
at least a portion of the chain is cyclic. Illustrative heteroatoms
include nitrogen, oxygen, and sulfur. In certain variations,
illustrative heteroatoms also include phosphorus, and selenium.
Illustrative cycloheteroalkyl include, but are not limited to,
tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,
morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the
like.
[0113] As used herein, the term "aryl" includes monocyclic and
polycyclic aromatic carbocyclic groups, each of which may be
optionally substituted. Illustrative aromatic carbocyclic groups
described herein include, but are not limited to, phenyl, naphthyl,
and the like. As used herein, the term "heteroaryl" includes
aromatic heterocyclic groups, each of which may be optionally
substituted. Illustrative aromatic heterocyclic groups include, but
are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl,
tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl,
pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl,
isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,
benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, and
the like.
[0114] As used herein, the term "amino" includes the group
NH.sub.2, alkylamino, and dialkylamino, where the two alkyl groups
in dialkylamino may be the same or different, i.e. alkylalkylamino.
Illustratively, amino includes methylamino, ethylamino,
dimethylamino, methylethylamino, and the like. In addition, it is
to be understood that when amino modifies or is modified by another
term, such as aminoalkyl, or acylamino, the above variations of the
term amino are included therein. Illustratively, aminoalkyl
includes H.sub.2N-alkyl, methylaminoalkyl, ethylaminoalkyl,
dimethylaminoalkyl, methylethylaminoalkyl, and the like.
Illustratively, acylamino includes acylmethylamino, acylethylamino,
and the like.
[0115] As used herein, the term "amino and derivatives thereof"
includes amino as described herein, and alkylamino, alkenylamino,
alkynylamino, heteroalkylamino, heteroalkenylamino,
heteroalkynylamino, cycloalkylamino, cycloalkenylamino,
cycloheteroalkylamino, cycloheteroalkenylamino, acylamino,
arylalkylamino, arylalkenylamino, arylalkynylamino,
heteroarylamino, heteroarylalkylamino, heteroarylalkenylamino,
heteroarylalkynylamino, acylamino, and the like, each of which is
optionally substituted. The term "amino derivative" also includes
urea, carbamate, and the like.
[0116] As used herein, the term "hydroxy and derivatives thereof"
includes OH, and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy,
heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy,
cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy,
arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy,
heteroarylalkenyloxy, heteroarylalkynyloxy, acyloxy, and the like,
each of which is optionally substituted. The term "hydroxy
derivative" also includes carbamate, and the like.
[0117] As used herein, the term "thio and derivatives thereof"
includes SH, and alkylthio, alkenylthio, alkynylthio,
heteroalkylthio, heteroalkenylthio, heteroalkynylthio,
cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio,
cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio,
arylalkynylthio, heteroarylthio, heteroarylalkylthio,
heteroarylalkenylthio, heteroarylalkynylthio, acylthio, and the
like, each of which is optionally substituted. The term "thio
derivative" also includes thiocarbamate, and the like.
[0118] As used herein, the term "acyl" includes formyl, and
alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,
heteroalkylcarbonyl, heteroalkenylcarbonyl, heteroalkynylcarbonyl,
cycloalkylcarbonyl, cycloalkenylcarbonyl, cycloheteroalkylcarbonyl,
cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl,
arylalkenylcarbonyl, arylalkynylcarbonyl, heteroarylcarbonyl,
heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl,
heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of
which is optionally substituted.
[0119] As used herein, the term "carboxylic acid and derivatives
thereof" includes the group CO.sub.2H and salts thereof, and esters
and amides thereof, and CN.
[0120] The term "optionally substituted" as used herein includes
the replacement of hydrogen atoms with other functional groups on
the radical that is optionally substituted. Such other functional
groups illustratively include, but are not limited to, amino,
hydroxyl, halo, thiol, alkyl, haloalkyl, heteroalkyl, aryl,
arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl,
heteroarylheteroalkyl, nitro, sulfonic acids and derivatives
thereof, carboxylic acids and derivatives thereof, and the like.
Illustratively, any of amino, hydroxyl, thiol, alkyl, haloalkyl,
heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is
optionally substituted.
[0121] As used herein, the terms "optionally substituted aryl" and
"optionally substituted heteroaryl" include the replacement of
hydrogen atoms with other functional groups on the aryl or
heteroaryl that is optionally substituted. Such other functional
groups illustratively include, but are not limited to, amino,
hydroxy, halo, thio, alkyl, haloalkyl, heteroalkyl, aryl,
arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl,
heteroarylheteroalkyl, nitro, sulfonic acids and derivatives
thereof, carboxylic acids and derivatives thereof, and the like.
Illustratively, any of amino, hydroxy, thio, alkyl, haloalkyl,
heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,
heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is
optionally substituted.
[0122] Illustrative substituents include, but are not limited to, a
radical --(CH.sub.2)--Z.sup.X, where x is an integer from 0-6 and
Z.sup.X is selected from halogen, hydroxy, alkanoyloxy, including
C.sub.1-C.sub.6 alkanoyloxy, optionally substituted aroyloxy,
alkyl, including C.sub.1-C.sub.6 alkyl, alkoxy, including
C.sub.1-C.sub.6 alkoxy, cycloalkyl, including C.sub.3-C.sub.8
cycloalkyl, cycloalkoxy, including C.sub.3-C.sub.8 cycloalkoxy,
alkenyl, including C.sub.2-C.sub.6 alkenyl, alkynyl, including
C.sub.2-C.sub.6 alkynyl, haloalkyl, including C.sub.1-C.sub.6
haloalkyl, haloalkoxy, including C.sub.1-C.sub.6 haloalkoxy,
halocycloalkyl, including C.sub.3-C.sub.8 halocycloalkyl,
halocycloalkoxy, including C.sub.3-C.sub.8 halocycloalkoxy, amino,
C.sub.1-C.sub.6 alkylamino, (C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl)amino, alkylcarbonylamino, N--(C.sub.1-C.sub.6
alkyl)alkylcarbonylamino, aminoalkyl, C.sub.1-C.sub.6
alkylaminoalkyl, (C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N--(C.sub.1-C.sub.6
alkyl)alkylcarbonylaminoalkyl, cyano, and nitro; or Z.sup.X is
selected from --CO.sub.2R.sup.4 and --CONR.sup.5R.sup.6, where
R.sup.4, R.sup.5, and R.sup.6 are each independently selected in
each occurrence from hydrogen, C.sub.1-C.sub.6 alkyl,
aryl-C.sub.1-C.sub.6 alkyl, and heteroaryl-C.sub.1-C.sub.6
alkyl.
[0123] The term "prodrug" as used herein generally refers to any
compound that when administered to a biological system generates a
biologically active compound as a result of one or more spontaneous
chemical reaction(s), enzyme-catalyzed chemical reaction(s), and/or
metabolic chemical reaction(s), or a combination thereof. In vivo,
the prodrug is typically acted upon by an enzyme (such as
esterases, amidases, phosphatases, and the like), simple biological
chemistry, or other process in vivo to liberate or regenerate the
more pharmacologically active drug. This activation may occur
through the action of an endogenous host enzyme or a non-endogenous
enzyme that is administered to the host preceding, following, or
during administration of the prodrug. Additional details of prodrug
use are described in U.S. Pat. No. 5,627,165; and Pathalk et al.,
Enzymic protecting group techniques in organic synthesis,
Stereosel. Biocatal. 775-797 (2000). It is appreciated that the
prodrug is advantageously converted to the original drug as soon as
the goal, such as targeted delivery, safety, stability, and the
like is achieved, followed by the subsequent rapid elimination of
the released remains of the group forming the prodrug.
[0124] Prodrugs may be prepared from the compounds described herein
by attaching groups that ultimately cleave in vivo to one or more
functional groups present on the compound, such as --OH--, --SH,
--CO.sub.2H, --NR.sub.2. Illustrative prodrugs include but are not
limited to carboxylate esters where the group is alkyl, aryl,
arylalkyl, heteroaryl, heteroarylalkyl, acyloxyalkyl,
alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and
amines where the group attached is an acyl group, an
alkoxycarbonyl, aminocarbonyl, phosphate or sulfate. Illustrative
esters, also referred to as active esters, include but are not
limited to 1-indanyl, N-oxysuccinimide; acyloxyalkyl groups such as
acetoxymethyl, pivaloyloxymethyl, .beta.-acetoxyethyl,
.beta.-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl,
(1-aminoethyl)carbonyloxymethyl, and the like;
alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl,
.alpha.-ethoxycarbonyloxyethyl, .beta.-ethoxycarbonyloxyethyl, and
the like; dialkylaminoalkyl groups, including di-lower alkylamino
alkyl groups, such as dimethylaminomethyl, dimethylaminoethyl,
diethylaminomethyl, diethylaminoethyl, and the like;
2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)
pent-2-enyl, 2-(ethoxycarbonyl)but-2-enyl, and the like; and
lactone groups such as phthalidyl, dimethoxyphthalidyl, and the
like.
[0125] Further illustrative prodrugs contain a chemical moiety,
such as an amide or phosphorus group functioning to increase
solubility and/or stability of the compounds described herein.
