U.S. patent application number 17/405772 was filed with the patent office on 2022-08-25 for antimicrobial compositions.
The applicant listed for this patent is Melinta Subsidiary Corp.. Invention is credited to Eric S. BURAK, David S. DRESBACK, Danping LI, Danielle B. LORD.
Application Number | 20220265636 17/405772 |
Document ID | / |
Family ID | 1000006211269 |
Filed Date | 2022-08-25 |
United States Patent
Application |
20220265636 |
Kind Code |
A1 |
LI; Danping ; et
al. |
August 25, 2022 |
ANTIMICROBIAL COMPOSITIONS
Abstract
The present invention relates to antimicrobial compositions and
more specifically compositions of quinolone carboxylic acid
derivatives. These compositions have improved solubility,
stability, and tolerability. These compositions are useful for
intravenous administration for treating, preventing, or reducing
the risk of infection.
Inventors: |
LI; Danping; (Middlebury,
CT) ; BURAK; Eric S.; (East Haddam, CT) ;
DRESBACK; David S.; (Stonington, CT) ; LORD; Danielle
B.; (Hamden, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Melinta Subsidiary Corp. |
Morristown |
NJ |
US |
|
|
Family ID: |
1000006211269 |
Appl. No.: |
17/405772 |
Filed: |
August 18, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16425580 |
May 29, 2019 |
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17405772 |
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15042886 |
Feb 12, 2016 |
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16425580 |
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13105513 |
May 11, 2011 |
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15042886 |
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PCT/US09/64220 |
Nov 12, 2009 |
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13105513 |
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61199253 |
Nov 15, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/47 20130101;
A61K 47/26 20130101; A61K 31/4709 20130101; A61K 9/08 20130101;
B82Y 5/00 20130101; A61K 9/19 20130101; A61K 9/0019 20130101; A61K
47/183 20130101; A61K 47/40 20130101; A61K 47/6951 20170801 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 47/18 20060101 A61K047/18; A61K 47/40 20060101
A61K047/40; A61K 9/00 20060101 A61K009/00; B82Y 5/00 20060101
B82Y005/00; A61K 31/47 20060101 A61K031/47; A61K 9/19 20060101
A61K009/19; A61K 9/08 20060101 A61K009/08; A61K 47/69 20060101
A61K047/69; A61K 47/26 20060101 A61K047/26 |
Claims
1-97. (canceled)
98. An intravenous pharmaceutical composition comprising: (a) a
quinolone carboxylic acid derivative or a pharmaceutically
acceptable salt or ester thereof, wherein the quinolone carboxylic
acid derivative corresponds to the following compound (A):
##STR00016## (b) meglumine; (c) a SBE-7-.beta.-CD; and (d) disodium
EDTA.
99. The intravenous pharmaceutical composition according to claim
98, wherein the quinolone carboxylic acid derivative is a
D-glucito1,1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt).
100. The intravenous pharmaceutical composition according to claim
99 wherein said quinolone carboxylic acid derivative is a
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt)
characterized, when measured at about 25.degree. C. with Cu-Ka
radiation, by the powder diffraction pattern shown in FIG. 1.
101. The intravenous pharmaceutical composition according to claim
98, wherein the quinolone carboxylic acid derivative has a
measurable improvement in solubility compared to the quinolone
carboxylic acid derivative in water, and/or the composition has
improved stability, and/or the composition provides a measurable
enhancement in venous toleration.
102. The intravenous pharmaceutical composition according to claim
98 which is in the form of a lyophile.
103. The intravenous pharmaceutical composition according to claim
98, wherein the cyclodextrin comprises from 0.01% to 50% by weight
of the composition.
104. The intravenous pharmaceutical composition according to claim
103, wherein the cyclodextrin comprises from 10% to 30% by weight
of the composition.
105. The intravenous pharmaceutical composition according to claim
98, wherein the composition has a pH from 7 to 11.
106. The intravenous pharmaceutical composition according to claim
105, wherein the composition has a pH from 8 to 10.
107. The intravenous pharmaceutical composition according to claim
106, wherein the composition has a pH from 8.5 to 9.5.
108. The intravenous pharmaceutical composition according to claim
107, wherein the composition has a pH from 8.8 to 9.2.
109. The intravenous pharmaceutical composition according to claim
108, wherein the composition has a pH of 9.0.
110. An intravenous pharmaceutical composition comprising: (a) from
100 mg to 500 mg of delafloxacin, (b) from 15 mg to 125 mg
meglumine, (c) from 500 mg to 5000 mg of a SBE-7-.beta.-CD; and (d)
from 0 mg to 4 mg disodium EDTA.
111. The intravenous pharmaceutical composition according to claim
110 comprising: (a) 100 mg of delafloxacin; (b) 19.52 mg of
meglumine; (c) 800 mg of the SBE-7-.beta.-CD; and (d) 0.44 mg of
disodium EDTA.
112. The intravenous pharmaceutical composition according to claim
110 comprising: (a) 300 mg of delafloxacin; (b) 58.56 mg of
meglumine; (c) 2400 mg of the SBE-7-.beta.-CD; and (d) 1.32 mg of
disodium EDTA.
113. The intravenous pharmaceutical composition according to claim
110 comprising: (a) 500 mg of delafloxacin; (b) 97.6 mg of
meglumine; (c) 4000 mg of the SBE-7-.beta.-CD; and (d) 2.2 mg of
disodium EDTA.
114. The intravenous pharmaceutical composition according to claim
110 which is in the form of a lyophile.
115. The intravenous pharmaceutical composition according to claim
110, wherein the quinolone carboxylic acid derivative has a
measurable improvement in solubility compared to the quinolone
carboxylic acid derivative in water, and/or the composition has
improved stability, and/or the composition provides a measurable
enhancement in venous toleration.
116. The intravenous pharmaceutical composition according to claim
110, wherein the composition has a pH from 7 to 11.
117. An intravenous pharmaceutical composition comprising: (a) from
100 mg to 500 mg of delafloxacin meglumine, (b) from 15 mg to 125
mg meglumine, (c) from 500 mg to 5000 mg of the SBE-7-.beta.-CD;
and (d) from 0 mg to 4 mg disodium EDTA.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/425,580, filed May 29, 2019, which is a
continuation of U.S. patent application Ser. No. 15/042,886, filed
Feb. 12, 2016, which is a continuation of U.S. patent application
Ser. No. 13/105,513, filed May 11, 2011, which is a continuation of
International Application No. PCT/US2009/064220, filed Nov. 12,
2009, which claims the benefit U.S. Provisional Application No.
61/199,253, filed Nov. 15, 2008, the entire disclosures of each of
which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to pharmaceutical compositions
comprising a quinolone carboxylic acid derivative antimicrobial
compound and a cyclodextrin. These compositions have improved
solubility, stability, and tolerability. These compositions are
useful for intravenous administration for treating, preventing, or
reducing the risk of infection.
BACKGROUND
[0003] An appropriate pharmaceutical carrier system is generally a
requirement for the safe and effective delivery of a pharmaceutical
drug active. The entire pharmaceutical composition, i.e., the
pharmaceutical drug active formulated in a pharmaceutical carrier,
can affect the bioavailability and also the pharmacokinetics and
pharmacodynamics of the drug active. It is therefore important that
a pharmaceutical composition be carefully developed and
manufactured to deliver the desired pharmaceutical drug active in a
safe and effective manner.
[0004] The delivery of antimicrobial agents for treating or
preventing microbial infections can present special challenges. To
provide therapeutic efficacy, it is generally desired that the
antimicrobial agent be administered to the patient to achieve
systemic concentrations in the bloodstream or target organs above a
minimum inhibitory concentration (MIC) for a sufficient time
against the particular microbial organism or organisms being
targeted. Consequently, an antimicrobial agent that otherwise
exhibits an effective antimicrobial profile in vitro can be
ineffective, or even harmful, unless properly formulated for in
vivo administration.
[0005] The challenge of developing suitable antimicrobial
compositions is further complicated for the development of liquid
formulations for parenteral administration, such as intravenous
administration. Intravenous delivery of a drug active is an
important route of administration where the drug cannot be
administered orally or by other means, for example where a patient
is unconscious, or seriously ill, and cannot otherwise take the
drug orally. Although not the case with the pyridine carboxylic
acid antimicrobial agents of the present invention, many drugs
cannot be delivererd orally because of low oral bioavailability or
low oral toleration. The development of suitable compositions for
intravenous administration often pose many and often complex
challenges including balancing the interplay of, solubility of the
drug active, chemical and physical stability of the composition,
and toleration of the composition upon infusion. In addition to
solubility, stability, and toleration, other considerations include
ease of manufacture of the composition, convenience of storing the
composition, and ease of reconstitution of the composition, e.g.,
in the case of compositions which are in the form of dry powders or
lyophils designed for reconstitution prior to administration.
[0006] Solubility of the pharmaceutical drug active is an important
consideration, if not the primary consideration, for a product
intended for intravenous administration because without sufficient
solubility, the pharmaceutical drug active might not be suitable
for intravenous administration. Also, limitations on the volume of
an intravenous formulation that can be safely and conveniently
administered will further constrain the parameters for developing a
practical formulation. If the pharmaceutical drug active cannot be
solubilized at a practical level, then it might not even be
possible to develop an intravenous formulation of the drug.
[0007] Stability of a pharmaceutical composition is another
important consideration. A pharmaceutical composition must have
sufficient chemical and physical stability such that the potency of
the pharmaceutical drug active is maintained above a required level
and the integrity of the overall formulation is maintained to
enable safe administration. It is important that the formation of
potentially harmful degredants and byproducts is minimized.
[0008] Tolerability of a pharmaceutical composition is yet another
important consideration, because an intravenous formulation should
not irritate or damage the blood vessels and surrounding tissue of
the patient. Furthermore, the composition should not cause undue
venous intoleration or undue discomfort during administration, or
alternatively should reduce venous intoleration or discomfort.
[0009] A pharmaceutical composition should have sufficient
efficacy. A pharmaceutical composition should also have sufficient
chemical and physical stability to enable administration to a
patient. A pharmaceutical composition should also maintain the
potency of the drug active over a useful length of time. Potency of
a drug active in a pharmaceutical composition can be maintained,
for example, by keeping the concentration or level of the drug
active constant, or nearly constant, in the composition over
time.
[0010] Therefore, the present invention addresses the foregoing and
other needs.
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1 shows a powder X-ray diffraction pattern of
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate (salt).
[0012] FIG. 2 shows a powder X-ray diffraction pattern of
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt).
SUMMARY OF THE INVENTION
[0013] The present invention relates to antimicrobial compositions
and more specifically compositions of quinolone carboxylic acid
derivatives. The present invention relates to a pharmaceutical
composition comprising a quinolone carboxylic acid derivative or a
pharmaceutically acceptable salt or ester thereof, and a
cyclodextrin selected from the group consisting of an
alpha-cyclodextrin, a beta-cyclodextrin, a gamma-cyclodextrin, and
mixtures thereof. These compositions have improved solubility of
the drug active, improved chemical and physical stability, i.e.
improved stability of the drug active and of the overall
composition, and improved tolerability for intravenous
administration or injection. These compositions are useful for
intravenous administration or injection, for treating, preventing,
or reducing the risk of infection.
[0014] In one aspect, the invention relates to a pharmaceutical
composition which prior to mixing comprises (a) a quinolone
carboxylic acid derivative or a pharmaceutically acceptable salt or
ester thereof, and (b) a cyclodextrin.
[0015] In one aspect, the invention relates to a pharmaceutical
composition which prior to mixing comprises (a) a quinolone
carboxylic acid derivative or a pharmaceutically acceptable salt or
ester thereof, (b) a cyclodextrin, and (c) a chelating agent.
[0016] In one aspect, the invention relates to a pharmaceutical
composition comprising (a) a quinolone carboxylic acid derivative
or a pharmaceutically acceptable salt or ester thereof, an (b) a
cyclodextrin.
[0017] In one aspect, the invention relates to a pharmaceutical
composition comprising (a) a quinolone carboxylic acid derivative
or a pharmaceutically acceptable salt or ester thereof, (b) a
cyclodextrin, and (c) a chelating agent.
[0018] In one aspect, the invention relates to a pharmaceutical
composition comprising an inclusion complex, said inclusion complex
comprising (a) a quinolone carboxylic acid derivative or a
pharmaceutically acceptable salt or ester thereof, and (b) a
cyclodextrin.
[0019] In one aspect, the invention relates to a pharmaceutical
composition comprising (a) an inclusion complex, said inclusion
complex further comprising (i) a quinolone carboxylic acid
derivative or a pharmaceutically acceptable salt or ester thereof,
and (ii) a cyclodextrin; and (b) a chelating agent.
[0020] In one aspect, the invention relates to a pharmaceutical
composition comprising (that is in the form of) an aqueous
solution.
[0021] In one aspect, the invention relates to a pharmaceutical
composition comprising (that is in the form of) a dry mixture. In
one aspect, the invention relates to a pharmaceutical composition
wherein said dry mixture is a lyophile. In one aspect, the
invention relates to a pharmaceutical composition wherein said dry
mixture is made by lyophylization. In one aspect, the invention
relates to a pharmaceutical composition wherein said dry mixture or
lyophile is reconstituted. In one aspect, the invention relates to
a pharmaceutical composition wherein said pharmaceutical
composition is diluted.
[0022] In one aspect, the invention relates to a pharmaceutical
composition wherein said cyclodextrin is selected from the group
consisting of alpha-cyclodextrins, beta-cyclodextrins,
gamma-cyclodextrins, and mixtures thereof. In one aspect, the
invention relates to a pharmaceutical composition said cyclodextrin
is selected from the group consisting of beta-cyclodextrins,
gamma-cyclodextrins, and mixtures thereof. In one aspect, the
invention relates to a pharmaceutical composition wherein said
cyclodextrin is a beta-cyclodextrin.
[0023] In one aspect, the invention relates to a pharmaceutical
composition wherein said cyclodextrin is a beta-cyclodextrin
selected from the group consisting of a beta-cyclodextrin ether, a
beta-cyclodextrin ester, and mixtures thereof. In one aspect, the
invention relates to a pharmaceutical composition wherein said
cyclodextrin is a hydroxyalkyl-beta-cyclodextrin. In one aspect,
the invention relates to a pharmaceutical composition wherein said
hydroxyalkyl-beta-cyclodextrin is a
hydroxypropyl-beta-cyclodextrin.
[0024] In one aspect, the invention relates to a pharmaceutical
composition wherein said cyclodextrin is a beta-cyclodextrin
corresponding to the following formula (3) (beta-cyclodextrin)-OR
(3) in which the residues R are hydrogen or hydroxyalkyl groups and
part of the residues R may optionally be alkyl groups, the
beta-cyclodextrin ether having a water-solubility of more than 1.8
g in 100 ml water. In one aspect, the invention relates to a
pharmaceutical composition wherein R is selected from the group
consisting of hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl,
or ethyl.
[0025] In one aspect, the invention relates to a pharmaceutical
composition wherein said R group is hydroxypropyl. In one aspect,
the invention relates to a pharmaceutical composition wherein said
hydroxypropyl beta-cyclodextrin has a molecular substitution per
anhydro glucose unit of about 0.86 to about 1.14. In one aspect,
the invention relates to a pharmaceutical composition wherein said
hydroxyl-propyl beta-cyclodextrin has a molecular substitution per
anhydro glucose unit of about 0.59 to about 0.73.
[0026] In one aspect, the invention relates to a pharmaceutical
composition wherein said hydroxypropyl beta-cyclodextrin
corresponds to the CAS Registry Number 128446-35-5.
[0027] In one aspect, the invention relates to a pharmaceutical
composition wherein said cyclodextrin is a sulfoalkyl ether
cyclodextrin derivative of Formula 1
##STR00001##
wherein n is 4, 5 or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 in Formula 1 are
each, independently, O.sup.- or a O--(C.sub.2-6
alkylene)-SO.sub.3.sup.- group, and at least one of R.sub.1 and
R.sub.2 is, independently, said O--(C.sub.2-6
alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3,
S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8 and S.sub.9 are each,
independently, a pharmaceutically acceptable cation, and wherein
said composition shows an absence of underivatized cyclodextrin as
measured by thin-layer chromatography. In one aspect, R.sub.1,
R.sub.2 and R.sub.3 are each, independently, said
O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group. In one aspect, at
least one of R.sub.1, R.sub.2 and R.sub.3 is, independently, a
O--(CH.sub.2).sub.m--SO.sub.3.sup.- group, wherein m is 2, 3, 4, 5
or 6. In one aspect, R.sub.1, R.sub.2 and R.sub.3 are each,
independently a O--(CH.sub.2).sub.m--SO.sub.3.sup.- group, wherein
m is 3 or 4. In one aspect, R.sub.4, R.sub.6 and R.sub.8 is,
independently, said O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group;
and R.sub.5, R.sub.7 and R.sub.9 are each --O.sup.-. In one aspect,
R.sub.4, R.sub.6 and R.sub.8 is, independently, said
O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group; and R.sub.5, R.sub.7
and R.sub.9 are each --O.sup.-. In one aspect, R.sub.4, R.sub.6 and
R.sub.8 are each a --O--(C.sub.2-6-alkylene)-SO.sub.3-- group; and
R.sub.5, R.sub.7 and R.sub.9 are each --O.sup.-. In one aspect,
S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7,
S.sub.8 and S.sub.9 are each, independently, H.sup.+, Li.sup.+,
Na.sup.+, K.sup.+, Ca.sup.+2, Mg.sup.+2, or ammonium.
[0028] In one aspect, the invention relates to a pharmaceutical
composition wherein said sulfoalkyl ether cyclodextrin is
sulfobutyl ether beta-cyclodextrin. In one aspect, said sulfoalkyl
ether beta-cyclodextrin corresponds to the CAS Registry Number
194615-04-8.
[0029] In one aspect, the invention relates to a pharmaceutical
composition wherein said cyclodextrin is a gamma-cyclodextrin.
[0030] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative
corresponds to the following structure of Formula 2
##STR00002##
wherein R.sup.1 represents a hydrogen atom or a carboxyl protective
group; R.sup.2 represents a hydroxyl group, a lower alkoxy group,
or a substituted or unsubstituted amino group; R.sup.3 represents a
hydrogen atom or a halogen atom; R.sup.4 represents a hydrogen atom
or a halogen atom; R.sup.5 represents a halogen atom or an
optionally substituted saturated cyclic amino group; R.sup.6
represents a hydrogen atom, a halogen atom, a nitro group, or an
optionally protected amino group; X, Y and Z may be the same or
different and respectively represent a nitrogen atom, --CH.dbd. or
--CR.sup.7.dbd. (wherein R.sup.7 represents a lower alkyl group, a
halogen atom, or a cyano group), with the proviso that at least one
of X, Y and Z represent a nitrogen atom, and W represents a
nitrogen atom or --CR.sup.8.dbd. (wherein R.sup.8 represents a
hydrogen atom, a halogen atom, or a lower alkyl group); with the
proviso that R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, W, X, Y, and Z as defined in this claim are
defined with respect to Formula 2, or a pharmaceutically acceptable
salt or ester thereof. In one aspect, when R.sup.1 represents a
hydrogen atom, R.sup.2 represents an amino group, R.sup.3 and
R.sup.4 represent a fluorine atom, R.sup.6 represents a hydrogen
atom, X represents a nitrogen atom, Y represents --CR.sup.7.dbd.
(wherein R.sup.7 represents a fluorine atom), Z represents
--CH.dbd., and W is --CR.sup.8.dbd. (wherein R.sup.8 represents a
chlorine atom), then R.sup.5 is not a 3-hydroxyazetidine-1-yl
group, or a pharmaceutically acceptable salt or ester thereof.
[0031] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative
corresponds to the following compound (A)
##STR00003##
or a pharmaceutically acceptable salt or ester thereof.
[0032] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative is a
D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt).
[0033] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative is a
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt)
characterized, when measured at about 25.degree. C. with Cu-Ka
radiation, by the powder diffraction pattern shown in FIG. 1.
[0034] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative is
D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt).
[0035] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative is
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-
hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt), characterized, when measured at about 25.degree. C. with
Cu-Ka radiation, by the powder diffraction pattern shown in FIG.
2.
[0036] In one aspect, the invention relates to a pharmaceutical
composition wherein said chelating agent is EDTA or a salt thereof.
In one aspect, said chelating agent is an EDTA salt selected from
the group consisting of a sodium salt, a potassium salt, a calcium
salt, a magnesium salt, and mixtures thereof. In one aspect, said
chelating agent is disodium EDTA.
[0037] In one aspect, the invention relates to a pharmaceutical
composition further comprising a polyhydroxyamine compound. In one
aspect, said polyhydroxyamine compound is meglumine.
[0038] In one aspect, the invention relates to a pharmaceutical
composition wherein said quinolone carboxylic acid derivative has a
measurable improvement in solubility compared to the quinolone
carboxylic acid derivative in water. In one aspect, said quinolone
carboxylic acid derivative has a solubility of at least about 1
mg/ml at 25.degree. C. In one aspect, said quinolone carboxylic
acid derivative has a solubility of at least about 2 mg/ml at
25.degree. C. In one aspect, quinolone carboxylic acid derivative
has a solubility of at least about 3 mg/ml at 25.degree. C. In one
aspect, said quinolone carboxylic acid derivative has a solubility
of at least about 5 mg/ml at 25.degree. C. In one aspect, said
quinolone carboxylic acid derivative has a solubility of at least
about 10 mg/ml at 25.degree. C. In one aspect, said quinolone
carboxylic acid derivative has a solubility of at least about 15
mg/ml at 25.degree. C. In one aspect, said quinolone carboxylic
acid derivative has a solubility of at least about 20 mg/ml at
25.degree. C. In one aspect, said quinolone carboxylic acid
derivative has a solubility of at least about 25 mg/ml at
25.degree. C. In one aspect, said quinolone carboxylic acid
derivative has a solubility of at least about 30 mg/ml at
25.degree. C.
[0039] In one aspect, the invention relates to a pharmaceutical
composition which has improved stability.
[0040] In one aspect, the invention relates to a pharmaceutical
composition having improved stability as measured by at least one
of the following parameters:
[0041] (a) the composition maintains a pH within about 10% of its
initial pH, or
[0042] (b) the composition retains at least about 90%, or at least
95%, of the initial amount of the quinolone carboxylic acid
derivative, or
[0043] (c) the composition does not form a precipitate such that
per unit container, the compositions has 6000 or less particles of
10 microns or greater and has 600 or less particles of 25 microns
or greater as measured using a standard light obscuration particle
test as described in USP Section 788 on Particulate Matter in
Injections.
[0044] In one aspect, the invention any of the parameters (a), (b),
or (c) are determined at least 30, 69, 90, 180 days, or one year
after the composition has been allowed to stand at room
temperature, during that time.
[0045] In one aspect, the invention relates to a pharmaceutical
composition wherein said composition provides a measurable
enhancement in venous toleration. In one aspect, said venous
toleration is measured in a rat tail infusion model. In one aspect,
said composition can be infused in a rat tail infusion model for at
least one hour at the rate of 10 ml/kg/hr. In one aspect, the
invention relates to a pharmaceutical composition according to
claim 65 wherein said composition can be infused on a least two,
three, four, or five consecutive days in a rat tail infusion model
for at least one hour at the rate of 10 ml/kg/hr.
[0046] In one aspect, the invention relates to a pharmaceutical
composition according wherein said quinolone carboxylic acid
derivative has a measurable improvement in solubility compared to
the quinolone carboxylic acid derivative in water, and/or the
composition has improved stability, and/or the composition provides
a measurable enhancement in venous toleration.
[0047] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0048] (a) from about 0.01% to about 50% by weight of delafloxacin,
as compared to the total weight of the composition;
[0049] (b) from about 0.1% to about 50% by weight of meglumine, as
compared to the total weight of the composition; and
[0050] (c) from about 1% to about 50% by weight of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8, as compared to the total weight of the
composition.
[0051] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0052] (a) from about 0.01% to about 50% by weight of delafloxacin,
as compared to the total weight of the composition;
[0053] (b) from about 0.1% to about 50% by weight of meglumine, as
compared to the total weight of the composition;
[0054] (c) from about 1% to about 50% by weight of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8, as compared to the total weight of the composition;
and
[0055] (d) from about 0.001% to about 0.10% by weight of disodium
EDTA, as compared to the total weight of the composition.
[0056] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0057] (a) from about 100 mg to about 500 mg of delafloxacin,
[0058] (b) from about 15 mg to about 125 mg of meglumine, and
[0059] (c) from about 1000 mg to about 5000 mg of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8.
[0060] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0061] (a) from about 100 mg to about 500 mg of delafloxacin,
[0062] (b) from about 15 mg to about 125 mg of meglumine,
[0063] (c) from about 500 mg to about 5000 mg of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8, and
[0064] (d) from 0 mg to about 4 mg disodium EDTA.
[0065] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0066] (a) from about 100 mg to about 500 mg of delafloxacin,
[0067] (b) from about 15 mg to about 125 mg of meglumine,
[0068] (c) from about 500 mg to about 5000 mg of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8, and
[0069] (d) from about 0.40 mg to about 4 mg disodium EDTA.
[0070] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0071] (a) about 100 mg of delafloxacin,
[0072] (b) about 24.4 mg of meglumine, and
[0073] (c) about 1000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8.
[0074] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0075] (a) about 300 mg of delafloxacin,
[0076] (b) about 73.2 mg of meglumine, and
[0077] (c) about 3000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8.
[0078] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0079] (a) about 500 mg of delafloxacin,
[0080] (b) about 122 mg of meglumine, and
[0081] (c) about 5000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8.
[0082] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0083] (a) about 100 mg of delafloxacin,
[0084] (b) about 19.52 mg of meglumine,
[0085] (c) about 800 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8, and
[0086] (d) about 0.44 mg of disodium EDTA.
[0087] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0088] (a) about 300 mg of delafloxacin,
[0089] (b) about 58.56 mg of meglumine,
[0090] (c) about 2400 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8, and
[0091] (d) about 1.32 mg of disodium EDTA.
[0092] In one aspect, the invention relates to a pharmaceutical
composition comprising
[0093] (a) about 500 mg of delafloxacin,
[0094] (b) about 97.6 mg of meglumine,
[0095] (c) about 4000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8, and
[0096] (d) about 2.2 mg of disodium EDTA
[0097] In one aspect, the invention relates to an aqueous
pharmaceutical composition comprising
[0098] (a) about 20 mg/ml of delafloxacin,
[0099] (b) about 4.88 mg/ml of meglumine,
[0100] (c) about 200 mg/ml of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8, and
[0101] (d) water.
[0102] In one aspect, the invention relates to an aqueous
pharmaceutical composition comprising
[0103] (a) about 25 mg/ml of delafloxacin,
[0104] (b) about 4.88 mg/ml of meglumine,
[0105] (c) about 200 mg/ml of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8,
[0106] (d) about 0.11 mg/ml of disodium EDTA, and
[0107] (e) water.
[0108] In one aspect, the invention relates to any pharmaceutical
composition taught above having a pH of about 9.+-.0.1 pH
units.
[0109] In one aspect, the invention relates to a pharmaceutical
composition which further comprises mannitol.
[0110] In one aspect, the invention relates to a pharmaceutical
composition in the form of a unit dosage.
[0111] In one aspect, the invention relates to a method for
treating, preventing, or reducing the risk of a bacterial infection
comprising administering to a patient in need thereof a composition
as taught herein.
[0112] In one aspect, the invention relates to a method for
treating, preventing, or reducing the risk of a bacterial infection
in a patient in need thereof, while reducing venous intoleration
during administration, comprising administering to a patient in
need thereof a composition as taught herein, e.g. using an i.v.
drip bag. The composition can comprise a saline or dextrose
carrier.
[0113] In one aspect, the invention relates to a kit comprising a
pharmaceutical composition according to any one of of claims 1 to
90 and a container. The container can be a bottle, a vial, a
syringe or a drip bag, or the composition can further comprise
container, e.g. a bottle, a vial, a syringe or a drip bag.
DETAILED DESCRIPTION OF THE INVENTION
[0114] In the present invention, it has surpriringly been found
that the combination of certain cyclodextrin compounds with a
quinolone carboxylic acid derivative antimiocrobial compound is
found to provide a desired balance of product solubility,
stability, and toleration. The final drug product formulation is
the result of a complex interplay of solubility, stability, and
toleration.
[0115] The present invention relates to a pharmaceutical
composition comprising a quinolone carboxylic acid derivative or a
pharmaceutically acceptable salt or ester thereof, and a
cyclodextrin selected from the group consisting of a
beta-cyclodextrin, a gamma-cyclodextrin, and mixtures thereof.