Further illustrative prodrugs for amino groups include, but are not
limited to, (C.sub.3-C.sub.20)alkanoyl;
halo-(C.sub.3-C.sub.20)alkanoyl; (C.sub.3-C.sub.20)alkenoyl;
(C.sub.4-C.sub.7)cycloalkanoyl;
(C.sub.3-C.sub.6)-cycloalkyl(C.sub.2-C.sub.16)alkanoyl; optionally
substituted aroyl, such as unsubstituted aroyl or aroyl substituted
by 1 to 3 substituents selected from the group consisting of
halogen, cyano, trifluoromethanesulphonyloxy,
(C.sub.1-C.sub.3)alkyl and (C.sub.1-C.sub.3)alkoxy, each of which
is optionally further substituted with one or more of 1 to 3
halogen atoms; optionally substituted
aryl(C.sub.2-C.sub.16)alkanoyl and optionally substituted
heteroaryl(C.sub.2-C.sub.16)alkanoyl, such as the aryl or
heteroaryl radical being unsubstituted or substituted by 1 to 3
substituents selected from the group consisting of halogen,
(C.sub.1-C.sub.3)alkyl and (C.sub.1-C.sub.3)alkoxy, each of which
is optionally further substituted with 1 to 3 halogen atoms; and
optionally substituted heteroarylalkanoyl having one to three
heteroatoms selected from O, S and N in the heteroaryl moiety and 2
to 10 carbon atoms in the alkanoyl moiety, such as the heteroaryl
radical being unsubstituted or substituted by 1 to 3 substituents
selected from the group consisting of halogen, cyano,
trifluoromethanesulphonyloxy, (C.sub.1-C.sub.3)alkyl, and
(C.sub.1-C.sub.3)alkoxy, each of which is optionally further
substituted with 1 to 3 halogen atoms. The groups illustrated are
exemplary, not exhaustive, and may be prepared by conventional
processes.
[0126] It is understood that the prodrugs themselves may not
possess significant biological activity, but instead undergo one or
more spontaneous chemical reaction(s), enzyme-catalyzed chemical
reaction(s), and/or metabolic chemical reaction(s), or a
combination thereof after administration in vivo to produce the
compound described herein that is biologically active or is a
precursor of the biologically active compound. However, it is
appreciated that in some cases, the prodrug is biologically active.
It is also appreciated that prodrugs may often serves to improve
drug efficacy or safety through improved oral bioavailability,
pharmacodynamic half-life, and the like. Prodrugs also refer to
derivatives of the compounds described herein that include groups
that simply mask undesirable drug properties or improve drug
delivery. For example, one or more compounds described herein may
exhibit an undesirable property that is advantageously blocked or
minimized may become pharmacological, pharmaceutical, or
pharmacokinetic barriers in clinical drug application, such as low
oral drug absorption, lack of site specificity, chemical
instability, toxicity, and poor patient acceptance (bad taste,
odor, pain at injection site, and the like), and others. It is
appreciated herein that a prodrug, or other strategy using
reversible derivatives, can be useful in the optimization of the
clinical application of a drug.
[0127] The term "therapeutically effective amount" as used herein,
refers to that amount of active compound or pharmaceutical agent
that elicits the biological or medicinal response in a tissue
system, animal or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes
alleviation of the symptoms of the disease or disorder being
treated. In one aspect, the therapeutically effective amount is
that which may treat or alleviate the disease or symptoms of the
disease at a reasonable benefit/risk ratio applicable to any
medical treatment. However, it is to be understood that the total
daily usage of the compounds and compositions described herein may
be decided by the attending physician within the scope of sound
medical judgment. The specific therapeutically-effective dose level
for any particular patient will depend upon a variety of factors,
including the disorder being treated and the severity of the
disorder; activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, gender
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 coincidentally with the specific compound employed; and like
factors well known to the researcher, veterinarian, medical doctor
or other clinician of ordinary skill.
[0128] It is also appreciated that the therapeutically effective
amount, whether referring to monotherapy or combination therapy, is
advantageously selected with reference to any toxicity, or other
undesirable side effect, that might occur during administration of
one or more of the compounds described herein. Further, it is
appreciated that the co-therapies described herein may allow for
the administration of lower doses of compounds that show such
toxicity, or other undesirable side effect, where those lower doses
are below thresholds of toxicity or lower in the therapeutic window
than would otherwise be administered in the absence of a
cotherapy.
[0129] As used herein, the term "composition" generally refers to
any product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combinations of the specified ingredients in the
specified amounts. It is to be understood that the compositions
described herein may be prepared from isolated compounds described
herein or from salts, solutions, hydrates, solvates, and other
forms of the compounds described herein. It is also to be
understood that the compositions may be prepared from various
amorphous, non-amorphous, partially crystalline, crystalline,
and/or other morphological forms of the compounds described herein.
It is also to be understood that the compositions may be prepared
from various hydrates and/or solvates of the compounds described
herein. Accordingly, such pharmaceutical compositions that recite
compounds described herein are to be understood to include each of,
or any combination of, the various morphological forms and/or
solvate or hydrate forms of the compounds described herein.
Illustratively, compositions may include one or more carriers,
diluents, and/or excipients. The compounds described herein, or
compositions containing them, may be formulated in a
therapeutically effective amount in any conventional dosage forms
appropriate for the methods described herein. The compounds
described herein, or compositions containing them, including such
formulations, may be administered by a wide variety of conventional
routes for the methods described herein, and in a wide variety of
dosage formats, utilizing known procedures (see generally,
Remington: The Science and Practice of Pharmacy, (21.sup.st ed.,
2005)).
[0130] Accordingly, it is to be understood herein that the source
of the drug or therapeutic agent, such as SOL, is not limiting. For
example, SOL may be included in the formulations described herein
starting from its neutral form, or one or more salt forms.
Alternatively, SOL may be included in the formulations described
herein starting from a reconstitutable form, such as any of the
various lyophilized forms of SOL, including CEM-101 lyo,
compositions described in PCT international application serial No.
US2011/027984, the disclosure of which is incorporated herein by
reference. Further, in any of the foregoing, the SOL may be
included in the formulations described herein starting from any
morphological form, such as amorphous, Form I, Form II, and the
like, such as described in PCT international application serial
Nos. US2004/006645 and US2011/029424, the disclosures of each of
which are incorporated herein by reference.
[0131] In another embodiment, the compound used in the compositions
described herein is SOL. In another embodiment, the SOL is neutral.
In another embodiment, the SOL is amorphous. In another embodiment,
the SOL is Form I. In another embodiment, the SOL is Form II. In
another embodiment, the SOL is a pharmaceutically acceptable salt.
In another embodiment, the SOL is a tartrate salt. In another
embodiment, the SOL is a hydrochloride salt. In another embodiment,
the SOL is lyophilizate comprising SOL, mannitol, and tartaric
acid. In another embodiment, the SOL is lyophilizate comprising
SOL, histidine, glutamic acid, and aspartic acid.
[0132] In another embodiment, the formulation comprises an amino
acid. Illustrative amino acids that may be included in the solid,
solution or liquid formulations described herein include any alpha
or beta amino acid, and pharmaceutically acceptable salts thereof.
In one embodiment, the amino acids are selected from the naturally
occurring amino acids and stereoisomers thereof, and
pharmaceutically acceptable salts of the foregoing. In another
embodiment, the amino acids are selected from the naturally
occurring amino acids having the natural configuration, and
pharmaceutically acceptable salts thereof. In another embodiment,
the amino acids are selected from the naturally occurring amino
acids having the natural configuration that have side chain
functional groups that are ionizable under physiological
conditions, and pharmaceutically acceptable salts thereof. In
another embodiment, the amino acids are selected from histidine,
aspartic acid, glutamic acid, and pharmaceutically acceptable salts
thereof.
[0133] In another embodiment, the solid, solution or liquid
formulations described herein include histidine, such as
L-(-)-histidine, and pharmaceutically acceptable salts thereof. In
another embodiment, the solid, solution or liquid formulations
described herein include glutamic acid, such as L-(+)-glutamic
acid, and pharmaceutically acceptable salts thereof. In another
embodiment, the solid, solution or liquid formulations described
herein include aspartic acid, such as L-(+)-aspartic acid, and
pharmaceutically acceptable salts thereof. In another embodiment,
the solid, solution or liquid formulations described herein include
lactic acid, such as L-lactic acid and DL-lactic acid, and
pharmaceutically acceptable salts thereof. In another embodiment,
the solid, solution or liquid formulations described herein include
mannitol, such as D-(+)-mannitol.
[0134] In another embodiment, described herein are solid
formulations of the compounds described herein that are adapted for
reconstitution into a carrier or vehicle. In another embodiment,
the solid formulation comprises SOL, histidine, glutamic acid, and
aspartic acid.
[0135] The term "administering" as used herein includes all means
of introducing liquid or solution formulations of compounds and
compositions described herein to the patient, including, but are
not limited to, oral (po), intravenous (iv), intramuscular (im),
subcutaneous (sc), transdermal, ocular, vaginal, rectal, and the
like. The compounds and compositions described herein may be
administered in unit dosage forms and/or formulations containing
conventional nontoxic pharmaceutically-acceptable carriers,
adjuvants, and vehicles.
[0136] Depending upon the disease as described herein, the
compounds and compositions described herein may be administered
locally or systemically.
[0137] Illustratively, administering includes local use, such as
when administered locally to the site of disease, injury, or
defect. Illustrative local administration may be performed during
open surgery, or other procedures when the site of disease, injury,
or defect is accessible. Local administration may be performed
using parenteral delivery where the compound or compositions
described herein are deposited locally to the site without general
distribution to multiple other non-target sites in the patient
being treated. It is further appreciated that local administration
may be directly in the disease site, or locally in the surrounding
tissue. Similar variations regarding local delivery to particular
tissue types, such as organs, and the like, are also described
herein. Illustratively, compounds may be administered directly to
the nervous system including, but not limited to, intracerebral,
intraventricular, intracerebroventricular, intrathecal,
intracisternal, intraspinal and/or peri-spinal routes of
administration by delivery via intracranial or intravertebral
needles and/or catheters with or without pump devices.
[0138] It is to be understood that in the methods described herein,
the individual components of a co-administration, or combination
can be administered by any suitable means, contemporaneously,
simultaneously, sequentially, separately or in a single
pharmaceutical formulation. Where the co-administered compounds or
compositions are administered in separate dosage forms, the number
of dosages administered per day for each compound may be the same
or different. The compounds or compositions may be administered via
the same or different routes of administration. The compounds or
compositions may be administered according to simultaneous or
alternating regimens, at the same or different times during the
course of the therapy, concurrently in divided or single forms.
[0139] Illustrative routes for parenteral administration include
intravenous, intraarterial, intraperitoneal, epidurial,
intraurethral, intrasternal, intramuscular and subcutaneous, as
well as any other art recognized route of parenteral
administration. Illustrative means of parenteral administration
include needle (including microneedle) injectors, needle-free
injectors and infusion techniques, as well as any other means of
parenteral administration recognized in the art.
[0140] The dosage of each compound of the claimed combinations
depends on several factors, including: the administration method,
the condition to be treated, the severity of the condition, whether
the condition is to be treated or prevented, and the age, weight,
and health of the person to be treated. Additionally,
pharmacogenomic (the effect of genotype on the pharmacokinetic,
pharmacodynamic or efficacy profile of a therapeutic) information
about a particular patient may affect the dosage used.
[0141] In addition to the foregoing illustrative dosages and dosing
protocols, it is to be understood that an effective amount of any
one or a mixture of the compounds described herein can be readily
determined by the attending diagnostician or physician by the use
of known techniques and/or by observing results obtained under
analogous circumstances. In determining the effective amount or
dose, a number of factors are considered by the attending
diagnostician or physician, including, but not limited to the
species of mammal, including human, its size, age, and general
health, the specific disease or disorder involved, the degree of or
involvement or the severity of the disease or disorder, the
response of the individual patient, the particular compound
administered, the mode of administration, the bioavailability
characteristics of the preparation administered, the dose regimen
selected, the use of concomitant medication, and other relevant
circumstances.
[0142] Parenteral Compositions. The parenteral pharmaceutical
composition may be administered by injection, infusion or
implantation (intravenous, intramuscular, subcutaneous, or the
like) in dosage forms, formulations, or via suitable delivery
devices or implants containing conventional, non-toxic
pharmaceutically acceptable carriers and adjuvants. The formulation
and preparation of such compositions are well known to those
skilled in the art of pharmaceutical formulation.
[0143] Compositions for parenteral use may be provided in unit
dosage forms (e.g., in single-dose ampoules), in vials containing
several doses and in which a suitable preservative may be added
(see below), or in prefilled syringes.
[0144] As indicated above, the pharmaceutical compositions
described herein may be in the form suitable for sterile injection.
To prepare such a composition, the suitable active drug(s) are
dissolved or suspended in a parenterally acceptable liquid vehicle.
Illustrative vehicles and solvents include, but are not limited to,
water, water adjusted to a suitable pH by addition of an
appropriate amount of hydrochloric acid, sodium hydroxide or a
suitable buffer, 1,3-butanediol. Ringer's solution, and isotonic
sodium chloride solution. The aqueous formulation may also contain
one or more preservatives (e.g., methyl, ethyl or n-propyl
p-hydroxybenzoate). In cases where one of the compounds is only
sparingly or slightly soluble in water, a dissolution enhancing or
solubilizing agent can be added, or the solvent may include 10-60%
w/w of propylene glycol or the like. In addition, the carriers may
also include any combination of tonicity agents, including but not
limited to, mannitol, such as 3-5% mannitol, 3% mannitol, 4%
mannitol, 4.3% mannitol, and 5% mannitol, phosphate, acetate,
additional tartrate, saline, such as physiological saline (0.9%),
1/2 physiological saline (0.45%), and 0.5% saline, and the
like.
[0145] In another embodiment, the parenteral formulation is a
hypotonic mannitol formulation. In another embodiment, the
parenteral formulation is a isotonic mannitol formulation. In
another embodiment, the parenteral formulation has an osmolality of
about 250 or less. In another embodiment, the parenteral
formulation has an osmolality of about 250 or less. In another
embodiment, the parenteral formulation has an osmolality of about
350 or less.
[0146] The pH of the solution or liquid formulations described
herein may be at any of a wide range of physiologically acceptable
or pharmaceutically acceptable values. Illustratively, the pH is in
the range from about 2 to about 8, from about 3 to about 7, from
about 4 to about 6.5, and the like. In another embodiment, the pH
of the solution or liquid formulations described herein is near
neutral. In another embodiment, the pH of the solution or liquid
formulations described herein is in the range from about 4 to about
6, from about 4 to about 5.5, from about 4 to about 5, from about 4
to about 4.5, from about 4.5 to about 6.5, from about 4.5 to about
6, from about 4.5 to about 5.5, or from about 4.5 to about 5.
[0147] Depending upon the needs of the patient, and the clinical
conditions, administration of a drug by the iv route is may be
favored for a number of different reasons, including rapid
introduction into the systemic circulation and high bioavailability
and other advantages obtained by avoiding issues of stability in
the gastrointestinal tract, absorption, distribution and metabolic
or toxic effects involving the liver on oral administration.
However, the solubility of the drug in blood may limit the
concentration or rate at which it may be administered by the
intravenous route.
[0148] Without being bound by theory, it is believed herein that if
the drug separates from the phase formed by the constituents of its
vehicle and the blood in which it is injected, a phase of oily
droplets or crystals may be formed in the veins. The separated
phase may redissolve in the blood relatively rapidly, resulting is
only a slight delay in bioavailability without loss of efficacy.
Otherwise, the effect may be uneven or delayed bioavailability.
Without being bound by theory, it is also believed herein that
precipitation of the therapeutic agent as crystalline particles can
cause cellular abrasion as the particles move along the wall of the
vein, an effect which is purely physical and not pharmacological.
Phlebitis, an inflammation of the vein wall, has been associated
with effects of particulate matter associated with iv injection.
Under conventional conditions of administration, in which the
injection rate of a parenteral drug does not exceed the blood flow
rate, this problem may be overcome by reducing the concentration of
the therapeutic agent in the injection vehicle or by extending the
time of the injection, each of which is an undesirable change.
Alternatively, modification of the formulation of the composition
of the injected drug may ameliorate the problem.
[0149] Without being bound by theory, it is also believed herein
that injection phlebitis can be caused by a number of different
factors including pH, tonicity, particulate matter, and
precipitation upon dilution in the bloodstream (see, for example,
Ward et al., 1993. Studies in Phlebitis VI: Dilution-Induced
Precipitation of Amidoarone HCl. Journal of Parenteral Science and
Technology. 47(4). 161-165). Injection of drugs formulated above or
below pH 7.4 may result in an exponential decrease in solubility
with dilution. This can overcome the linear decrease in
concentration upon dilution, thereby producing precipitation (see,
for example, Narazaki et al., 2007. Estimation of Precipitation
Upon Dilution of pH-Controlled Formulations. Molecular
Pharmaceutics. 4(4), 550-555). Using a buffer may inhibit
precipitation by minimizing the pH increase in the vicinity of the
injected basic drug in blood. On the other hand, using a buffer may
lead to the formation of an insoluble salt between the drug and the
acid buffer ion.
[0150] Although a number of animal models have been developed for
measuring in vivo precipitation and in vivo phlebitis, it may be
desirable to utilize quantitative in vitro models to measure
precipitation upon injection of a therapeutic agent (see, for
example, Yalkowsky et al., 1998. Journal of Pharmaceutical
Sciences, 87(7), 787-796). For example, an apparatus and a dynamic
precipitation model using isotonic Sorensen's phosphate buffer
(ISPB) as the blood surrogate has been described (see, for example,
Johnson et al., 2003 Prediction of Precipitation-Induced Phlebitis:
A Statistical Validation of an In Vitro Model. Journal of
Pharmaceutical Sciences, 92(8), 1574-1581).