These compositions are useful for intravenous administration or
injection, for treating, preventing, or reducing the risk of
infection. These compositions have enhanced stability, enhanced
solubility of the quinolone carboxylic acid, and enhanced patient
toleration when administered intravenously or as an injection.
Enhanced stability is important because a pharmaceutical
composition must possess sufficient shelf life to be conveniently
stored for a useful period of time. Enhanced solubility is
important, because some quinolone carboxylic acid compounds do not
have sufficient aqueous solubility to be formulated at a desired
target concentration. The present invention provides compositions
having enhanced solubility compared to what would otherwise be
achievable not employing the present invention. Enhanced patient
toleration is important, because the invention provides
compositions that are safe and well tolerated. It is not sufficient
for a pharmaceutical composition to be efficacious, it is important
that efficacy be achieved at an appropriate safety and toleration
level. Therefore, the compositions of the present invention provide
an advantage over the state of the art.
[0116] In one embodiment, the present invention relates to a
pharmaceutical composition which prior to mixing comprises (a) a
quinolone carboxylic acid derivative or a pharmaceutically
acceptable salt or ester thereof, and (b) a cyclodextrin. In other
embodiments, the present invention relates to a pharmaceutical
composition comprising (a) a quinolone carboxylic acid derivative
or a pharmaceutically acceptable salt or ester thereof, and (b) a
cyclodextrin. In one embodiment, the composition comprises a
quinolone carboxylic acid derivative and a cyclodextrin. In another
embodiment, the composition comprises a pharmaceutically acceptable
salt of a quinolone carboxylic acid derivative and a cyclodextrin.
In another embodiment, the composition comprises a pharmaceutically
acceptable ester of a quinolone carboxylic acid derivative and a
cyclodextrin. In other embodiments, the present invention relates
to a pharmaceutical composition comprising an inclusion complex,
said inclusion complex comprising (a) a quinolone carboxylic acid
derivative or a pharmaceutically acceptable salt or ester thereof,
and (b) a cyclodextrin. In one embodiment, the composition
comprises a quinolone carboxylic acid derivative or
pharmaceutically acceptable salt or ester thereof within the
cyclodextrin.
[0117] In other embodiments, the present invention relates to a
pharmaceutical composition comprising (that is in the form of) an
aqueous solution.
[0118] In other embodiments, the present invention relates to a
pharmaceutical composition comprising (that is in the form of) a
dry mixture. In other embodiments, the present invention relates to
a pharmaceutical composition wherein said dry mixture is a
lyophile. In other embodiments, the present invention relates to a
pharmaceutical composition wherein said dry mixture is made by
lyophylization. In other embodiments, the present invention relates
to a pharmaceutical composition wherein said dry mixture or
lyophile is reconstituted. In other embodiments, the present
invention relates to a pharmaceutical composition wherein said
pharmaceutical composition is further diluted.
[0119] In one embodiment, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is selected
from the group consisting of alpha-cyclodextrins,
beta-cyclodextrins, gamma-cyclodextrins, and mixtures thereof. In
other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is selected
from the group consisting of beta-cyclodextrins,
gamma-cyclodextrins, and mixtures thereof. In one embodiment, the
free hydroxyls of the cyclodextrin are completely or partially
derivatized. In another embodiment, the free hydroxyls of the
cyclodextrin are completely derivatized. In another embodiment, the
free hydroxyls of the cyclodextrin are partially derivatized. In
other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
beta-cyclodextrin selected from the group consisting of a
beta-cyclodextrin ether, a beta-cyclodextrin ester, and mixtures
thereof. In other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
hydroxyalkyl-beta-cyclodextrin. In other embodiments, the present
invention relates to a pharmaceutical composition wherein said
hydroxyalkyl-beta-cyclodextrin is a
hydroxypropyl-beta-cyclodextrin. In other embodiments, the present
invention relates to a pharmaceutical composition wherein said
cyclodextrin is a beta-cyclodextrin corresponding to the following
formula (3):
(beta-cyclodextrin)-OR (3)
in which the residues R are hydroxyalkyl groups and part of the
residues R may optionally be alkyl groups, the beta-cyclodextrin
ether having a water-solubility of more than 1.8 g in 100 ml water.
In other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
beta-cyclodextrin corresponding to the following formula:
(beta-cyclodextrin)-OR, in which all or part of the residues R are
optionally and independently hydrogen, hydroxyalkyl groups or alkyl
groups. In other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
beta-cyclodextrin corresponding to the following formula (3):
(beta-cyclodextrin)-OR, in which all or part of the residues R are
optionally and independently hydroxyalkyl groups or alkyl groups.
In one embodiment, the beta-cyclodextrin has a water-solubility of
more than 1.8 g in 100 mL water. In other embodiments, the present
invention relates to a pharmaceutical composition wherein R is
selected from the group consisting of hydroxyethyl, hydroxypropyl,
dihydroxypropyl, methyl, or ethyl. In other embodiments, the
present invention relates to a pharmaceutical composition wherein
said R group is hydroxypropyl. In other embodiments, the present
invention relates to a pharmaceutical composition wherein said
hydroxypropyl beta-cyclodextrin has a molecular substitution per
anhydro glucose unit of about 0.86 to about 1.14. In other
embodiments, the present invention relates to a pharmaceutical
composition wherein said hydroxyl-propyl beta-cyclodextrin has a
molecular substitution per anhydro glucose unit of about 0.59 to
about 0.73. In other embodiments, the present invention relates to
a pharmaceutical composition wherein said hydroxypropyl
beta-cyclodextrin corresponds to the CAS Registry Number
128446-35-5.
[0120] In other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
sulfoalkyl ether cyclodextrin derivative of the formula 1
##STR00004##
wherein n is 4, 5 or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each,
independently, O.sup.- or a O--(C.sub.2-6 alkylene)-SO.sub.3.sup.-
group, and at least one of R.sub.1 and R.sub.2 is, independently,
said O--(C.sub.2-6 alkylene)-SO.sub.3.sup.- group; and S.sub.1,
S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8 and
S.sub.9 are each, independently, a pharmaceutically acceptable
cation, and wherein said composition shows an absence of
underivatized cyclodextrin as measured by thin-layer
chromatography. In other embodiments, the present invention relates
to a composition, wherein R.sub.1, R.sub.2 and R.sub.3 are each,
independently, said O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group.
In other embodiments, the present invention relates to a
composition, wherein at least one of R.sub.1, R.sub.2 and R.sub.3
is, independently, a O--(CH.sub.2)m-SO.sub.3--.sup.- group, wherein
m is 2, 3, 4, 5 or 6. In other embodiments, the present invention
relates to a composition, wherein R.sub.1, R.sub.2 and R.sub.3 are
each, independently a O--(CH.sub.2).sub.m--SO.sub.3.sup.- group,
wherein m is 3 or 4. In other embodiments, the present invention
relates to a composition, wherein at least one of R.sub.4, R.sub.6
and R.sub.8 is, independently, said
O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group; and R.sub.5, R.sub.7
and R.sub.9 are each O.sup.-. In other embodiments, the present
invention relates to a composition, wherein at least one of
R.sub.4, R.sub.6 and R.sub.8 is, independently, said
O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group; and R.sub.5, R.sub.7
and R.sub.9 are each O.sup.-. In other embodiments, the present
invention relates to a composition, wherein: R.sub.4, R.sub.6 and
R.sub.8 are each a O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group;
and R.sub.5, R.sub.7 and R.sub.9 are each O.sup.-. In other
embodiments, the present invention relates to a pharmaceutical
composition wherein said sulfoalkyl ether cyclodextrin is
sulfobutyl ether beta-cyclodextrin. In other embodiments, the
present invention relates to a pharmaceutical composition wherein
said sulfoalkyl ether beta-cyclodextrin corresponds to the CAS
Registry Number 194615-04-8.
[0121] In other embodiments, the present invention relates to a
pharmaceutical composition wherein said cyclodextrin is a
gamma-cyclodextrin.
[0122] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative
corresponds to the following structure of Formula 2:
##STR00005##
wherein R.sup.1 represents a hydrogen atom or a carboxyl protective
group; R.sup.2 represents a hydroxyl group, a lower alkoxy group,
or a substituted or unsubstituted amino group; R.sup.3 represents a
hydrogen atom or a halogen atom; R.sup.4 represents a hydrogen atom
or a halogen atom; R.sup.5 represents a halogen atom or an
optionally substituted saturated cyclic amino group; R.sup.6
represents a hydrogen atom, a halogen atom, a nitro group, or an
optionally protected amino group; X, Y and Z may be the same or
different and respectively represent a nitrogen atom, --CH.dbd. or
--CR.sup.7.dbd. (wherein R.sup.7 represents a lower alkyl group, a
halogen atom, or a cyano group), with the proviso that at least one
of X, Y and Z represent a nitrogen atom, and W represents a
nitrogen atom or --CR.sup.8.dbd. (wherein R.sup.8 represents a
hydrogen atom, a halogen atom, or a lower alkyl group); with the
proviso that R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, W, X, Y, and Z as defined as described in this
paragraph are defined for Formula 2, and not as defined for the
cyclodextrins, or a pharmaceutically acceptable salt or ester
thereof.
[0123] In one embodiment, when R.sup.1 represents a hydrogen atom,
R.sup.2 represents an amino group, R.sup.3 and R.sup.4 represent a
fluorine atom, R.sup.6 represents a hydrogen atom, X represents a
nitrogen atom, Y represents --CR.sup.7.dbd. (wherein R.sup.7
represents a fluorine atom), Z represents --CH.dbd., and W is
--CR.sup.8.dbd. (wherein (wherein R.sup.8 represents a chlorine
atom), then R.sup.5 is not a 3-hydroxyazetidine-1-yl group;
[0124] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative
corresponds to the following compound (A),
##STR00006##
or a pharmaceutically acceptable salt or ester thereof. In other
embodiments, the present invention relates to a composition wherein
said quinolone carboxylic acid derivative is a D-glucitol,
1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (salt). In other
embodiments, the present invention relates to a composition wherein
said quinolone carboxylic acid derivative is a crystalline
D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3- quinolinecarboxylate (salt). In yet
other embodiments, the present invention relates to a composition
wherein said quinolone carboxylic acid derivative is a crystalline
D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo- 3-quinolinecarboxylate (salt)
characterized, when measured at about 25.degree. C. with Cu-Ka
radiation, by the powder diffraction pattern shown in FIG. 1.
[0125] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative is
D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt). In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative is
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt). In yet other embodiments, the present invention relates to
a composition wherein said quinolone carboxylic acid derivative is
crystalline D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3- quinolinecarboxylate trihydrate
(salt) characterized, when measured at about 25.degree. C. with
Cu-Ka radiation, by the powder diffraction pattern shown in FIG.
2.
[0126] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative has a
measurable improvement in solubility. In other embodiments, the
present invention relates to a composition wherein said quinolone
carboxylic acid derivative has a measurable improvement in
solubility compared to the quinolone carboxylic acid derivative
alone in water.
[0127] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative has a
solubility of at least about 1 mg/ml at 25.degree. C. In other
embodiments, the present invention relates to a composition wherein
said quinolone carboxylic acid derivative has a solubility of at
least about 2 mg/ml at 25.degree. C. In other embodiments, the
present invention relates to a composition wherein said quinolone
carboxylic acid derivative has a solubility of at least about 3
mg/ml at 25.degree. C. In other embodiments, the present invention
relates to a composition wherein said quinolone carboxylic acid
derivative has a solubility of at least about 5 mg/ml at 25.degree.
C. In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative has a
solubility of at least about 10 mg/ml at 25.degree. C. In other
embodiments, the present invention relates to a composition wherein
said quinolone carboxylic acid derivative has a solubility of at
least about 15 mg/ml at 25.degree. C. In other embodiments, the
present invention relates to a composition wherein said quinolone
carboxylic acid derivative has a solubility of at least about 20
mg/ml at 25.degree. C. In other embodiments, the present invention
relates to a composition wherein said quinolone carboxylic acid
derivative has a solubility of at least about 25 mg/ml at
25.degree. C. In other embodiments, the present invention relates
to a composition wherein said quinolone carboxylic acid derivative
has a solubility of at least about 30 mg/ml at 25.degree. C.
[0128] In other embodiments, the present invention relates to a
composition which has improved stability. In other embodiments, the
present invention relates to a composition which has improved
stability as measured by at least one of the following parameters:
(a) the composition maintains a pH within about 10% of its initial
pH, or (b) the composition retains at least about 90%, or 95%, of
the initial amount of the quinolone carboxylic acid derivative, or
(c) the composition does not form a precipitate such that per unit
container, the compositions has 6000 or less particles of 10
microns or greater and has 600 or less particles of 25 microns or
greater as measured using a standard light obscuration particle
test as described in USP Section 788 on Particulate Matter in
Injections.
[0129] The pharmaceutical compositions of the invention have
sufficient chemical and physical stability to enable administration
to a patient and maintain efficacy of the pharmaceutical active
over a useful length of time. In one embodiment, in the
pharmaceutical composition, the potency of the quinoline carboxylic
acid derivative active ingredient is maintained by retaining the
pharmaceutical active in solution, by limiting chemical degradation
of the pharmaceutical active or other components of the
pharmaceutical composition, or by limiting physical degradation of
the composition. In one embodiment, the composition retains the
solubility of the drug, the drug efficacy, or protects the drug or
components of the composition from chemical or physical
degradation. In another embodiment, the composition retains the
drug potency of the initial formulation, or a potency substantially
similar to the initial formulation.
[0130] In other embodiments, the present invention relates to a
composition wherein any of the parameters (a), (b), or (c) are
determined at least 30 days after the composition has been allowed
to stand at room temperature. In other embodiments, the present
invention relates to a composition wherein any of the parameters
(a), (b), or (c) are determined at least 60 days after the
composition has been allowed to stand at room temperature. In other
embodiments, the present invention relates to a composition wherein
any of the parameters (a), (b), or (c) are determined at least 90
days after the composition has been allowed to stand at room
temperature. In other embodiments, the present invention relates to
a composition wherein any of the parameters (a), (b), or (c) are
determined at least 180 days after the composition has been allowed
to stand at room temperature. In other embodiments, the present
invention relates to a composition wherein any of the parameters
(a), (b), or (c) are determined at least 1 year after the
composition has been allowed to stand at room temperature.
[0131] In other embodiments, the present invention relates to a
composition wherein said composition provides a measurable
enhancement in venous toleration. In other embodiments, the present
invention relates to a composition wherein said venous toleration
is measured in a rat tail infusion model. In other embodiments, the
present invention relates to a composition wherein said composition
can be infused in a rat tail infusion model for at least one hour
at the rate of 10 ml/kg/hr.