[0151] In the dynamic precipitation model described in detail
herein, solutions of test compound, such as SOL, as a tartrate
buffered solution of greater than or equal to 1 mg/mL of SOL in
0.45% saline, administered at approximately 1 mL/min or faster, may
exhibit precipitation. This precipitation suggests that intravenous
injection of SOL at concentrations and infusion rates higher than
about 1 mg/mL at about 1 mL/min may be associated with
precipitation resulting in pain associated with precipitation
induced phlebitis. Therefore, to avoid such precipitation, the rate
of administration requires, for example, almost seven hours for the
administration of a dose of 400 mg of SOL. Thus, there is needed a
pharmaceutical composition which enables administration of SOL at a
higher concentration and/or a higher rate for clinical use.
[0152] Azithromycin, administered in the dynamic precipitation
model as a citrate buffered solution in 0.45% saline at 2 mg/mL and
4 mL/min, does not exhibit precipitation; so the pain which is
observed upon intravenous injection of azithromycin most likely is
not attributable to precipitation. Instead, it has been reported
that the pain observed with azithromycin injection may be
pharmacologic pain. However, SOL has been discovered to not exhibit
pharmacologic pain. Nevertheless, SOL similarly formulated in
citrate buffer may cause pain. Without being bound by theory, it is
believed herein that although citrate has three buffering
carboxylate units. SOL may yet exhibit precipitation at
concentrations and infusion rates higher than about 1 mg/mL at
about 1 mL/min.
[0153] An intravenous infusion solution of SOL and related
compounds suitable for treatment in a disease such as moderately
severe to severe community acquired bacterial pneumonia (CABP) is
needed. Toxicology studies of 28 days in dog and monkey, dosing a
tartrate-buffered solution of 1 mg/mL of SOL in 3% mannitol infused
at approximately 1 mL/min, are successfully complete without
evidence of pain or other adverse events. However, without being
bound by theory, it is believed herein that infusion at higher
concentrations and/or at higher rates of infusion, which are highly
desirable in the clinical setting, may not be practical with
current formulations due to the substantially lower solubility
observed with SOL and related compounds compared to other
macrolide, enolide, and ketolide compounds.
[0154] It has been found, surprisingly, that use of lactate
formulating agents greatly improves the solubility of
solithromycin. Accordingly, provided herein are pharmaceutical
compositions comprising lactate formulating agents adapted for the
parenteral administration of the fluoroketolide antibiotic SOL and
related compounds, as well as methods for their use in the
treatment of bacterial, protozoal, and other infections.
[0155] It has also been found, surprisingly, that use of amino acid
formulating agents greatly improves the solubility of
solithromycin. Accordingly, provided herein are pharmaceutical
compositions comprising amino acid formulating agents adapted for
the parenteral administration of the fluoroketolide antibiotic SOL
and related compounds, as well as methods for their use in the
treatment of bacterial, protozoal, and other infections.
[0156] Although it is to be understood herein that solithromycin
itself may not cause pharmacologic pain, changes in the solubility
and solution characteristics of solithromycin solutions may cause
pain due to, for example, precipitation. As further described
below, to evaluate the potential for pain related to such an iv
infusion at doses and rates which are comparable to the usual
hospital use with azithromycin, iv infusion solutions of SOL are
evaluated in a rabbit ear vein model, using azithromycin for
injection for comparison. It is found that iv infusion solutions of
SOL formulations as described herein are well accepted in single
dose and multiple dose studies using the rabbit ear vein model. In
contrast, azithromycin for injection caused considerable pain at
the concentration and infusion rate of the usual hospital use.
[0157] It has been discovered that a dramatic reduction in
precipitation is observed with the use of lactate buffer in the
formulations of SOL for intravenous administration as determined by
the dynamic precipitation model. It has also been discovered that a
dramatic reduction in precipitation is observed with the use of
amino acid buffers in the formulations of SOL for intravenous
administration as determined by the dynamic precipitation
model.
[0158] As shown in the Examples described herein, using the dynamic
precipitation model, when SOL and related compounds are
administered at 3 mg/mL in 0.45% saline, precipitation is noted at
rates greater than or equal to 1.0 mL/min. At the lower
concentrations, 2 or 1 mg/mL in 0.45% saline, precipitation is
noted at rates greater than 1.0 mL/min, and 1.0 mL/min is
borderline. The amounts of precipitation in 5% mannitol are similar
to those in 0.45% saline without the added mannitol.
[0159] In contrast, when using SOL and related compounds in both
0.5% and 1% lactate buffer (pH 4) in 0.45% saline, precipitation in
the model is reduced below the delineating opacity value for
determining precipitation with phlebitic potential at 1 mg/mL and 2
mg/mL at a rate of 3 mL/min. The use of either L-lactate buffer or
DL-lactate buffer reduced precipitation in all cases. However,
using 0.5, 1 and 5 mM citrate buffer (pH 4) in 0.45% saline does
not significantly reduce precipitation in the dynamic precipitation
model at concentrations of 2 mg/mL and 3 mg/mL SOL. Similarly, 10
or 25 mM tartrate buffer (pH 4) in 0.45% saline does not
significantly reduce precipitation in the dynamic precipitation
model at concentrations of 2 mg/mL and 3 mg/mL SOL. Addition of a
citrate or tartrate co-buffer to the lactate buffer had minimal
effect in the dynamic precipitation model. In all cases in which
precipitation is observed, the amount of precipitation, as
reflected by the amount of absorbance, increases with the injection
rate and concentration.
[0160] In addition, when using SOL/amino acid formulations in
various lactate, phosphate and acetate buffers, at various pH
levels, in a suitable tonicity carrier, such as 0.45% saline, 3-5%
mannitol, and the like, precipitation in the model is reduced below
the delineating opacity value for determining precipitation with
phlebitic potential at 1 mg/mL and 2 mg/mL at a rate of 3
mL/min.
[0161] Azithromycin and clarithromycin have been approved for i.v.
administration. However, their use has been reportedly limited due
to inflammation, pharmacologic pain, hepatotoxicity, and/or adverse
cardiac effects, such as QT prolongation. It is appreciated herein
that such side effects are exacerbated by the higher exposure that
occurs from parenteral administration compared to oral
administration. For example, clarithromycin reportedly accumulates
in cardiac tissue. In addition, though azithromycin does not cause
high cardiac tissue exposure, azithromycin reportedly has high
potency in causing QT prolongation, such that even minimal exposure
precautions may be necessary. Ketolides, such as telithromycin are
reportedly particularly not suitable for parenteral, such as i.v.,
administration due to unwanted side effects.
[0162] It has been unexpectedly discovered herein that the
triazole-containing ketolide compounds and compositions described
herein do not elicit significant pharmacologic pain,
hepatotoxicity, or cardiac effects, such as QT prolongation.
Described herein are compositions adapted for parenteral, including
i.v., administration that are pain free, or substantially pain
free. Described herein are compositions adapted for parenteral,
including i.v., administration that do not cause, or do not
substantially cause hepatotoxicity. Described herein are
compositions adapted for parenteral, including i.v., administration
that are free of, or substantially free of adverse cardiac effects,
such as QT prolongation. Described herein are compositions adapted
for parenteral, including i.v., administration that do not cause,
or do not substantially cause inflammation.
[0163] The following examples further illustrate specific
embodiments of the invention; however, the following illustrative
examples should not be interpreted in any way to limit the
invention.
EXAMPLES
Example
[0164] Any source of SOL may be used in preparing the formulations
described herein. Illustratively, the source of SOL is a
reconstitutable lyophilizate, as also generally described in WO
2011/112864. Illustratively, the source of SOL is a reconstitutable
lyophilizate prepared from the following aqueous solution. The
theoretical quantities include 6% excess to cover overfill. The
density of SOL solution is approximately 1.030 g/mL.
TABLE-US-00001 Qty/Vial % w/w (mg/5 mL) Theoretical SOL 5.0 250
0.53 Mannitol, USP (Pearlitol 5.0 250 0.53 PF) L (+) - Tartaric
Acid, USP 0.6 29 61.5 Sodium Hydroxide, USP -- -- For pH adjustment
(e.g. to pH 4) Water for Injection (WFI), q.s to 100% q.s. to 5 mL
q.s. to 10.9 kg USP TOTAL 100 5.2 g (5 mL) 10.9 kg
Example
[0165] SOL from any source may be directly dissolved into a
formulation solution described herein. Illustratively, the
following final formulation comprises 150 mM Histidine, 150 mM
Glutamic Acid, and 150 mM Aspartic Acid, at pH 4.5.
Example
[0166] SOL from any source may be directly dissolved into a
formulation solution described herein. Illustratively, the
following formulation agents are used in preparing the
pharmaceutical compositions described herein. The density of 150 mM
histidine, 150 mM glutamic acid, and 150 mM aspartic acid solution
at ambient temperature is approximately 1.027 g/mL.