[0132] In other embodiments, the present invention relates to a
composition wherein said composition can be infused on a least two
consecutive days in a rat tail infusion model for at least one hour
at the rate of 10 ml/kg/hr. In other embodiments, the present
invention relates to a composition wherein said composition can be
infused on a least three consecutive days in a rat tail infusion
model for at least one hour at the rate of 10 ml/kg/hr. In other
embodiments, the present invention relates to a composition wherein
said composition can be infused on a least four consecutive days in
a rat tail infusion model for at least one hour at the rate of 10
ml/kg/hr. In other embodiments, the present invention relates to a
composition wherein said composition can be infused on a least five
consecutive days in a rat tail infusion model for at least one hour
at the rate of 10 ml/kg/hr.
[0133] In other embodiments, the present invention relates to a
composition wherein said quinolone carboxylic acid derivative has a
measurable improvement in solubility compared to the quinolone
carboxylic acid derivative in water, and/or the composition has
improved stability, and/or the composition provides a measurable
enhancement in venous toleration.
[0134] In other embodiments, the present invention relates to a
pharmaceutical composition comprising (a) from about 100 mg to
about 500 mg of delafloxacin meglumine, and (b) from about 1000 mg
to about 5000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8. In other
embodiments, the present invention relates to a pharmaceutical
composition comprising (a) about 300 mg of delafloxacin meglumine,
and (b) about 3000 mg of sulfobutyl ether beta-cyclodextrin
corresponding to the CAS Registry Number 194615-04-8. In other
embodiments, the present invention relates to a pharmaceutical
composition which prior to mixing comprises (a) about 300 mg of
delafloxacin meglumine, and (b) about 3000 mg of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8.
[0135] In other embodiments, the present invention relates to an
aqueous pharmaceutical composition comprising (a) about 300 mg of
delafloxacin meglumine, (b) about 3000 mg of sulfobutyl ether
beta-cyclodextrin corresponding to the CAS Registry Number
194615-04-8, and (c) water, wherein said composition has a volume
at about 25.degree. C. of about 15 ml and a pH of about 9. In other
embodiments, the present invention relates to a composition which
is in the form of a lyophile. In other embodiments, the present
invention relates to a composition which further comprises
mannitol.
[0136] In other embodiments, the present invention relates to a
method for treating, preventing, or reducing the risk of a
bacterial infection comprising administering to a patient in need
thereof a composition as described herein. In other embodiments,
the present invention relates to a method for treating, preventing,
or reducing the risk of a bacterial infection in a patient in need
thereof, while reducing discomfort upon infusion, comprising
administering to a patient in need thereof a composition as
described herein.
1. DEFINITIONS
[0137] The term "patient", as used herein, means the human or
animal (in the case of an animal, more typically a mammal) subject.
The patient is usually one that is in need of the compositions or
methods described herein. "In need of," can mean that the patient
has or is diagnosed as having an infection, e.g. a microbial
infection, or that the patient is at risk of contracting an
infection due to an injury, a medical or surgical procedure, or
microbial exposure, or could be in a position that could subject
the patient to such exposure. Such infections can be due to, e.g.,
a skin infection, nosocomial pneumonia, post-viral pneumonia, an
abdominal infection, a urinary tract infection, bacteremia,
septicemia, endocarditis, an atrio-ventricular shunt infection, a
vascular access infection, meningitis, infection due to surgical or
invasive medical procedures, a peritoneal infection, a bone
infection, a joint infection, a methicillin-resistant
Staphylococcus aureus infection, a vancomycin-resistant Enterococci
infection, a linezolid-resistant organism infection, tuberculosis,
a quinolone resistant Gram-positive infection, a ciprofloxacin
resistant methicillin resistant (MRSA) infection, bronchitis, a
complicated skin and skin structure infection (cSSSI), an
uncomplicated skin and skin structure infection (uSSSI), a
community respiratory-tract infection, and a multi drug resistant
(MDR) Gram-negative infection.
[0138] The term "preventing", as used herein, means e.g., to
completely or almost completely stop an infection from occurring,
for example when the patient is predisposed to an infection or at
risk of contracting an infection.
[0139] The term "reducing the risk of", as used herein means, e.g.
to lower the likelihood or probability of an infection occurring,
for example when the patient is predisposed to an infection or at
risk of contracting an infection.
[0140] The term "treating" as used herein means, e.g. to cure,
inhibit, arrest the development, relieve the symptoms or effects
of, ameliorating, or cause the regression of an infection in a
patient having an infection.
[0141] It should be recognized that the terms "preventing",
"reducing the risk of", and "treating" are not intended to limit
the scope of the invention and that there can be overlap amongst
these terms.
[0142] As used herein, the term "effective amount" means an amount
of a pharmaceutically active compound, i.e. a drug active, e.g. a
quinolone carboxylic acid antimicrobial agent or pharmaceutically
acceptable salt or ester thereof, given to a recipient patient
sufficient to elicit biological activity, for example,
anti-infective activity, e.g., anti-microbial activity.
[0143] The term "prophylactically effective amount" means an amount
of a pharmaceutically active compound, i.e. a drug active, e.g. a
quinolone carboxylic acid antimicrobial agent given to a recipient
patent sufficient to prevent or reduce the risk of a microbial
infection.
[0144] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds, materials, compositions, carriers,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0145] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. Examples of
pharmaceutically acceptable salts include, but are not limited to,
mineral or organic acid salts of basic residues such as amines,
alkali or organic salts of acidic residues such as carboxylic
acids, and the like. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include, but are not limited to, those derived from
inorganic and organic acids selected from 2-acetoxybenzoic,
2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic,
benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic,
ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic,
glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic,
hydrobromic, hydrochloric, hydroiodic, hydroxymaleic,
hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,
maleic, malic, mandelic, methane sulfonic, napsylic, nitric,
oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
polygalacturonic, propionic, salicyclic, stearic, subacetic,
succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene
sulfonic, and the commonly occurring amine acids, e.g., glycine,
alanine, phenylalanine, arginine, etc.
[0146] The pharmaceutically acceptable salts of the present
invention can be synthesized from a parent compound that contains a
basic or acidic moiety by conventional chemical methods. Generally,
such salts can be prepared by reacting the free acid or base forms
of these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two. In one embodiment, non-aqueous media, for example ether,
ethyl acetate, ethanol, isopropanol, or acetonitrile are useful for
forming salts of the present compounds. Lists of suitable salts are
found in Remington's Pharmaceutical Sciences, 18.sup.th ed. (Mack
Publishing Company, 1990). For example, salts can include, but are
not limited to, the hydrochloride and acetate salts of the
aliphatic amine-containing, hydroxyl amine-containing, and
imine-containing compounds of the present invention.
[0147] Additionally, the compounds of the present invention, for
example, the salts of the compounds, can exist in either hydrated
or unhydrated (the anhydrous) form or as solvates with other
solvent molecules. Nonlimiting examples of hydrates include
monohydrates, dihydrates, etc. Nonlimiting examples of solvates
include ethanol solvates, acetone solvates, etc.
[0148] As used herein, "pharmaceutically acceptable esters" refer
to derivatives of the disclosed compounds wherein the parent
compound is modified by an alcohol ester of a carboxylic acid or a
carboxylic acid ester of an alcohol. The compounds of the present
invention can also be prepared as esters, for example
pharmaceutically acceptable esters. For example a carboxylic acid
function group in a compound can be converted to its corresponding
ester, e.g., a methyl, ethyl, or other ester. Also, an alcohol
group in a compound can be converted to its corresponding ester,
e.g., an acetate, propionate, or other ester.
[0149] As used herein, the term "unit dosage", means a single dose
of a pharmaceutical composition that is intended to be administered
in its entirety. A unit dosage is a convenient form for
administering a premeasured amount of a drug active.
[0150] In the specification, the singular forms also include the
plural, unless the context clearly dictates otherwise. Unless
defined otherwise, all technical and scientific terms used herein
have the same meaning as commonly understood by one of ordinary
skill in the art to which this invention belongs. In the case of
conflict, the present specification will control.
[0151] All percentages and ratios used herein, unless otherwise
indicated, are by weight.
[0152] Throughout the description, where compositions are described
as having, including, or comprising specific components, it is
contemplated that compositions also consist essentially of, or
consist of, the recited components. Similarly, where methods or
processes are described as having, including, or comprising
specific process steps, the processes also consist essentially of,
or consist of, the recited processing steps. Further, it should be
understood that the order of steps or order for performing certain
actions is immaterial so long as the invention remains operable.
Moreover, two or more steps or actions can be conducted
simultaneously.
2. COMPOSITIONS OF THE PRESENT INVENTION
[0153] The compositions of the present invention comprise all or
some of the following components. The compositions can be defined
either prior to or after mixing of the components.
[0154] Suitable components are described in e.g., Eds. R. C. Rowe,
et al., Handbook of Pharmaceutical Excipients, Fifth Edition,
Pharmaceutical Press (2006); Remington's Pharmaceutical Sciences,
18.sup.th ed.(Mack Publishing Company, 1990); and Remington: The
Science and Practice of Pharmacy, 20.sup.th Edition, Baltimore,
Md.: Lippincott Williams & Wilkins, 2000, which are
incorporated by reference herein in their entirety. Even though a
functional category can be provided for many of these carrier
components, such a functional category is not intended to limit the
function or scope of the component, as one of ordinary skill in the
art will recognize that a component can belong to more than one
functional category and that the level of a specific component and
the presence of other components can effect the functional
properties of a component.
a. Quinolone Carboxylic Acid Derivative
[0155] The compositions of the present invent comprise a quinolone
carboxylic acid derivative, (alternatively known as, inter alia, a
pyridonecarboxylic acid derivative or a pyridone carboxylic acid
derivative), or a pharmaceutically acceptable salt or ester
thereof, as an antimicrobial compound, i.e. as the active
pharmaceutical ingredient, or API, of the compositions of the
present invention. The invention further provides methods for
synthesizing any one of the compounds of the present invention. The
invention also provides pharmaceutical compositions comprising an
effective amount of one or more of the compounds of the present
invention and a pharmaceutically acceptable carrier. The present
invention further provides methods for making these compounds,
carriers, and pharmaceutical compositions.
[0156] Quinolone carboxylic acid derivatives, useful herein are
described, including their syntheses, formulation, and use, in U.S.
Pat. No. 6,156,903, to Yazaki et al., issued Dec. 5, 2000 and its
certificates of correction of Nov. 13, 2001 and Dec. 11, 2001; U.S.
Pat. No. 6,133,284, to Yazaki et al., issued Oct. 17, 2000; U.S.
Pat. No. 5,998,436, to Yazaki et al., issued Dec. 7, 1999 and its
certificates of correction of Jan. 23, 2001, Oct. 30, 2001, and
Dec. 17, 2002; PCT Application No. WO 2006/110815, to Abbott
Laboratories, published Oct. 19, 2006; PCT Application No. WO
2006/042034, to Abbott Laboratories, published Apr. 20, 2006, PCT
Application No. WO 2006/015194, to Abbott Laboratories, published
Feb. 9, 2006; PCT Application No. WO 01/34595, to Wakunaga
Pharmaceutical Co., Ltd., published May 17, 2001; and PCT
Application No. WO 97/11068, to Wakunaga Pharmaceutical Co., Ltd.,
published Mar. 27, 1997, the contents of each of which are hereby
incorporated by reference in their entireties.
[0157] Quinolone carboxylic acid derivatives useful in the methods,
compositions, and uses of the present invention include compounds
corresponding to Formula 2
##STR00007##
wherein with respect to Formula 2, R.sup.1 represents a hydrogen
atom or a carboxyl protective group; R.sup.2 represents a hydroxyl
group, a lower alkoxy group, or a substituted or unsubstituted
amino group; R.sup.3 represents a hydrogen atom or a halogen atom;
R.sup.4 represents a hydrogen atom or a halogen atom; R.sup.5
represents a halogen atom or an optionally substituted saturated
cyclic amino group; R.sup.6 represents a hydrogen atom, a halogen
atom, a nitro group, or an optionally protected amino group; X, Y
and Z may be the same or different and respectively represent a
nitrogen atom, --CH.dbd. or --CR.sup.7.dbd. (wherein R.sup.7
represents a lower alkyl group, a halogen atom, or a cyano group),
with the proviso that at least one of X, Y and Z represent a
nitrogen atom, and W represents a nitrogen atom or --CR.sup.8.dbd.
(wherein R.sup.8 represents a hydrogen atom, a halogen atom, or a
lower alkyl group).
[0158] In one embodiment, when R.sup.1 represents a hydrogen atom,
R.sup.2 represents an amino group, R.sup.3 and R.sup.4 represent a
fluorine atom, R.sup.6 represents a hydrogen atom, X represents a
nitrogen atom, Y represents --CR.sup.7.dbd. (wherein R.sup.7
represents a fluorine atom), Z represents --CH.dbd., and W is
--CR.sup.8.dbd. (wherein R.sup.8 represents a chlorine atom), then
R.sup.5 is not a 3-hydroxyazetidine-1-yl group; or a
pharmaceutically acceptable salt, ester, or prodrug thereof.
[0159] When R.sup.1 is a carboxyl protective group, it may be any
carboxylate ester residue which cleaves relatively easily, such as
in vivo, to generate the corresponding free carboxyl group.
Exemplary carboxyl protective groups include those which may be
eliminated by hydrolysis, catalytic reduction, and other treatments
under mild conditions such as lower alkyl groups such as methyl
group, ethyl group, n-propyl group, i-propyl group, n-butyl group,
i-butyl group, t-butyl group, pentyl group, hexyl group, and heptyl
group; lower alkenyl groups such as vinyl group, allyl group,
1-propenyl group, butenyl group, pentenyl group, hexenyl group, and
heptenyl group; aralkyl groups such as benzyl group; and aryl
groups such as phenyl group and naphthyl group; and those which may
be readily eliminated in the body such as lower alkanoyloxy lower
alkyl groups such as acetoxymethyl group and pivaloyloxymethyl
group; lower alkoxycarbonyloxy lower alkyl group such as
methoxycarbonyloxymethyl group and 1-ethoxycarbonyloxyethyl group;
lower alkoxymethyl group such as methoxymethyl group; lactonyl
group such as phthalidyl; di-lower alkylamino lower alkyl group
such as 1-dimethylaminoethyl group; and
(5-methyl-2-oxo-1,3-dioxole-4-yl)methyl group.