TABLE-US-00002 Qty/Vial Theoretical % w/v (g/25 mL) (kg)
L-Histidine, USP 2.3% 0.58 0.98 L-Aspartic Acid, USP 2.0% 0.50 0.84
L-Glutamic Acid, FCC 2.2% 0.55 0.93 Multicompendial (BP & EP)
Sodium Hydroxide, NF -- -- For pH adjustment Hydrochloric Acid, NF
-- -- For pH adjustment Water for Injection (WFI), q.s to 100% q.s.
to 25 mL q.s. to 43 kg USP TOTAL 100 26 g (25 mL) 43 kg
Example
[0167] Any source of SOL may be used in preparing the formulations
described herein. Illustratively, the source of SOL is a
reconstitutable lyophilizate prepared from the following aqueous
solution. The theoretical quantities include 7% to cover overfill.
The water for injection is removed during lyophilization. The
density of the filling solution is approximately 1.041 g/ml. The
final target pH of the formulation is 4.5.
TABLE-US-00003 Quantity per Theoretical % Vial Quantity per w/w
(mg) Batch (g) SOL 1.9 428 642 L-Histidine, USP, EP 2.8 623 934
L-Glutamic Acid, FCC 2.7 590 886 Multicompendial (BP & EP)
L-Aspartic Acid, USP, EP 2.4 534 801 Sodium Hydroxide, NF NA pH
adjustment pH adjustment Hydrochloric Acid, NF NA pH
adjustment.sup.e pH adjustment.sup.e Water for Injection.sup.c
(WFI), USP QS QS QS Total 100 2230 33400
Example
[0168] Saline vehicles are prepared from 0.9% sodium chloride
injection, USP, or diluted to 0.45% with water for injection. All
formulations are optionally filtered using a 0.45 .mu.M filter,
such as an Alltec 0.45 .mu.M filter.
Method Example
[0169] Dynamic Precipitation Model. The dynamic precipitation
apparatus is shown in FIG. 1, and is also described in Johnson et
al., (2003). The apparatus includes a predetermined distance,
illustratively a 15 cm distance, between the tip of the injection
needle and the UV flow cell, and three main components to simulate
blood flow and different infusion rates of drug. Illustratively, a
Cole-Palmer-Masterflex.RTM. 7520-00 peristaltic pump is used to
direct the flow of blood surrogate at 5 mL/min. Illustratively, a
Harvard Apparatus Precision Syringe Pump 22 is used to infuse drug
formulations into the system at various injection rates.
Illustratively, a Cary UV-50 Bio Spectrophotometer with a 1.00 cm
flow cell is used to monitor absorbance as a measure of
precipitation in the formulation-blood surrogate system.
[0170] Each sample is prepared by dissolving test compound and
formulation agents into water or vehicle, and adjusting the pH with
either 1 M HCl or 1 M NaOH, as appropriate to the indicated final
concentration of test compound. Lactic, citric, and tartaric acid
formulation agent stock solutions are made by dissolving the
predetermined weight of solid or liquid into water and adjusting pH
with either 1 M HCl or 1 M NaOH.
[0171] The blood surrogate (Isotonic Sorensen's Phosphate Buffer,
0.067 M, pH 7.4) is pumped from a reservoir through Tygon.RTM.
tubing (R-6306) fitted with 2 IV-set Y-injection sites that pass
into the flow cell and terminate in a waste container. A Dwyer
MMA-35 flow meter, along with a timer and graduated cylinder, is
used to measure the rate of surrogate blood flow through the
system. Illustratively, flow is 5 mL/min.
[0172] The test compound formulations are infused at different
rates through the downstream second Y-injection site into the flow
of the blood surrogate entering into the flow cell. A 0.001 M HCl
solution is injected into the first Y-injection site following each
infusion of test compound to flush the downstream tubing and flow
cell. All injections are performed at 25.degree. C. The
spectrophotometer software (Cary UVWin) is set to read a constant
absorbance, illustratively 500 nm, versus time.
[0173] Samples are made with buffer and drug concentrations as
described. After the flow rate is confirmed at 5 mL/min, the
spectrophotometer is set to record absorbance at 500 nm for 5-10
minutes, and injections are performed at different rates as
specified. To prevent any residual precipitation build up in the
tubing or flow cell, a flush of pH 3 HCl is performed between
injections. The flow cell is optionally visually inspected between
runs for the presence of precipitation. Static precipitation
measurements are also optionally performed by a two-fold serial
dilution of test compound formulation in blood surrogate using a
laser pointer as a Tyndall beam to determine the presence of
particulates.
[0174] An absorbance (opacity value) of 0.003 is considered to be
the threshold level for detection and assessing precipitation
having phlebitic potential. Control (placebo/vehicle) formulation
shows absorbance of about 0.003 or less. An absorbance at or above
0.05 is considered to be the threshold level for assessing
precipitation having phlebitic potential. An absorbance of about
0.05 or less is considered to be an acceptable potential for
precipitation having phlebitic potential. An absorbance of about
0.03 or less is considered to be a low potential for precipitation
having phlebitic potential. An absorbance of about 0.01 or less is
considered to be a very low potential for precipitation having
phlebitic potential.
[0175] The control vehicles, 0.45% saline and 5.0% mannitol, are
tested and show BQL absorbance.
Comparative Example
[0176] SOL formulations using conventional excipients. Various SOL
salts were dissolved in a vehicle and tested in the Dynamic
Precipitation Model. All water was filtered through a Millipore
Milli-Q water system dispensing water at 18M.OMEGA.cm resistivity.
and was filtered using a 0.45 .mu.m (Alltech) membrane filter. The
pH was adjusted as needed with 1 M HCl, or 1 M NaOH. Azitromycin
citrate and erythromycin lactobionate were each used as positive
controls, and showed BQL (<0.003).
TABLE-US-00004 Example Concentration Infusion Rate pH Vehicle
Absorbance SOL 3 mg/mL 3 mL/min 4.0 0.9% NaCl - SOL-citrate 3 mg/mL
3 mL/min 4.0 5.0% mannitol - SOL-lactobionate 2 mg/mL 3 mL/min 4.0
5.0% mannitol ++ SOL-tartrate 2 mg/mL 3 mL/min 4.0 5.0% mannitol ++
SOL-oxalate 2 mg/mL 3 mL/min 4.0 5.0% mannitol ++ SOL-gluconate 2
mg/mL 3 mL/min 5.3 5.0% mannitol +++ erythromycin-lactobionate 2
mg/mL 3 mL/min n/a 0.9% NaCl ++++ Azitromycin citrate 2 mg/mL 4
mL/min n/a 0.45% NaCl ++++ (-) = .gtoreq.0.05 (+) = <0.05 (++) =
<0.03 (+++) = <0.01 (++++) = BQL of <0.003
Comparative Example
[0177] SOL at 2 mg/mL in 38.5 mM Tartaric Acid and 0.5%
Monothioglycerol in 3% Mannitol at pH 4.0 injected at 2 mL/min, 3
mL/min, or 4 mL/min, with an infusion duration of 5 minutes, showed
minimal precipitation.
Comparative Example
[0178] SOL at 2 mg/mL in 38.5 mM Tartaric Acid and in 5% Mannitol
at pH 4.0 injected at 2 mL/min, 3 mL/min, or 4 mL/min with an
infusion duration of 5 minutes, showed minimal precipitation.
Comparative Example
[0179] SOL at 2 mg/mL in 20 mM Tartaric Acid in 5% Mannitol at pH
4.2 injected at 3 mL/min with an infusion duration of 1 minute,
showed minimal precipitation.
Comparative Example
[0180] SOL at 2 mg/mL in 10 mM Tartaric Acid in 5% Mannitol at pH
4.2 injected at 3 mL/min with an infusion duration of 1 minute,
showed minimal precipitation.
Comparative Example
[0181] SOL at 3 mg/mL in 5 mM Tartaric Acid in 5% Mannitol at pH
4.2 injected at 2 mL/min or 3 mL/min was compared with SOL at 2
mg/mL in 5% Mannitol injected at 2 mL/min or 3 mL/min each with an
infusion duration of 2 minutes. The addition of tartaric acid
substantially decreases the amount of observed precipitation at
both infusion rates.
Comparative Example
[0182] SOL at 3 mg/mL in 0.45% Saline vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates greater than or equal
to 1.0 mL/min, showing BQL, about 0.02, about 0.1, and about 0.3,
respectively.
Comparative Example
[0183] SOL at 2 mg/mL in 0.45% Saline vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates of 3.0 and 6.0 mL/min;
and 1.0 mL/min is borderline, showing BQL, BQL, about 0.02, and
about 0.1, respectively.
Comparative Example
[0184] SOL at 1 mg/mL in 0.45% Saline vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates of 3.0 and 6.0 mL/min;
and 1.0 mL/min is borderline, showing BQL, BQL, BQL, and about 0.1,
respectively.
Comparative Example
[0185] SOL at 3 mg/mL in 5% Mannitol vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates greater than or equal
to 1.0 mL/min, showing BQL, about 0.1, about 0.4, and about 0.6,
respectively.
Comparative Example
[0186] SOL at 2 mg/mL in 5% Mannitol vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates greater than or equal
to 1.0 mL/min, showing BQL, about 0.03, about 0.06, and about 0.1,
respectively.
Comparative Example
[0187] SOL at 1 mg/mL in 5% Mannitol vehicle: When infused at the
injection rate of 0.3, 1.0, 3.0 and 6.0 mL/min (infusion started at
t=1.0 min), precipitation is noted at rates greater than or equal
to 3.0 mL/min, showing BQL, BQL, 0.01, and about 0.05,
respectively. Generally, the addition of mannitol decreases the
observed amount of precipitation.
Example
[0188] Lactic acid based formulations. The following illustrative
formulations are prepared using CEM-101 lyo (which includes the
tartrate indicated as Buffer 1) where the effect of lactic acid is
compared to 0.45% saline alone.
TABLE-US-00005 (mg/ Com- mL) Buffer-1 Buffer-2 pound Drug % %
Saline % pH CEM-101 2 Tartrate 0.023 0.45 CEM-101 3 Tartrate 0.035
0.45 CEM-101 1 Tartrate 0.012 L-lactate 1.000 0.45 4.09 CEM-101 2
Tartrate 0.023 L-lactate 1.000 0.45 4.09 CEM-101 3 Tartrate 0.035
L-lactate 1.000 0.45 3.94
In each case, the addition of lactic acid decreases the observed
amount of precipitation to BQL.
Example
[0189] Lactic acid based formulations including citrate. The
following illustrative formulations are prepared using CEM-101 lyo
(which includes the tartrate indicated as Buffer 1) where the
effect of lactic acid is compared to 0.45% saline alone and
citrate.
TABLE-US-00006 (mg/ mL) Buffer-1 Buffer-2 Saline Compound Drug % %
% pH Azithro- 2 Citrate 0.153 0.45 mycin CEM-101 2 Tartrate 0.023
0.45 CEM-101 3 Tartrate 0.035 0.45 CEM-101 2 Tartrate 0.023 Citrate
0.096 0.45 3.96 CEM-101 3 Tartrate 0.035 Citrate 0.096 0.45 3.96
CEM-101 1 Tartrate 0.012 L-lactate 1.000 0.45 4.09 CEM-101 2
Tartrate 0.023 L-lactate 1.000 0.45 4.09 CEM-101 3 Tartrate 0.035
L-lactate 1.000 0.45 3.94
In each case, the addition of lactic acid decreases the observed
amount of precipitation to BQL. The addition of lactic acid also
decreases the amount of precipitation observed in the samples that
include citrate. Azithromycin infused as a citrate buffered
solution in 0.45% saline at 2 mg/mL and 4 mL/min, does not exhibit
precipitation (BQL). Comparison of 3 mg/mL CEM-101 lyo in 5 mM
citrate buffer at pH 4 with 3 mg/mL CEM-101 lyo in 0.45% saline at
infusion rates of 1 mL/min, 2 mL/min and 3 mL/min shows
precipitation from both solutions at all infusion rates, but
precipitation at 1 mL/min is reduced in the 5 mM citrate buffer
solution, where at 1 mL/min an absorbance of <0.05 was observed,
where as at 2 or 3 mL/min, an absorbance of >0.05 was observed.
The use of a citrate buffer diluent did not dramatically reduce
precipitation in the absence of lactate.
Variation of Lactate Forms and Buffer Concentrations
Example
[0190] Lactic acid based formulations in 0.45% saline vehicle. The
following are prepared using CEM-101 lyo (which includes the 0.012%
tartrate per gram of CEM-101 and any additional tartrate necessary
for the concentration indicated as Buffer 1) and the indicated
lactate buffer.
TABLE-US-00007 (mg/mL) % % Compound Drug Tartrate Lactate % Saline
pH CEM-101 2 0.023 0.50 CEM-101 2 0.023 L-Lactate 0.500 0.50 4.06
CEM-101 2 0.023 DL-Lactate 0.500 0.50 3.91 CEM-101 2 0.075
L-Lactate 0.500 0.50 3.95 CEM-101 2 0.150 L-Lactate 0.500 0.50 3.98
CEM-101 2 0.023 L-Lactate 0.250 0.50 4.09 CEM-101 2 0.075 L-Lactate
0.250 0.50 4.02 CEM-101 2 0.150 L-Lactate 0.250 0.50 3.96 CEM-101 2
0.375 L-Lactate 0.250 0.50 4.04 CEM-101 2 0.023 L-Lactate 0.500
0.50 4.00 CEM-101 2 0.023 DL-Lactate 0.500 0.50 4.00
TABLE-US-00008 (mg/mL) % % % % Compound Drug Tartrate L-Lactate
Citrate Saline pH Placebo 0 0.45 CEM-101 2 0.023 0.50 CEM-101 3
0.035 0.50 CEM-101 2 0.023 0.500 0.50 4.04 CEM-101 2 0.150 1.000
0.50 3.94 CEM-101 3 0.150 1.000 0.50 3.93 CEM-101 2 0.375 1.000
0.50 3.96 CEM-101 3 0.375 1.000 0.50 3.97 CEM-101 2 0.023 1.000
0.009 0.50 4.00 CEM-101 3 0.035 1.000 0.009 0.50 4.02 CEM-101 2
0.023 1.000 0.019 0.50 3.98 CEM-101 3 0.035 1.000 0.019 0.50 3.97
CEM-101 2 0.023 1.000 0.096 0.50 3.90 CEM-101 3 0.035 1.000 0.096
0.50 3.92
Evaluation of 2 mg/mL and 1 mg/mL CEM-101 lyo-based Formulation
(CEM-101) in 0.5% lactate buffer at pH 4 in 0.5% saline at infusion
rates of 1 mL/min, 2 mL/min and 3 mL/min shows precipitation below
the threshold absorbance level of 0.003 at each of the three rates
(showing comparison with 2 mg/mL CEM-101 lyo-based Formulation
(CEM-101) in 0.45% saline). All lactate containing formulations
showed an absorbance <0.01. All non-lactate containing gave
showed an absorbance of about 0.03 in at least one
infusion/concentration combination.
[0191] Infusions of 2 mg/mL CEM-101 lyo in 1% lactate formulation
at pH 4 in 0.5% saline with a variety of vehicles at infusion rates
of 1 mL/min, 2 mL/min and 3 mL/min generally show precipitation
below the threshold absorbance level of 0.003 at each of the three
rates. Similar infusions of 3 mg/mL CEM-101 lyo-based Formulation
show precipitation greatly reduced compared to the formulation
without 1% lactate buffer or show precipitation below the threshold
absorbance level of 0.003. Overall, the use of 1.0% and 0.5%
L-lactate produces a greater reduction of precipitation than 0.25%
L-lactate.
[0192] Infusions of solutions using DL-lactic acid buffer gives
results comparable to those of solutions using L-lactic acid
buffers and shows infusions at infusion rates of 1 mL/min, 2 mL/min
and 3 mL/min of 2 mg/mL CEM-101 lyo-based Formulation (CEM-101) in
0.5% saline, 0.5% L-lactate buffer at pH 4 in 0.5% saline, 0.5%
DL-lactate buffer at pH 4 in 0.5% saline, and 0.5% L-lactate buffer
plus 5 mM tartaric acid buffer at pH 4 in 0.5% saline).
[0193] The use of additional tartrate buffer did not dramatically
reduce precipitation. The use of either L-lactate buffer or
DL-lactate buffer reduced precipitation in all cases.
[0194] In summary, 0.5, 1 and 5 mM citrate buffer (pH 4) in 0.45%
saline does not significantly reduce precipitation in the dynamic
precipitation model at concentrations of 2 mg/mL and 3 mg/mL SOL
formulations. 10 or 25 mM tartrate buffer (pH 4) in 0.45% saline
does not significantly reduce precipitation in the dynamic
precipitation model at concentrations of 2 mg/mL and 3 mg/mL SOL
formulations. In both 0.5% and 1% lactate buffer (pH 4) in 0.45%
saline precipitation is reduced below the 0.003 absorbance level at
1 mg/mL and 2 mg/mL at a rate of 3 mL/min. Addition of a citrate or
tartrate co-buffer to the lactate buffer had minimal effect in the
dynamic precipitation model.
Example
[0195] Amino Acid Formulations. The following illustrative
formulations are prepared using SOL. It is understood that any
source of SOL may be used as described herein. The illustrative
formulations are tested in the Dynamic Precipitation Model and show
an absorbance of less than about 0.01.