[0160] In one embodiment, R.sup.1 in Formula 2 is H.
[0161] In one embodiment, R.sup.2 in Formula 2 is --NH.sub.2.
[0162] In one embodiment, R.sup.3 in Formula 2 is halogen.
[0163] In another embodiment, R.sup.3 in Formula 2 is fluorine.
[0164] In one embodiment, R.sup.4 in Formula 2 is halogen.
[0165] In another embodiment, R.sup.4 in Formula 2 is fluorine.
[0166] In one embodiment, R.sup.5 in Formula 2 is a substituted
cyclic amino group.
[0167] In one embodiment, R.sup.5 in Formula 2 is
##STR00008##
[0168] In one embodiment, R.sup.6 in Formula 2 is hydrogen.
[0169] In one embodiment, X in Formula 2 is a nitrogen atom.
[0170] In one embodiment, Y in Formula 2 is .dbd.CR.sup.7--.
[0171] In one embodiment, R.sup.7 in Formula 2 is a halogen.
[0172] In another embodiment, R.sup.7 in Formula 2 is fluorine.
[0173] In one embodiment, Z in Formula 2 is .dbd.CH--.
[0174] In one embodiment, W in Formula is 2 .dbd.CR.sup.8--.
[0175] In one embodiment, R.sup.8 in Formula 2 is a halogen.
[0176] In another embodiment, R.sup.8 in Formula 2 is chlorine.
[0177] It is noted that the substituents R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, A, J.sup.1,
J.sup.2, J.sup.3, W, X, Y, Z, e, f, and g are defined herein for
convenience with respect to the chemical structure for the
quinolone carboxylic acid derivatives, for example for Formula
2.
[0178] In other embodiments, the present invention relates to a
method, composition, or use for a compound of Formula 2, wherein W
is --CR.sup.8.dbd., wherein R.sup.8 represents a hydrogen atom, a
halogen atom, or a lower alkyl group.
[0179] In other embodiments, the present invention relates to a
method, composition, or use for a quinolone carboxylic acid
derivative of Formula 2, wherein R.sup.5 is a group represented by
the following formula (a) or (b):
##STR00009##
wherein A represents an oxygen atom, sulfur atom or NR.sup.9
(wherein R.sup.9 represents hydrogen atom or a lower alkyl group),
e represents a number from 3 to 5, f represents a number from 1 to
3, g represents a number from 0 to 2, J.sup.1, J.sup.2 and J.sup.3,
which may be the same or different from one another, represent a
hydrogen atom, hydroxyl group, lower alkyl group, amino lower alkyl
group, amino group, lower alkylamino group, lower alkoxy group, or
a halogen atom.
[0180] In other embodiments, the present invention relates to a
method, composition, or use for a quinolone carboxylic acid
derivative of Formula 2, wherein R.sup.5 is a group represented by
formula (a).
##STR00010##
[0181] In other embodiments, the present invention relates to a
method, composition, or use for a quinolone carboxylic acid
derivative of structure Quinolone Carboxylic Acid Derivative 1,
wherein e in the formula (a) is 3 or 4.
##STR00011##
[0182] In other embodiments, the present invention relates to a
method, composition, or use for a quinolone carboxylic acid
derivative of structure Quinolone Carboxylic Acid Derivative 1,
wherein R.sup.1 is a hydrogen atom; R.sup.2 is an amino group,
lower alkylamino group, or a di-lower alkylamino group; R.sup.3 is
a halogen atom; R.sup.4 is a halogen atom; R.sup.6 is hydrogen
atom; X is a nitrogen atom; Y and Z are --CH.dbd. or
--CR.sup.7.dbd. (wherein R.sup.7 is a lower alkyl group or a
halogen atom); and W is --CR.sup.8.dbd. (wherein R.sup.8 is a
halogen atom or a lower alkyl group).
[0183] In other embodiments, the present invention relates to a
method, composition, or use for a quinolone carboxylic acid
derivative of structure Quinolone Carboxylic Acid Derivative 1,
wherein R.sup.2 is amino group; R.sup.3 is fluorine atom; R.sup.4
is a fluorine atom; Y is --CF.dbd.; Z is --CH.dbd.; W is
--CR.sup.8.dbd. (wherein R.sup.8 is a chlorine atom, bromine atom
or a methyl group), and e in formula (a) is 3.
##STR00012##
[0184] It should be noted that the variables used to describe the
quinolone carboxylic acid derivatives are intended to be separate
from the variables used to define the cyclodextrins.
[0185] In other embodiments, the present invention relates to a
method, composition, or use wherein said quinolone carboxylic acid
corresponds to the compound (A):
##STR00013##
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
This foregoing quinolone carboxylic acid derivative, compound (A),
is also known by the USAN, delafloxacin, the publicly disclosed
code names RX-3341, ABT-492 and WQ 3034, and also by, inter alia,
the chemical name
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-
hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid or
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylic acid. This
carboxylic acid form of the compound corresponds to the CAS
Registry Number 189279-58-1. Furthermore, WO 2006/042034, cited
above discloses the 1-deoxy-1-(methylamino)-D-glucitol salt of this
compound, also known as D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3- quinolinecarboxylate (salt), and the
trihydrate of the 1-deoxy-1-(methylamino)-D-glucitol salt of this
compound, also known as D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate
(salt). The 1-deoxy-1-(methylamino)-D-glucitol salt and the
1-deoxy-1-(methylamino)-D-glucitol salt trihydrate correspond to
the CAS Registry Numbers 352458-37-8 and 883105-02-0, respectively.
1-Deoxy-1-(methylamino)-D-glucitol corresponds to the CAS Registry
Number 6284-40-8. 1-Deoxy-1-(methylamino)-D-glucitol is also known
by the name meglumine. D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1- azetidinyl)-4-oxo-3-quinolinecarboxylate, which is the
meglumine salt of delafloxacin, is also known as delafloxacin
meglumine. D-glucitol, 1-deoxy-1-(methylamino)-,
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate trihydrate, which
is the trihydrate of the meglumine salt of delafloxacin, is also
known as delafloxacin meglumine trihydrate. WO 2006/042034 also
discloses a crystalline form of the
1-deoxy-1-(methylamino)-D-glucitol salt characterized when measured
at about 25.degree. C. with Cu-Ka radiation, by the powder
diffraction pattern shown in FIG. 1 (see WO 2006/042034) and a
crystalline form of the 1-deoxy-1-(methylamino)-D-glucitol salt
trihydrate when measured at about 25.degree. C. with Cu-Ka
radiation, by the powder diffraction pattern shown in FIG. 2 (see
WO 2006/042034, which is hereby incorporated by reference in its
entirety). These 1-deoxy-1-(methylamino)-D-glucitol salts are
useful in the present invention. Also, see A. R. Haight et al.,
"Synthesis of the Quinolone ABT-492: Crystallizations for Optimal
Processing", Organic Process Research & Development (2006),
10(4), 751-756, which is hereby incorporated by reference in its
entirety.
[0186] Additionally other pharmaceutically acceptable salts of the
forgoing compound, delafloxacin, include the potassium salt and the
tris salt. Tris is a common abbreviation for
tris(hydroxymethyl)aminomethane, which is known by the IUPAC name
2-Amino-2-hydroxymethyl-propane-1,3-diol.
[0187] The quinolone carboxylic acid antimicrobial agent comprises
from about 0.01% to about 50% by weight of the composition. In
further embodiments, the quinolone carboxylic acid antimicrobial
agent comprises from about 0.25% to about 20% by weight of the
composition. In yet further embodiments, the quinolone carboxylic
acid antimicrobial agent comprises from about 0.5% to about 10% by
weight of the composition. In yet further embodiments, the
quinolone carboxylic acid antimicrobial agent comprises from about
1% to about 5% by weight of the composition. The weight percentage
of the quinolone carboxylic acid antimicrobial agent is determined
on an active weight basis of the parent compound. In other words,
appropriate adjustments and calculations well known to one of
ordinary skill in the art can be readily performed to determine the
active weight basis. As a nonlimiting example, if the parent free
carboxylic acid of delafloxacin, i.e.
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-h-
ydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid, is used, its
weight would have to be adjusted if a salt such as the sodium salt
were to be used, because the molecular weight of the compound would
increase by about 21.9, although the amount of active compound
delivered is the same.
[0188] The dose of the pharmaceutical active and mode of
administration of the pharmaceutical composition will depend upon
the intended patient or subject and the targeted microorganism,
e.g., the target bacterial organism.
[0189] As further described below, it is often advantageous to mill
the pharmaceutical active to a small and uniform particle size,
usually in the micron range, i.e. micronization. Milling can be
performed using standard techniques well known to one of ordinary
skill in the art. In one embodiment, useful particle size ranges
for the pharmaceutical active are generally from about 0.01 microns
to about 100 microns. In another embodiment, useful particle size
ranges for the pharmaceutical active are from about 0.1 microns to
about 20 microns. In another embodiment, useful particle size
ranges for the pharmaceutical active are from about 0.5 microns to
about 5 microns.
b. Cyclodextrins
[0190] The compositions of the present invention comprise a
cyclodextrin (sometimes abbreviated as "CD"). Cyclodextrins are
cyclic oligosaccharides composed of five or more
alpha-D-glucopyranoside units, i.e. sugar units. Cyclodextrins are
produced from starch by means of enzymatic conversion.
Cyclodextrins having six sugar units are referred to as
alpha-cyclodextrins (also ".alpha.-cyclodextrins"). Cyclodextrins
having seven sugar units are referred to as beta-cyclodextrins
(also ".beta.-cyclodextrins"). Cyclodextrins having eight sugar
units are referred to as gamma-cyclodextrins (also
".gamma.-cyclodextrins"). Cyclodextrins are further described in
the Handbook of Pharmaceutical Excipients, Third Edition, Edited by
A. H. Kibbe, pages 165-168, American Pharmaceutical Association and
Pharmaceutical Press (2000), which are incorporated by reference
herein in there entirety.
[0191] Cyclodextrins, which are cyclic oligosaccharides, have been
reported for use in pharmaceutical formulations. Also, publications
in the field of pharmaceutical product development have reported
various formulations and technologies relating to drug solubility
and stability, and also to tolerability of intravenous
formulations. See, for example, U.S. Pat. No. 6,407,079 B1, to
Muller et al., issued Jun. 18, 2002; U.S. Pat. No. 5,874,418, to
Stella et al., issued Feb. 23, 1999; U.S. Pat. No. 5,376,645, to
Stella et al., issued Dec. 27, 1994; U.S. Pat. No. 5,134,127, to
Stella et al., issued Jul. 28, 1992; and U.S. Pat. No. 5,084,276,
to Yunker et al., issued Jan. 28, 1992, each of which is hereby
incorporated by reference in its entirety.
[0192] However, although cyclodextrins have been taught as
excipients for formulating pharmaceutical compositions for
intravenous administration, not all cyclodextrins are automatically
useable to provide the desired formulation characteristics and
benefits. Based on what is taught in the literature, one cannot a
priori select a cyclodextrin for use with a particular drug product
to obtain the desired end result. The final drug product
formulation is the result of a complex interplay of solubility,
stability, and toleration.
[0193] The cyclodextrin comprises from about 0.01% to about 50% by
weight of the composition. In further embodiments, the quinolone
carboxylic acid antimicrobial agent comprises from about 0.25% to
about 20% by weight of the composition.
[0194] In one embodiment, the compositions of the present invention
comprise a cyclodextrin selected from the group consisting of an
alpha-cyclodextrin, a beta-cyclodextrin, a gamma-cyclodextrin, and
mixtures thereof. In one embodiment, the compositions of the
present invention comprise a cyclodextrin selected from the group
consisting of a beta-cyclodextrin, a gamma-cyclodextrin, and
mixtures thereof.
[0195] Beta-cyclodextrins useful herein comprise beta-cyclodextrin
ethers, beta-cyclodextrin esters, and mixtures thereof.
Beta-cyclodextrins are further described in U.S. Pat. No.
6,407,079, to Muller et al., issued Jun. 18, 2002, which is
incorporated by reference herein in its entirety. This '079 patent
describes these beta-cyclodextrins as corresponding to the
following formula (3):
(beta-Cyclodextrin)-OR (3)
in which the residues R are hydrogen or hydroxyalkyl groups and
part of the residues R may optionally be alkyl groups, the
beta-cyclodextrin ether having a water-solubility of more than 1.8
g in 100 ml water. In one embodiment, the residues R are
hydroxyalkyl groups and part of the residues R may optionally be
alkyl groups. In another embodiment, the beta-cyclodextrin ether
having a water-solubility of more than 1.8 g in 100 ml water. In
still another embodiment, the residues R are hydroxyalkyl groups
and part of the residues R may optionally be alkyl groups, the
beta-cyclodextrin ether having a water-solubility of more than 1.8
g in 100 ml water.
[0196] In one embodiment, a partially etherified beta-cyclodextrin
of formula 3 is used in which some of the residues R are
hydroxyethyl, hydroxypropyl or dihydroxypropyl groups. Optionally
part of the residues R may for instance be methyl or ethyl groups.
In one embodiment, the use of partially methylated
beta-cyclodextrin ethers with 7 to 14 methyl groups in the
beta-cyclodextrin molecule, as they are known from German
Offenlegungsschrift 31 18 218 do not come under the present
invention. In one embodiment, partial ethers of beta-cyclodextrin
comprising only alkyl groups (methyl, ethyl) may be suitable in
accordance with the invention if they have a low degree of
substitution (as defined below) of 0.05 to 0.2.
[0197] Beta-cyclodextrin is a compound with ring structure
consisting of 7 anhydro glucose units; it is also referred to as
cycloheptaamylose. Each of the 7 glucose rings contains in 2-, 3-,
and 6-position three hydroxy groups which may be etherified. In the
partially etherified beta-cyclodextrin derivatives used according
to the invention only part of these hydroxy groups is etherified
with hydroxyalkyl groups and optionally further with alkyl groups.
When etherifying with hydroxy alkyl groups which can be carried out
by reaction with the corresponding alkylene oxides, the degree of
substitution is stated as molar substitution (MS), viz. in mole
alkylene oxide per anhydroglucose unit, compare U.S. Pat. No.
3,459,731, column 4. In the hydroxyalkyl ethers of
betabeta-cyclodextrin used in accordance with the invention the
molar substitution is between 0.05 and 10. In another embodiment,
the molar substitution is between 0.2 and 2. In another embodiment,
the molar substitution is about 0.25 to about 1.
[0198] The etherification with alkyl groups may be stated directly
as degree of substitution (DS) per glucose unit which--as stated
above--is 3 for complete substitution. Partially etherified
betabeta-cyclodextrins are used within the invention which comprise
besides hydroxyalkyl groups also alkyl groups, especially methyl or
ethyl groups, up to a degree of substitution of 0.05 to 2.0. In one
embodiment, the degree of substitution with alkyl groups is between
0.2 to 1.5. In one embodiment, the degree of substitution with
alkyl groups is between about 0.5 and about 1.2.
[0199] In one embodiment, he molar ratio of drug to
beta-cyclodextrin ether is about 1:6 to 4:1, especially about 1:2
to 1:1. In one embodiment, the complex forming agent is used in a
molar excess.
[0200] Useful complex forming agents are especially the
hydroxyethyl, hydroxypropyl and dihydroxypropyl ether, their
corresponding mixed ethers, and further mixed ethers with methyl or
ethyl groups, such as methyl-hydroxyethyl, methyl-hydroxypropyl,
ethyl-hydroxyethyl and ethyl-hydroxypropyl ether of
beta-cyclodextrin.
[0201] The preparation of the hydroxyalkyl ethers of
beta-cyclodextrin may be carried out using the method of U.S. Pat.
No. 3,459,731. Suitable preparation methods for beta-cyclodextrin
ethers may further be found in J. Sziejtli et al., Starke 32, 165
(1980) and A. P. Croft and R. A. Bartsch, Tetrahedron 39, 1417
(1983). Mixed ethers of beta-cyclodextrin can be prepared by
reacting beta-cyclodextrin in a basic liquid reaction medium
comprising an alkali metal hydroxide, water and optionally at least
one organic solvent (e.g. dimethoxyethane or isopropanol) with at
least two different hydroxyalkylating and optionally alkylating
etherifying agents (e.g. ethylene oxide, propylene oxide, methyl or
ethyl chloride).
[0202] Beta-cyclodextrins useful herein include
hydroxypropyl-beta-cyclodextrins.
[0203] Examples of hydroxypropyl-beta-cyclodextrins useful herein
include Cavitron.RTM. W7 HP7 Pharma, CAS Registry Number
128446-35-5, which is a hydroxypropyl-beta-cyclodextrin having
seven glucose units and a molecular substitution per anhydro
glucose unit of 0.86-1.14 and Cavitron.RTM. W7 HP5 Pharma, which is
a hydroxypropyl-beta-cyclodextrin having seven glucose units and a
molecular substitution per anhydro glucose unit of 0.59-0.73.
Sulfoalkyl Ether Cyclodextrin Derivatives
[0204] Sulfoalkyl ether cyclodextrins useful herein include
sulfoalkyl ether cyclodextrin derivatives further described in U.S.
Pat. No. 5,874,418, to Stella et al., issued Feb. 23, 1999; U.S.
Pat. No. 5,376,645, to Stella et al., issued Dec. 27, 1994, along
with its certificate of correction of May 19, 2008; and U.S. Pat.
No. 5,134,127, to Stella et al., issued Jul. 28, 1992, which are
incorporated by reference herein in their entirety. These patents
describe the sulfoalkyl ether cyclodextrins as follows:
[0205] This invention also provides cyclodextrin derivatives
suitable for pharmaceutical use. These derivatives are suitable for
use as clathrating agents with drugs to provide clathrate complexes
which are useful in parenteral and other pharmaceutical
formulations. Procedures for making and isolating the cyclodextrin
derivatives are also provided.
[0206] The sulfoalkyl ether cyclodextrin derivatives of the present
invention are functionalized with (C.sub.2-6
alkylene)-SO.sub.3.sup.- groups, and are thus charged species. The
fact that these compounds have been discovered to possess a very
low level of toxicity is surprising in light of the prior art's
belief that cyclodextrin derivatives must retain electroneutrality
to sustain lack of toxicity (cf. Pitha, "Amorphous Water-Soluble"
"Third International Symposium on Recent Advances in Drug Delivery
Systems, Salt Lake City, Utah, Feb. 23-27, 1987).
[0207] The high aqueous solubility of the cyclodextrin derivatives
of the present invention, and their resulting lowered
nephrotoxicity, is further surprising in light of U.S. Pat. No.
4,727,064's disclosure that to maintain a high level of solubility
for cyclodextrin derivatives, a mixture of derivatives should be
used.
[0208] The aqueous solubility exhibited by the present sulfoalkyl
cyclodextrin derivatives appears to be obtained through solvation
of the sulfonic acid moieties. Thus heterogeneous mixture of the
present cyclodextrin derivatives is not a requirement for the
observed enhanced solvation to occur. Although a mixture of
sulfoalkyl ether derivatives can be used in accordance with the
present invention, such a mixture is not required for enhanced
solubility.
[0209] In an embodiment, the sulfoalkyl ether cyclodextrin
derivatives of this invention have structures represented by
formula (1) shown immediately below:
##STR00014##
wherein: n is 4, 5 or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each
independently, O.sup.- or a O--(C.sub.2-6 alkylene)-SO.sub.3.sup.-
group, wherein at least one of R.sub.1 and R.sub.2 is independently
a O--(C.sub.2-6 alkylene)-SO.sub.3.sup.- group, for example a
O--(CH.sub.2).sub.m--SO.sub.3.sup.- group, wherein m is 2 to 6, for
example 2 to 4, (e.g. OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.- or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); and S.sub.1,
S.sub.2, S.sub.3, S.sub.4, S.sub.5, S.sub.6, S.sub.7, S.sub.8 and
S.sub.9 are each, independently, a pharmaceutically acceptable
cation which includes, for example, H.sup.+, alkali metals (e.g.
Li.sup.+, Na.sup.+, K.sup.+), alkaline earth metals (e.g.,
Ca.sup.+2, Mg.sup.+2), ammonium ions and amines cations such as the
cations C.sub.1-6 alkylamines, piperidine, pyrazine, C.sub.1-6
alkanolamine and C.sub.4-8 cycloalkanolamine.
[0210] In another embodiment (2):
R.sub.1 is a O--(C.sub.2-6 alkylene)-SO.sub.3.sup.- group, for
example a O--(CH.sub.2).sub.m--SO.sub.3.sup.- group, (e.g.
OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.- or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); R.sub.2 to
R.sub.9 are O.sup.-; and S.sub.1 to S.sub.9 are as defined for
formula 1, supra.
[0211] In another embodiment (3):
R.sub.1, R.sub.2 and R.sub.3 are each, independently, a
O--(C.sub.2-6 alkylene)-SO.sub.3.sup.- group, for example a
O--(CH.sub.2).sub.mSO.sub.3.sup.- group, (e.g.
OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.- or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); R.sub.4 to
R.sub.9 are O.sup.-; and S.sub.1 to S.sub.9 are as defined for
formula 1, supra.
[0212] In another embodiment (4):
R.sub.1 to R.sub.3 are as defined in embodiments (2) or (3); supra;
at least one of R.sub.4, R.sub.6 and R.sub.8 is a
O--C.sub.2-6-alkylene-SO.sub.3.sup.- group, for example a
O--(CH.sub.2).sub.mSO.sub.3.sup.- group (e.g.
OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.- or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-). R.sub.5, R.sub.7
and R.sub.9 are O.sup.-; and S.sub.1 to S.sub.9 are as defined for
formula 1, supra.
[0213] In another embodiment (6):
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.8 are each,
independently, a O--(C.sub.2-6-alkylene)-SO.sub.3.sup.- group, for
example a O--(CH.sub.2)--.sub.mSO.sub.3.sup.- group (e.g.
OCH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.- or
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2SO.sub.3.sup.-); R.sub.5, R.sub.7
and R.sub.9 are O.sup.-; and S.sub.1 to S.sub.9 are as defined for
formula 1, supra.
[0214] The terms "alkylene" and "alkyl" in this text (e.g., in the
O--(C.sub.2-6-alkylene)SO.sub.3.sup.- group or in the alkylamines)
include both linear and branched, saturated and unsaturated (i.e.,
containing one double bond) divalent alkylene groups and monovalent
alkyl groups, respectively. The term "alkanol" in this text
likewise includes both linear and branched, saturated and
unsaturated alkyl components of the alkanol groups, in which the
hydroxyl groups may be situated at any position on the alkyl
moiety. The term "cycloalkanol" includes unsubstituted or
substituted (e.g., by methyl or ethyl) cyclic alcohols.
[0215] In one embodiment, the present invention provides
compositions containing a mixture of cyclodextrin derivatives
having the structure set out in formula (1), where the composition
overall contains on the average at least 1 and up to 3n+6
alkylsulfonic acid moieties per cyclodextrin molecule. The present
invention also provides compositions containing essentially only
one single type of cyclodextrin derivative.
[0216] In one embodiment, the present cyclodextrin derivatives are
either substituted at least at one of the primary hydroxyl groups
(i.e., at least one of R.sub.1 to R.sub.3 is a substituent), or
they are substituted at both the primary hydroxyl group and at the
3-position hydroxyl group (i.e., both at least one of R.sub.1 to
R.sub.3 and at least one of R.sub.4, R.sub.6 and R.sub.8 are a
substituent). In another embodiment, substitution at the 2-position
hydroxyl group, while theoretically possible, does not appear to
appear to be substantial in the products of the invention. The
cyclodextrin derivatives of the present invention are obtained (as
discussed below) as purified compositions, for example as
compositions containing at least 95 wt. % of cyclodextrin
derivative(s) with the substitution occurring at least on the
primary hydroxyl group of the cyclodextrin molecule (i.e. R.sub.1,
R.sub.2 or R.sub.3 of formula (1)), as determined by 300 MHz
.sup.1H NMR). In an embodiment, purified compositions containing at
least 98 wt. % cyclodextrin derivative(s) can be obtained.
[0217] In one embodiment, this is to be contrasted with the U.S.
Pat. No. 3,426,011 disclosure which reports obtaining only reaction
products of the reaction of a cyclodextrin with a sulfone reactant.
The reaction products in the '011 patent contain considerable
quantities of unsubstituted cyclodextrin starting material.
[0218] In one embodiment of compositions of the invention,
unreacted cyclodextrin has been substantially removed, with the
remaining impurities (i.e., .ltoreq.5 wt. % of composition) being
inconsequential to the performance of the cyclodextrin
derivative-containing composition.
[0219] It should be noted that the variables used to describe the
cyclodextrins are intended to be separate from the variables used
to define the quinolone carboxylic acid derivatives.
[0220] The more highly substituted alkyl sulfonic acid cyclodextrin
derivatives of the present invention have been discovered to
possess, in addition to notably enhanced solubility characteristics
and low toxicity, the advantageous property of causing less
membrane disruption. In red blood cell hemolysis studies, the more
highly substituted cyclodextrin derivatives demonstrated negligible
membrane disruption. The mono-substituted cyclodextrin derivatives
caused about the same amount of membrane disruption as the
hydroxypropyl derivative.
[0221] In one embodiment, improved characteristics are achieved by
purified compositions of the invention, containing <5%, for
example less than 2%, of unreacted beta-cyclodextrin, for example
for compositions to be administered to a patient by parenteral
administration. In one embodiment, compositions containing somewhat
higher amounts of unreacted beta-cyclodextrin, are useful for oral
administration.
[0222] The allowance for residual beta-cyclodextrin can be broader
for a sulfoalkylether cyclodextrin preparation when used in an oral
formulation. The oral absorption of beta-cyclodextrin can sometimes
be limited (if it occurs at all) and the elimination of
beta-cyclodextrin in the feces would preclude any nephrotoxicity.
However, the level of beta-cyclodextrin which might be tolerated in
an oral formulation would still be dependent upon other
characteristics of the material particularly on its intrinsic
aqueous solubility.
[0223] In one embodiment, the sulfoalkylether cyclodextrins of the
present invention may be used for oral formulations, even if
unreacted beta-cyclodextrin is contained in an amount of up to
about 50%. In one embodiment, the amount is limited to less than
40%. In one embodiment, the amount is limited to less than about
25%.
Preparation of the Cyclodextrin (CD) Derivatives
[0224] The cyclodextrin derivatives described may be generally
prepared by dissolving the cyclodextrin in aqueous base at an
appropriate temperature, e.g., 70 degrees to 80 degrees C., at the
highest concentration possible. For example, to prepare the
cyclodextrin derivatives of an embodiment herein, an amount of an
appropriate alkyl sulfone, corresponding to the number of moles of
primary CD hydroxyl group present, is added with vigorous stirring
to ensure maximal contact of the heterogeneous phase.
[0225] To prepare the cyclodextrin derivatives of an embodiment
herein, a molar amount of the alkyl sulfone, corresponding to the
number of moles of CD used, is used. As would be readily
determinable by one of skill in this art, to prepare cyclodextrin
derivatives of an embodiment herein, an amount of alkyl sulfone
between that stated above is used. Other cyclodextrin derivatives
provided by the present invention are prepared Mutatis
Mutandis.
[0226] The mixtures are allowed to react until one phase results
which is indicative of depletion of the alkyl sulfone. The reaction
mixture is diluted with an equal volume of water and neutralized
with an acid such as hydrochloric acid. The solution is then
dialyzed to remove impurities followed by concentration of the
solution by ultrafiltration.
[0227] The concentrated solution is then subjected to ion-exchange
chromatography to remove unreacted cyclodextrin, and then
freeze-dried to yield the desired product.
[0228] The CD used in this invention may be any CD obtained by
known methods, e.g., by the action of
cyclodextrin-glucanotransferase (CGTase, E.C., 2.4.1.19.) upon
starch. Thus CD herein means alpha-CD in which six glucose units
are linked together through alpha-1,4 bond, beta-CD in which seven
glucose units are linked together, or gamma-CD in which eight
glucose units are linked together, or a mixture thereof. In one
embodiment, beta-CD is useful for production of partially
derivatized products of broad utility.
[0229] As noted herein and depending on the cyclodextrin derivative
sought, the amount of alkyl sulfone used as the derivatizing agent
should be not more than about one molar equivalent, based on the
number of primary hydroxyl groups present in the CD, although the
optimum amount may be somewhat dependent on the reactant
concentration. Lithium hydroxide, sodium hydroxide and potassium
hydroxide may be used as the accelerator. In one embodiment, sodium
hydroxide is useful because of its low cost. Its amount must be
more than about 30 molar equivalents, and should preferably be in
the range of 80 to 200 molar equivalents, with the reactant
concentration being set at a level higher than 10% (wt/wt),
preferably in the range of 40 to 60% (wt/wt). Any solvent which is
substantially inert to the partial alkylation may be used as
reaction medium. Typical examples are water, DMF, DMSO, and
mixtures thereof. In one embodiment, the use of water alone eases
after-treatment. The type and concentration of alkylsulfone and
alkali are not critical to the reaction. However, the reaction is
normally carried out with stirring at 10.degree. to 80.degree. C.
for one hour, or at 20.degree. to 50.degree. C. for 5 to 20
hours.