TABLE-US-00009 SOL Infusion Formulation Agents pH Concentration
Rate 25 mM Histidine + 25 mM Glutamic Acid + 25 mM Acetic n/a 0
mg/ml 3 ml/min Acid 25 mM Histidine + 25 mM Glutamic Acid + 15 mM
Acetic n/a 0 mg/ml 3 ml/min Acid 25 mM Histidine + 25 mM Glutamic
Acid + 25 mM Aspartic n/a 0 mg/ml 3 ml/min Acid 25 mM Histidine +
25 mM Glutamic Acid 5.0 2 mg/ml 3 ml/min 20 mM Histidine + 25 mM
Glutamic Acid 5.0 2 mg/ml 3 ml/min 20 mM Histidine + 20 mM Glutamic
Acid 5.0 2 mg/ml 3 ml/min 20 mM Histidine + 20 mM Glutamic Acid +
20 mM Tartic 5.0 2 mg/ml 3 ml/min Acid 20 mM Histidine + 20 mM
Glutamic Acid + 20 mM Acetic 5.0 2 mg/ml 3 ml/min Acid 25 mM
Histidine + 25 mM Glutamic Acid + 25 mM Acetic 5.0 2 mg/ml 3 ml/min
Acid 25 mM Histidine + 25 mM Glutamic Acid + 25 mM Acetic 5.0 2
mg/ml 3 ml/min Acid 15 mM Histidine + 15 mM Glutamic Acid + 15 mM
Acetic 5.0 2 mg/ml 3 ml/min Acid 15 mM Histidine + 15 mM Glutamic
Acid + 15 mM Acetic 5.0 2 mg/ml 3 ml/min Acid 10 mM Histidine + 10
mM Glutamic Acid + 10 mM Acetic 5.0 2 mg/ml 3 ml/min Acid 25 mM
Histidine + 25 mM Glutamic Acid + 15 mM Acetic 5.0 2 mg/ml 3 ml/min
Acid 15 mM Histidine + 15 mM Glutamic Acid + 15 mM Acetic 5.0 2
mg/ml 3 ml/min Acid* 25 mM Histidine + 25 mM Acetic Acid 5.0 2
mg/ml 3 ml/min 25 mM Histidine + 25 mM Acetate 6.0 2 mg/mL 3 mL/min
15 mM Histidine + 15 mM Glutamic Acid + 15 mM Acetic 4.5 2 mg/ml 3
ml/min Acid 15 mM Histidine + 15 mM Glutamic Acid + 15 mM Acetic
4.2 2 mg/ml 3 ml/min Acid 15 mM Histidine + 15 mM Glutamic Acid +
15 mM 4.5 2 mg/ml 3 ml/min Aspartic Acid 15 mM Histidine + 15 mM
Glutamic Acid + 15 mM 4.5 2 mg/ml 3 ml/min Aspartic Acid 15 mM
Histidine + 15 mM Glutamic Acid + 15 mM Lactic 4.5 2 mg/ml 3 ml/min
Acid 15 mM Histidine + 15 mM Glutamic Acid + 15 mM 4.2 2 mg/ml 3
ml/min Aspartic Acid 15 mM Histidine + 15 mM Glutamic Acid + 15 mM
Lactic 4.2 2 mg/ml 3 ml/min Acid 25 mM Histidine + 25 mM Glutamic
Acid + 25 mM 4.0 2 mg/ml 3 ml/min Aspartic Acid 15 mM Histidine +
15 mM Glutamic Acid 5.0 2 mg/ml 3 ml/min 25 mM Histidine + 25 mM
Lactic Acid + 6.0 2 mg/mL 3 mL/min 25 mM Histidine + 25 mM Acetic
Acid + 6.0 2 mg/mL 3 mL/min 25 mM Histidine + 25 mM Lactate + 25 mM
Acetate 6.0 2 mg/mL 3 mL/min 25 mM Histidine 6.0 2 mg/mL 3 mL/min
25 mM Histidine 5.5 2 mg/mL 3 mL/min 25 mM Histidine + 25 mM
Phosphate 5.5 2 mg/mL 3 mL/min 25 mM Histidine + 10 mM Phosphate
5.5 2 mg/mL 3 mL/min 5 mM Glutamic Acid + 5mM Histidine + 5 mM
Acetic 5.5 2 mg/mL 3 mL/min Acid + 5% Mannitol 5 mM Glutamic Acid +
5 mM Histidine + 5% Mannitol 5.5 2 mg/mL 3 mL/min 5 mM Glutamic
Acid + 10 mM Histidine + 5% Mannitol 5.5 2 mg/mL 3 mL/min 5 mM
Glutamic Acid + 15 mM Histidine + 5% Mannitol 5.5 2 mg/mL 3 mL/min
15 mM Histidine + 5% Mannitol 5.5 2 mg/mL 3 mL/min 10 mM Histidine
+ 0.5% Poloxamer-188 + 5% Mannitol 6.0 2 mg/mL 3 mL/min 15 mM
Histidine + 0.5% Poloxamer-188 + 5% Mannitol 6.0 2 mg/mL 3 mL/min
10 mM Histidine + 1.0% Captisol + 5% Mannitol 6.0 2 mg/mL 3 mL/min
10 mM Histidine + 2.0% Captisol + 5% Mannitol 6.0 2 mg/mL 3 mL/min
15 mM Histidine + 15 mM Glutamic Acid + 15 mM 5.4 2 mg/mL 10 mL/min
Aspartic Acid + 4.3% Mannitol 15 mM Histidine + 15 mM Glutamic Acid
+ 15 mM 5.4 2 mg/mL 5 mL/min Aspartic Acid + 4.3% Mannitol 25 mM
Histidine + 15 mM Glutamic Acid + 4.6% 5.5 2 mg/mL 10 mL/min
Mannitol 15 mM Histidine + 25 mM Lactic Acid + 4.3% Mannitol 6.0 2
mg/mL 10 mL/min 25 mM Histidine + 25 mM Lactic Acid + 25 mM Acetic
6.1 2 mg/mL 10 mL/min Acid + 3.4% Mannitol 25 mM Histidine + 15 mM
Glutamic Acid + 4.7% 6.1 2 mg/mL 10 mL/min Mannitol 15 mM Histidine
+ 25 mM Lactic Acid + 4.3% Mannitol 6.5 2 mg/mL 10 mL/min 25 mM
Histidine + 25 mM Lactic Acid + 25 mM Acetic 6.6 2 mg/mL 10 mL/min
Acid + 3.2% Mannitol 25 mM Histidine + 15 mM Glutamic Acid + 4.6%
6.5 2 mg/mL 10 mL/min Mannitol 15 mM Histidine + 15 mM Glutamic
Acid + 4.7% 6.4 2 mg/mL 10 mL/min Mannitol 15 mM Histidine + 15 mM
Acetic Acid + 15 mM Lactic 5.4 2 mg/mL 10 mL/min Acid + 4.4%
Mannitol 15 mM Histidine + 15 mM Acetic Acid + 15 mM Lactic 5.8 2
mg/mL 10 mL/min Acid + 4.4% Mannitol 15 mM Histidine + 15 mM Acetic
Acid + 15 mM Lactic 5.5 2 mg/mL 10 mL/min Acid + 0.9% NaCl 15 mM
Histidine + 15 mM Glutamic Acid + 15 mM 5.4 2 mg/mL 10 mL/min
Aspartic Acid + 0.9% NaCl 15 mM Histidine + 15 mM Acetic Acid + 15
mM Lactic 5.5 2 mg/mL 10 mL/min Acid + 0.45% NaCl 15 mM Histidine +
15 mM Glutamic Acid + 15 mM 5.6 2 mg/mL 10 mL/min Aspartic Acid +
0.45% NaCl 15 mM Histidine + 15 mM Glutamic Acid + 15 mM Acetic 5.0
2 mg/mL 10 mL/min Acid + 4.3% Mannitol 15 mM Histidine + 15 mM
Glutamic Acid + 15 mM 4.5 2 mg/mL 10 mL/min Aspartic Acid + 5%
Mannitol 15 mM Histidine + 15 mM Glutamic Acid + 15 mM 4.5 4 mg/mL
10 mL/min Aspartic Acid + 2% Mannitol + 0.45% NaCl 15 mM Histidine
+ 15 mM Glutamic Acid + 15 mM 4.5 4 mg/mL 5 mL/min Aspartic Acid +
2% Mannitol + 0.45% NaCl 15 mM Histidine + 15 mM Glutamic Acid + 15
mM 4.5 4 mg/mL 10 mL/min Aspartic Acid + 0.9% NaCl 15 mM Histidine
+ 15 mM Glutamic Acid + 15 mM 4.5 4 mg/mL 5 mL/min Aspartic Acid +
0.9% NaCl
Method Example
[0196] Pain Tolerance Evaluation Following Intravenous Infusion in
Rabbit. Single Dose Rabbit Ear Vein Model Study. New Zealand White
female rabbits weighing 2.5-3.2 kg are evaluated for pain, ear
inflammation and phlebitis after intravenous infusion of test
compound. Commercial azithromycin citrate is used as a positive
control.
[0197] CEM-101 lyo (SOL (250.0 mg), mannitol, USP (250.0 mg),
L(+)-tartaric acid, USP (29.0 mg), sodium hydroxide, NF (for pH
adjustment to pH 4.2)) is reconstituted in a vehicle or formulation
as described herein. The placebo is the same formulation without
SOL. The reconstituted SOL or placebo is dissolved in an
appropriate vehicles, such as 0.45% saline, 0.5% lactic acid at pH
4 in 0.45% saline, 0.5% lactic acid with 10 mM tartaric acid at pH
4 in 0.45% saline. CEM-101 lyo is dissolved in the appropriate
vehicle at concentrations of 2 mg/mL or 3 mg/mL. The CEM-101
placebo formulation is dissolved in 0.45% saline. All rabbits are
weighed to calculate dosing volumes.