[0230] Techniques commonly used in this field may be employed to
isolate and purify the objective compounds from reaction mixtures.
These include extraction with organic solvents, dialysis,
adsorption chromatography with activated charcoal, silica gel,
alumina and other adsorbents, chromatography using, as carrier,
crosslinked dextrin, styrene/divinylbenzene copolymers and other
cross-linked polymers, and combinations thereof.
[0231] Sulfoalkyl ether cyclodextrin derivatives useful herein
include sulfobutyl ether cyclodextrins, including sulfobutyl ether
beta-cyclodextrins.
[0232] An example of a sulfoalkyl ether cyclodextrin derivative
useful herein includes Captisol.RTM.,
sulfobutylether-.beta.-cyclodextrin, sodium salt, CAS Registry
Number 182410-00-0.
[0233] The cyclodextrin comprises from about 1% to about 50% by
weight of the composition. In further embodiments, the
cyclodlextrin comprises from about 5% to about 40% by weight of the
composition. In yet further embodiments, the cyclodextin comprises
from about 10% to about 30% by weight of the composition. In yet
further embodiments, the cyclodextrin comprises from about 15% to
about 25% by weight of the composition.
c. Water
[0234] In one embodiment, the compositions of the present invention
comprise from about 0.1% to about 99.9% water, in further
embodiments from about 1% to about 99% water, in yet further
embodiments from about 5% to about 95% water, and in yet further
embodiments from about 10% to about 90% water. In defining a
composition, the amount of water can be designated as "q.s." or
"Q.S.", which means as much as suffices, to provide a final
composition or volume of 100%.
d. Sugars and Sugar Alcohols
[0235] The compositions of the present invention, when further made
into a lyophile, can further comprise a sugar, a sugar alcohol, or
mixtures thereof. Without being limited by theory, these sugars and
sugar alcohols are believed to aid in the formation of the lyophile
during the lyophilization process. Typically, the lyophile is made
by drying the composition under appropriate conditions, such as,
for example, by freeze drying. Nonlimiting examples of sugars
include mannose, sucrose, dextrose, sorbitol, mannitol, and
mixtures thereof. Nonlimiting examples of sugar alcohols useful
herein include mannitol and xylitol and mixtures thereof.
[0236] In one embodiment, the compositions comprise from about 0.1%
to about 50% of a sugar or sugar alcohol.
e. Polyhydroxy Amine Compound
[0237] In one embodiment, the compositions of the present invention
comprise a polyhydroxy amine compound. The polyhydroxy amine
compound is separate from and does not encompass the polyhydroxy
compound of the compositions of the present invention. The
polyhydroxy amine compound is generally a C.sub.3-C.sub.8 straight,
branched, or cyclic compound having 2 or more hydroxy substituents,
and at least one amine (either substituted or unsubstituted)
substituent.
[0238] In further embodiments the polyhydoxy amine compound is
meglumine. Meglumine corresponds to CAS Registry Number 6284-40-8
and is also known as meglumine, USP;
1-Deoxy-1-(methylamino)-D-glucitol; N-Methyl-D-glucamine; Glucitol,
1-deoxy-1-(methylamino)-, D-(8Cl); Sorbitol,
1-deoxy-1-methylamino-(6Cl); 1-Deoxy-1-(methylamino)-D-glucitol;
1-Deoxy-1-methylaminosorbitol; D-(-)-N-Methylglucamine; Meglumin;
Methylglucamin; Methylglucamine; N-Methyl-D(-)-glucamine;
N-Methyl-D-glucamine; N-Methylglucamine; N-Methylsorbitylamine; NSC
52907; NSC 7391. It also has the CA Index Name D-Glucitol,
1-deoxy-1-(methylamino)-(9Cl). A chemical formula for meglumine is
as follows:
##STR00015##
[0239] In one embodiment, the polyhydroxy amine compound comprises
from about 0.1% to about 50% by weight of the composition. In
further embodiments, the polyhydroxy amine compound comprises from
about 0.25% to about 20% by weight of the composition. In yet
further embodiments, the polyhydroxy amine compound comprises from
about 0.5% to about 10% by weight of the composition. In yet
further embodiments, the polyhydroxy amine compound comprises from
about 1% to about 5% by weight of the composition.
f. Chelating Agents
[0240] The compositions of the present invention can further
comprise a chelating agent. The chelating agent is defined herein
as excluding the cyclodextin, the polyhydroxy amine compound, or
any of the other components described herein, even though the
cyclodextrin, the polyhydroxy amine compound, or other components
described herein can also have chelating properties. An example of
a chelating agent useful herein is EDTA, also known as
ethylenediaminetetraacetic acid, or a salt thereof. Useful salts
include, for example, a sodium salt, a potassium salt, a calcium
salt, a magnesium salt, and mixtures of these salts. An example of
a mixture of salts or a mixed salt is the monosodium monocalcium
salt of EDTA. It is found that the disodium salt of EDTA, also
known as disodium EDTA, is useful herein. For convenience, the
disodium EDTA can first be separately prepared as an aqueous
solution for use in formulating the compositions of the present
invention.
[0241] In one embodiment, the disodium EDTA comprises from about
0.0010% to about 0.10% by weight of the composition. In further
embodiments, the disodium EDTA comprises from about 0.0050% to
about 0.050% by weight of the composition. In yet further
embodiments, the disodium EDTA comprises from about 0.010% to about
0.020% by weight of the composition. In other embodiments the
disodium EDTA comprises about 0.010% of the composition, or about
0.011% of the composition, or about 0.012% of the composition, or
about 0.013% of the composition, or about 0.014% of the
composition, or about 0.015% of the composition, or about 0.016% of
the composition, or about 0.017% of the composition, or about
0.018% of the composition, or about 0.019% of the composition, or
about 0.020% of the composition. These weight percentages of the
disodium EDTA described herein are on the basis of the
etheylenediaminetetracetic acid.
g. pH Modifiers and pH of the Compositions
[0242] The compositions of the present invention can further
comprise various materials for modifying or adjusting the pH of the
composition. Such materials include acids, bases, buffer systems,
etc. Nonlimiting examples of such pH modifiers include, for
example, hydrochloric acid and sodium hydroxide. Examples of other
useful materials include triethanolamine, sodium carbonate, and
lysine. Furthermore, the polyhydroxy amine compound, such as
described above, can be used as a pH modifier. More specifically,
the polyhydroxy amine compound, meglumine, can be used as a pH
modifier.
[0243] The compositions of the present invention should have a pH
so that the composition is suitable for administration to a patient
or subject. The compositions have a pH from about pH 7 to about pH
11. In further embodiments, the compositions have a pH from about
pH 8 to about pH 10. In further embodiments, the compositions have
a pH from about pH 8.5 to about pH 9.5. In further embodiments, the
compositions have a pH from about pH 8.8 to about pH 9.2. In
further embodiments, the compositions have a pH of about 9.0.
h. Additional Components
[0244] The compositions of the present invention can further
comprise one or more additional components selected from a wide
variety of excipients known in the pharmaceutical formulation art.
According to the desired properties of the tablet or capsule, any
number of ingredients can be selected, alone or in combination,
based upon their known uses in preparing the compositions of the
present invention. Such ingredients include, but are not limited to
solvents (e.g. ethanol); colorants; waxes, gelatin; preservatives
(e.g., methyl paraben, sodium benzoate, and potassium benzoate);
antioxidants [e.g., butylated hydroxyanisole ("BHA"), butylated
hydroxytoluene ("BHT"), and vitamin E and vitamin E esters such as
tocopherol acetate]; surfactants; UV-absorbers, etc.
[0245] In one embodiment, the compositions of the present invention
comprise a carrier. The carrier can be a dextrose solution or
saline, at a pharmaceutically acceptable concentration. The
composition comprising a carrier can be administered to a patient
via an i.v. bag.
3. PROCESSING
[0246] The compositions of the present invention are made using
convention equipment and mixing techniques.
[0247] Lyophilization, also known as freeze-drying is a dehydration
process to remove the liquid, typically water and other relatively
volatile solvents, from a material. Freeze drying works by freezing
the material and then reducing the surrounding pressure and, as
appropriate, adding enough heat to allow the frozen mobile water
and other solvents in the material to sublime directly from the
solid phase to gas.
4. PACKAGING
[0248] The compositions of the present invention can be packaged in
standard, commercially available containers such as vials for
liquid or lyophile storage. Generally, the vial is glass. The glass
can be colorless or colored, clear or amber. Various types of
closure systems can be used such as screw vials (closed with screw
cap), lip vials (closed with a stopper), or crimp vials (closed
with a rubber stopper and a metal cap).
[0249] Additionally, the compositions of the present invention,
including a reconstituted lyophile, can be further diluted into an
intravenous delivery bag or bottle.
[0250] The invention encompasses kits that can simplify the
administration of a quinolone carboxylic acid derivative or a
composition comprising it to a subject. In one embodiment, a kit of
the invention comprises a unit dosage form of a quinolone
carboxylic acid derivative. In one embodiment the unit dosage form
is a container, which can be sterile, containing an effective
amount of a quinolone carboxylic acid derivative and a
physiologically acceptable carrier or vehicle. Physiologically
acceptable carriers include saline and dextrose solutions at
pharmaceutically acceptable concentrations. Such compositions can
be contained in an i.v. drip bag. The kit can further comprise a
label or printed instructions instructing the use of the quinolone
carboxylic acid derivative to treat, prevent, or reduce the risk of
an infection. Kits of the invention can further comprise a device
that is useful for administering the unit dosage forms. Examples of
such a device include, but are not limited to, a bottle, a vial, a
syringe and a drip bag. Other examples of devices include, but are
not limited to, a patch, an inhaler, and an enema bag. In one
embodiment, the device that is useful for administering the unit
dosage forms is the container.
5. DOSES AND METHODS OF TREATING, PREVENTING, OR REDUCING THE RISK
OF INFECTIONS
[0251] The compositions of the present invention are useful for
treating, preventing or reducing the risk of infection due to,
e.g., a skin infection, nosocomial pneumonia, post-viral pneumonia,
an abdominal infection, a urinary tract infection, bacteremia,
septicemia, endocarditis, an atrio-ventricular shunt infection, a
vascular access infection, meningitis, infection due to surgical or
invasive medical procedures, a peritoneal infection, a bone
infection, a joint infection, a methicillin-resistant
Staphylococcus aureus infection, a vancomycin-resistant Enterococci
infection, a linezolid-resistant organism infection, tuberculosis,
a quinolone resistant Gram-positive infection, a ciprofloxacin
resistant methicillin resistant (MRSA) infection, bronchitis, a
complicated skin and skin structure infection (cSSSI), an
uncomplicated skin and skin structure infection (uSSSI), a
community respiratory-tract infection, and a multi drug resistant
(MDR) Gram-negative infection.
[0252] The dose of active compound and mode of administration,
e.g., injection, intravenous drip, etc. will depend upon the
intended patient or subject and the targeted microorganism, e.g.,
the target bacterial organism. Dosing strategies are disclosed in
L. S. Goodman, et al., The Pharmacological Basis of Therapeutics,
201-26 (5th ed. 1975), the entire contents of which is herein
incorporated in its entirety.
[0253] Compositions can be formulated in dosage unit form for ease
of administration and uniformity of dosage. Dosage unit form refers
to physically discrete units suited as unitary dosages for the
subject to be treated; each unit containing a predetermined
quantity of active compound calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. The specification for the dosage unit forms of the
invention are dictated by and directly dependent on the unique
characteristics of the active compound and the therapeutic effect
to be achieved, and the limitations inherent in the art of
compounding such an active compound for the treatment of
individuals. Furthermore, administration can be by periodic
injections of a bolus, or can be made more continuous by
intravenous, intramuscular or intraperitoneal administration from
an external reservoir (e.g., an intravenous bag).
[0254] Where the active compound is to be used as part of a
transplant procedure, it can be provided to the living tissue or
organ to be transplanted prior to removal of tissue or organ from
the donor. The compound can be provided to the donor host.
Alternatively or, in addition, once removed from the donor, the
organ or living tissue can be placed in a preservation solution
containing the active compound. In all cases, the active compound
can be administered directly to the desired tissue, as by injection
to the tissue, or it can be provided systemically, by parenteral
administration, using any of the methods and formulations described
herein and/or known in the art. Where the drug comprises part of a
tissue or organ preservation solution, any commercially available
preservation solution can be used to advantage. For example, useful
solutions known in the art include Collins solution, Wisconsin
solution, Belzer solution, Eurocollins solution and lactated
Ringer's solution.
[0255] In conjunction with the methods of the present invention,
pharmacogenomics (i.e., the study of the relationship between an
individual's genotype and that individual's response to a foreign
compound or drug) can be considered. Differences in metabolism of
therapeutics can lead to severe toxicity or therapeutic failure by
altering the relation between dose and blood concentration of the
pharmacologically active drug. Thus, a physician or clinician can
consider applying knowledge obtained in relevant pharmacogenomics
studies in determining whether to administer a drug as well as
tailoring the dosage and/or therapeutic regimen of treatment with
the drug.
[0256] Generally, an effective amount of dosage of active compound
will be in the range of from about 0.1 to about 100 mg/kg of body
weight/day. In one embodiment, the amount will be from about 1.0 to
about 50 mg/kg of body weight/day. The amount administered will
also likely depend on such variables as the overall health status
of the patient, the relative biological efficacy of the compound
delivered, the formulation of the drug, the presence and types of
excipients in the formulation, the route of administration, and the
infection to be treated, prevented, or reducing the risk of. Also,
it is to be understood that the initial dosage administered can be
increased beyond the above upper level in order to rapidly achieve
the desired blood-level or tissue level, or the initial dosage can
be smaller than the optimum.
[0257] Nonlimiting doses of active compound comprise from about 0.1
to about 1500 mg per dose. Nonlimiting examples of doses, which can
be formulated as a unit dose for convenient administration to a
patient include: about 25 mg, about 50 mg, about 75 mg, about 100
mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about
225 mg, about 250 mg, about 275 mg, about 300 mg, about 325, about
350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg,
about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575
mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg about
700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg,
about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925
mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about
1050, mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150
mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg,
about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about
1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475
mg, and about 1500 mg. The foregoing doses are useful for
administering the compounds of the present invention according to
the methods of the present invention. The foregoing doses are
particularly useful for administering the quinolone carboxylic acid
derivatives of the present invention, particularly the compound
known by the name delafloxacin and pharmaceutically acceptable
salts, esters and prodrugs thereof.
[0258] As is understood by one of ordinary skill in the art,
generally, when dosages are described for a pharmaceutical active,
the dosage is given on the basis of the parent or active moiety.
Therefore, if a salt, hydrate, or another form of the parent or
active moiety is used, a corresponding adjustment in the weight of
the compound is made, although the dose is still referred to on the
basis of the parent or active moiety delivered. As a nonlimiting
example, if the parent or active moiety of interest is a
monocarboxylic acid having a molecular weight of 250, and if the
monosodium salt of the acid is desired to be delivered to be
delivered at the same dosage, then an adjustment is made
recognizing that the monosodium salt would have a molecular weight
of approximately 272 (i.e. minus 1H or 1.008 atomic mass units and
plus 1 Na or 22.99 atomic mass units). Therefore, a 250 mg dosage
of the parent or active compound would correspond to about 272 mg
of the monosodium salt, which would also deliver 250 mg of the
parent or active compound. Said another way, about 272 mg of the
monosodium salt would be equivalent to a 250 mg dosage of the
parent or active compound.
[0259] In one embodiment, compositions of the invention is useful
in the manufacture of a medicament for treating, preventing or
reducing the risk of infection in a patient in need thereof. In
another embodiment, delafloxacin, or a pharmaceutically acceptable
salt or ester thereof, is useful in the manufacture of a medicament
for treating, preventing or reducing the risk of infection in a
patient in need thereof. Such infections can be due to, e.g., a
skin infection, nosocomial pneumonia, post-viral pneumonia, an
abdominal infection, a urinary tract infection, bacteremia,
septicemia, endocarditis, an atrio-ventricular shunt infection, a
vascular access infection, meningitis, infection due to surgical or
invasive medical procedures, a peritoneal infection, a bone
infection, a joint infection, a methicillin-resistant
Staphylococcus aureus infection, a vancomycin-resistant Enterococci
infection, a linezolid-resistant organism infection, tuberculosis,
a quinolone resistant Gram-positive infection, a ciprofloxacin
resistant methicillin resistant (MRSA) infection, bronchitis, a
complicated skin and skin structure infection (cSSSI), an
uncomplicated skin and skin structure infection (uSSSI), a
community respiratory-tract infection, and a multi drug resistant
(MDR) Gram-negative infection.
[0260] Using delafloxacin as a nonlimiting example, an example of a
composition useful in the methods of the present invention can
contain about 300 mg of delafloxacin, or a pharmaceutically
acceptable salt or ester thereof.
6. EXAMPLES
[0261] The following examples further describe and demonstrate
embodiments within the scope of the present invention. The examples
are given solely for the purpose of illustration and are not to be
construed as limitations of the present invention, as many
variations thereof are possible without departing from the spirit
and scope of the invention.
[0262] Ingredients are identified by chemical, USP, or CTFA
name.
[0263] The following formulations are preparing using mixing
techniques and equipment familiar to one of ordinary skill in the
art.
[0264] These formulations are useful for intravenous
administration, either infusion or bolus, such as injection, to a
patient for treating, preventing, or reducing the risk of a
microbial infection, e.g., a skin infection, including
uncomplicated skin infections, skin and soft tissue infections,
complicated skin infections, pneumonia, including e.g., community
acquired pneumonia, nosocomial (hospital acquired) pneumonia,
hospital acquired community pneumonia, post-viral pneumonia, an
abdominal infection, a urinary tract infection, bacteremia,
septicemia, endocarditis, an atrio-ventricular shunt infection, a
vascular access infection, meningitis, infection due to surgical or
invasive medical procedures, a peritoneal infection, a bone
infection, a joint infection, a methicillin-resistant
Staphylococcus aureus infection, a vancomycin-resistant Enterococci
infection, a linezolid-resistant organism infection, and
tuberculosis. More specifically, this formulation is useful for
reducing the risk of or preventing infection due to a surgical or
invasive medical procedure to be performed upon the patient, and in
such case, the formulation can be administered just prior to or up
to about 1 hour prior to the surgical or invasive medical
procedure.
Example 1
Composition of Delafloxacin-Meglumine Formulation for Intravenous
Administration
TABLE-US-00001 [0265] Batch size, 1000 gram mL Batch % (weight/ Amt
(g)/ Ingredient Mg/mL volume) batch Delafloxacin Meglumine 20.000
2.00% 20.000 (amount as free acid) Meglumine (anhydrous, mw 195.21)
4.88 0.49% 4.880 Captisol .RTM. (sulfobutylether-.beta.- 200 20.00%
200 cyclodextrin, sodium salt) Water for Injection q.s. q.s. q.s. 1
N NaOH and/or HCl acid q.s. q.s. q.s. Density 1.082 g/ml Final pH
9.0 (.+-. 0.1)
API supplied as Meglumine salt of delafloxacin, 28.86 mg/mL
Delafloxacin Meglumine salt=20 mg/mL as free base Conversion factor
between RX-3341 salt/free acid=1.4429 Volume for 150 mg dose, mL
8
Procedure:
[0266] 1. Weigh Water for Injection approximately 70% of the total
batch weight into a suitable container.
[0267] 2. Add the required amount of Captisol.RTM.
(sulfobutylether-.beta.-cyclodextrin, sodium salt) to the solution
and mix until dissolved.
[0268] 3. Add the required amount of Meglumine to the solution and
mix until dissolved.
[0269] 4. Add the required amount of delafloxacin corrected for
purity and salt content and mix until dissolved.
[0270] 5. Test for pH. The target pH is 9.0 (.+-.0.1).
[0271] Adjust with Hydrochloric Acid (as a 1N solution) or Sodium
Hydroxide (as a 1N solution) as needed.
[0272] 6. q.s. to the final weight or volume with Water for
Injection.
[0273] 7. Sterile filter solution (two filters 0.22 um) and fill
into vials.
[0274] Based on the above foregoing formulation table, the
following mg of the indicated component is delivered in a given
dosage.
TABLE-US-00002 100 mg 300 mg 500 mg strength strength strength
dosage dosage dosage Delafloxacin 100 mg 300 mg 500 mg Meglumine
24.4 mg 73.2 mg 122 mg Captisol .RTM. 1000 mg 3000 mg 5000 mg
(sulfobutylether-.beta.- cyclodextrin, sodium salt
[0275] The foregoing composition is useful for intravenous
administration to a patient for treating, preventing, or reducing
the risk of a microbial infection.
Example 2
Composition of Delafloxacin-Meglumine Formulation for Intravenous
Administration
TABLE-US-00003 [0276] Batch size, 1000 gram mL Batch % (weight/ Amt
(g)/ Ingredient Mg/ml volume batch Delafloxacin Meglumine 25.000
2.50% 25.000 (amount as free acid) Meglumine (anhydrous, mw 195.21)
4.88 0.49% 4.880 Captisol .RTM. (sulfobutylether-.beta.- 200 20.00%
200 cyclodextrin, sodium salt) Disodium EDTA, 0.1 M Solution 0.11*
0.011% 0.11 Water for Injection q.s. q.s. q.s. 1 N NaOH and/or HCl
acid q.s. q.s. q.s. Density 1.087 g/ml Final pH 9.0 (.+-. 0.1)
API supplied as Meglumine salt of delafloxacin, 28.86 mg/mL
Delafloxacin Meglumine salt=20 mg/mL as free base The disodium EDTA
concentration is expressed on a free acid basis. Conversion factor
between delafloxacin salt to free acid is 1.4429 Volume for 150 mg
dose, mL 6
Procedure:
[0277] 1. Weigh Water for Injection approximately 70% of the total
batch weight into a suitable container.
[0278] 2. Add the required amount of Captisol.RTM.
(sulfobutylether-.beta.-cyclodextrin, sodium salt) to the solution
and mix until dissolved.
[0279] 3. Add the required amount of Meglumine to the solution and
mix until dissolved.
[0280] 4 Add the EDTA solution and mix.
[0281] 5. Add the required amount of delafloxacin corrected for
purity and salt content and mix until dissolved.
[0282] 6. Test for pH. The target pH is 9.0 (.+-.0.1).
[0283] Adjust with Hydrochloric Acid (as a 1N solution) or Sodium
Hydroxide (as a 1N solution) as needed.
[0284] 7. q.s. to the final weight or volume with Water for
Injection.
[0285] 8. Sterile filter solution (two filters 0.22 um) and fill
into vials.
[0286] The foregoing composition is useful for intravenous
administration to a patient for treating, preventing, or reducing
the risk of a microbial infection.
[0287] Based on the above foregoing formulation table, the
following mg of the indicated component is delived in a given
dosage.
TABLE-US-00004 100 mg 300 mg 500 mg strength strength strength
dosage dosage dosage Delafloxacin 100 mg 300 mg 500 mg Meglumine
19.52 mg 58.56 mg 97.6 mg Captisol .RTM. (sulfobutylether-.beta.-
800 mg 2400 mg 4000 mg cyclodextrin, sodium salt) Disodium EDTA
0.44 mg 1.32 mg 2.2 mg
Example 3: Lyophilisates for Reconstitution for Intravenous
Administration
[0288] Formulations can also be prepared as lyophilisates. For
example, the formlations of Examples 1 and 2, above can also be
prepared as lyophiles. This is accomplished by sterile filtering
the solutions into lyophile vials, and then freeze drying the vials
using conventional freeze drying techniques.
[0289] Such formulations are reconstituted with water or another
appropriate aqueous based solution. These lyophilisates are a
compact and convenient form to store the formulation.
Example 4. Solubility
[0290] The solubility of the quinolone carboxylic acid
antimicrobial active in the compositions of the present invention
is evaluated.
[0291] For room temperature equilibrium solubility measurements, an
excess of the quinolone carboxylic acid antimicrobial compound to
be evaluated tested is mixed with a test vehicle. The initial pH is
recorded and then the pH is adjusted to the target pH for the study
with either HCl or NaOH. Samples are placed at 25.degree. C. in a
rotating shaker at 200 rpm for 24 to 72 hours, with multiple
timepoints generally taken for each sample to ensure that
equilibrium has been reached. For each timepoint an aliquot is
removed and centrifuged at 14K rpm for 10 minutes. The supernantant
is decanted and the pH was measured. A sample was then diluted with
methanol for HPLC analysis.
[0292] For 4.degree. C. solubility measurements, a sample of the
supernatant from the room temperature solubility study is placed at
4.degree. C. Multiple timepoints are generally taken to ensure that
equilibrium has been reached. For each timepoint an aliquot is
removed and centrifuged at 14K rpm for 10 minutes while the sample
is still cold. The supernantant is decanted and the pH is measured
once the sample warms to room temperature. A sample is then diluted
with methanol for HPLC analysis.
[0293] It is found that the compositions of the present invention
provide better solubility, i.e. have enhanced solubility, for the
quinolone carboxylic acid antimicrobial agent, compared to
compositions outside of the present invention.
Example 5. Stability
[0294] The stability of the compositions of the present invention
is evaluated.
[0295] Stability samples are placed on a stability test at -20, 4,
40, and 55.degree. C., and at room temperature. The samples are
placed in 20 mL serum crimp vials (Wheaton) with Gray Bromobutyl 39
Fluorinated Polymer stoppers (Wheaton). The pH, concentration, and
stability profile are measured at 10 days, 1 month, 2 months, and 3
months. Samples at -20.degree. C. are thawed prior to analysis by
thawing at room temperature until no more ice is present and then
placing in a 37.degree. C. water bath for 10 minutes. Samples are
then shaken or agitated briefly (approximately 15 seconds) to
ensure all the solids are dissolved.
[0296] It is found that the compositions of the present invention
provide compositions having enhanced stability, compared to
compositions outside of the present invention.
Example 6. Venous Toleration
[0297] The venous toleration of the compositions of the present can
be evaluated in vivo in a rat tail model. To study venous
toleration, the composition of interest is infused using a
peristaltic pump into a single vein in a rat tail. Compositions are
infused on consecutive days, up to about five days. Each daily
infusion is over a period of about one hour at the rate of 10
ml/kg/hr. The condition of the rat tail is visually assessed using
a grading scale. The venous tolerability of the composition is
assessed from the condition of the rat tail and from the number of
consecutive days the composition can be infused. In other words, a
composition that can be successfully infused on four consecutive
days has a better venous toleration than a composition that can
only be successfully infused on two consecutive days. Appropriate
control compositions can also be evaluated. It is found that the
compositions of the present invention are better tolerated, i.e.
have enhanced venous toleration, compared to compositions outside
of the present invention.
[0298] For measuring the venous toleration, rats are placed under a
heat lamp for warming. They are restrained throughout the infusion
period by use of the Advance Infusion System (CellPoint
Scientific). The rat is placed within a triangular 6 mil
polyethylene bag (DecapiCone, Braintree Scientific). The bagged
rodent is then held in place on the infusion table
(153/4''.times.153/4'') using 3 body restraint bands made of
silicone tubing. An Abbocath-T (G720-A01, 4535-24, 24
G.times.3/4'', Abbott, Ireland) indwelling catheter is placed in
either the right or left lateral tail vein, and secured in place at
the site of insertion with surgical tape (3M, Hypoallergenic
Micropure). Correct placement is confirmed by flashback of blood
into catheter. A 16'' IV extension set (Baxter, 2C5643) attached to
a 5 ml syringe and pre-primed with dosing solution is attached to
the indwelling catheter and secured in place by surgical tape. A 1
hr. slow infusion (10 ml/kg/hour) of compound is administered by
Harvard Apparatus Infusion Pump. Following the infusion, the
surgical tape is removed and the catheter is gently pulled from the
site of insertion, while applying light pressure with gauze. The
tails are cleaned of any residual blood by washing with warm water.
The rats are then removed from the Decapi-Cone bag and returned to
their cage.
INCORPORATION BY REFERENCE
[0299] The entire disclosure of each of the patent documents,
including certificates of correction, patent application documents,
scientific articles, governmental reports, websites, and other
references referred to herein is incorporated by reference in its
entirety for all purposes.
EQUIVALENTS
[0300] The invention can be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting on the invention
described herein.
* * * * *