[0198] Azithromycin lyophilized vials are commercially available
azithromycin citrate for injection (ZITHROMAX IV) in lyophilized
form in a 10-mL vial equivalent to 500 mg of azithromycin for
intravenous administration. Reconstitution, according to label
directions, results in approximately 5 mL of ZITHROMAX for
intravenous injection with each mL containing azithromycin
dihydrate equivalent to 100 mg of azithromycin. Reconstituted
azithromycin Citrate, 2 mg/mL, is dissolved in its vehicle, 0.45%
saline.
[0199] Two rabbits are dosed with vehicle then with azithromycin
citrate via intravenous infusion in a marginal ear vein at a dose
volume of 5 mL and an infusion rate of 4 mL/min. Two rabbits are
dosed with vehicle (4 mL/min) then with test compound in a
formulation described herein or a comparative formulation saline
via intravenous infusion in a marginal ear vein at a dose volume of
5 mL and/or concentration of 2 mg/mL and/or 3 mg/mL at infusion
rates of 1, 2, 3, and/or 4 mL/min. After evaluation, the study
continued with dosing of CEM-101/Mannitol/Tartrate Formulation in
the lactate containing vehicles. All rabbits received vehicle, 0.5
N saline (azithromycin citrate) or CEM-101 placebo formulation in
0.45% saline (CEM-101 dosed animals) in the left ear and test
article in the right ear. Thirty minutes was allowed to lapse
between each infusion in the same animal.
[0200] Animals were observed during and post (30 minutes) each
infusion, and reactions were scored according to a modified Draize
Score and recorded. The Modified Draize Score used to evaluate the
rabbits' reactions to test article administration was as
follows:
[0201] 0--No Reaction
[0202] 1--slight twitch of the ear when IV infusion
administered
[0203] 2--ear twitch and head movement
[0204] 3--strong head movement on administration but quiets in 20
seconds
[0205] 4--strong movement of ear, head, and body with
vocalization
[0206] Rabbits receiving SOL in 0.45% saline experienced adverse
effects from a slight twitch of the ear upon test article
administration to strong head movement on administration, though
becoming calm in approximately 20 seconds. The severity of the
reactions correlated with the increasing infusion rate. Rabbits
receiving SOL in any of the lactate formulations displayed no
reactions upon test article administration during any of the
infusions at either concentration (2 mg/mL or 3 mg/mL); and pain,
inflammation and phlebitis were not observed.
[0207] Rabbits receiving Azithromycin Citrate experienced strong
movement of ear, head and body with vocalization upon test article
administration and were removed from the study.
Modified Draize Scores for Tested Formulations
TABLE-US-00010 [0208] Example Vehicle 1 mL/min 2 mL/min 3 mL/min 4
mL/min SOL in 0.45% saline 1 1 1 2 3 (2 mg/mL) SOL in 0.5% lactic
acid at pH 4 in 0 0 0 0 0 0.45% saline (2 mg/mL) SOL in 0.5% lactic
acid at pH 4 in 0 0 0 0 0 0.45% saline (3 mg/mL) SOL in 0.5% lactic
acid with 10 mM 0 0 0 0 0 tartaric acid at pH 4 in 0.45% saline (2
mg/mL) SOL in 0.5% lactic acid with 10 mM 0 0 0 0 0 tartaric acid
at pH 4 in 0.45% saline (3 mg/mL) Azithromycin Citrate in 0.45%
saline 0 -- -- -- 4 (2 mg/mL)
Method Example
[0209] Tolerance Evaluation of Following Intravenous Infusion in
the Rabbit. Multiple-Dose Rabbit Ear Vein Model Study. New Zealand
White female rabbits weighing 2.5-3.2 kg are evaluated for pain,
ear inflammation and phlebitis after receiving an intravenous
infusion of test compound once daily for 5 days.
[0210] SOL is dissolved in a 0.5% lactic acid formulation at pH 4,
and then into 0.45% saline at concentrations of 2 mg/mL or 3
mg/mL.
[0211] Four rabbits are dosed; one vehicle-dosed and one each at 2
mg/mL (rate of 3 mL/min), 3 mg/mL (rate of 3 mL/min) and 3 mg/mL
(rate of 4 mL/min). All rabbits receive a dose volume of 5 mL and
are dosed via intravenous infusion in the right marginal ear vein
once daily for 5 days. Animals are observed during and post (30
minutes) each infusion and reactions recorded.
[0212] No adverse effects were observed in any of the rabbits on
Days 1 and 2. On Days 4 and 5, mechanical irritation around the
needle stick, without reaction distal to the needle, was seen in
the vehicle-treated and 2 mg/mL (rate of 3 mL/min) rabbits. Rabbits
receiving SOL at a concentration of 3 mg/mL and rates of 3 or 4
mL/min experienced vessel dilation and irritation around and past
the needle stick beginning on Day 3 and continuing until day 5.
Head and ear twitching was also observed in the rabbit receiving 3
mg/mL of SOL at a rate of 4 mL/min.
Method Example
[0213] Dermal Erythema, Edema, and Phlebitis model. Test compounds
are compared to the corresponding vehicle controls. The test and
vehicle control formulations are prepared fresh on the day of
dosing and used within 4 hours of preparation. The control 0.9%
NaCl for Injection, USP is used as supplied. The vehicle controls
are prepared five days prior to the start of dosing in a quantity
sufficient enough for a treatment period of up to 5 days. All
formulations are prepared using Sterile Water for Injection USP.
Twenty-six (26) male New Zealand White rabbits (Oryctolagus
cuniculus) are used in this Example. Rabbits are generally 3 to 4
months old and their body weights range from 2.3 to 3.6 kg. Test
compounds are administered as a single dose over a period of 2 or
20 minutes (total volume of 10 mL) by intravenous infusion to New
Zealand White rabbits (n=3). Test compounds are injected into the
marginal ear veins (right ear) via disposable indwelling catheters.
Corresponding vehicle controls are injected into the marginal ear
veins (left ear) via disposable indwelling catheters. A positive
control group is tested with 0.9% NaCl for Injection, USP in each
ear. All test animals are evaluated for ear dermal erythema and/or
edema. Infusion rates are fixed and independent of animal weight.
Final dose level in mg/kg is dependent on the individual animal's
body weight.
TABLE-US-00011 Infusion Dose Concentration Rate Infusion
Formulation Vehicle (mg) (mg/mL) (mL/min) Length (min) 15 mM
L-(-)-Histidine 4.3% D-(+)- 25 2.5 5 2 15 mM L-(+)-Glutamic Acid
Mannitol at pH 15 mM L-(+)-Aspartic acid 4.5 15 mM L-(-)-Histidine
0.9% Saline at 25 2.5 5 2 15 mM L-(+)-Glutamic Acid pH 4.5 15 mM
L-(+)-Aspartic acid 38.5 mM L-(-)-Tartaric acid 3% D-(+)- 25 2.5 5
2 0.5% Monothioglycerol (1- Mannitol at pH thioglycerol) 4.2 15 mM
L-(-)-Histidine 4.3% D-(+)- 25 2.5 0.5 20 15 mM L-(+)-Glutamic Acid
Mannitol at pH 15 mM L-(+)-Aspartic acid 4.5 15 mM L-(-)-Histidine
0.9% Saline at 25 2.5 0.5 20 15 mM L-(+)-Glutamic Acid pH 4.5 15 mM
L-(+)-Aspartic acid 38.5 mM L-(-)-Tartaric acid 3% D-(+)- 25 2.5
0.5 20 0.5% Monothioglycerol (1- Mannitol at pH thioglycerol) 4.2
15 mM L-(-)-Histidine 4.1% Mannitol at 25 2.5 0.5 20 15 mM
L-(+)-Glutamic Acid pH 5.0 15 mM Acetic Acid (from Sodium acetate
trihydrate)
[0214] Following dosing, all animals were observed for
approximately 24 hours and then euthanized and subjected to an
external examination followed by collection of tissues for
histopathological examinations. Parameters monitored include
mortality, clinical observations, body weight, dermal changes
(using a modified Draize scoring scheme) and macroscopic and
microscopic (histopathological) examination of the ear (dosing
site) and jugular veins. Only one rabbit in Group 3 (15 mM
L-(-)-Histidine, 15 mM L-(+)-Glutamic Acid, 15 mM L-(+)-Aspartic
acid in 0.9% Saline vehicle at pH 4.5) developed a well-defined
erythema at 23 hour after the dosing. Ear edema was not observed in
any groups under either infusion condition. No Macroscopic findings
at necropsy were observed in any of the treatment groups. The
histopathological findings at 1 cm and most distal location
(junction of the ear and head) at approximately 2 cm from the
catheter tips were minimal or mild in all the groups. No findings
were observed at the jugular vein site in any groups dosed at 5
mL/min or 0.5 mL/min.
* * * * *