Note: Descriptions are shown in the official language in which they were submitted.
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ANTIBIOTIC COMPOSITIONS FOR
TREATMENT OF THE EYE, EAR AND NOSE
Background of the Invention
io
The present invention is directed to the provision of topical antibiotic
pharmaceutical compositions for the treatment of ophthalmic, otic and nasal
infections,
particularly bacterial infections, and to methods of treating ophthalmic, otic
and nasal
infections by applying those compositions to the affected tissues. The
compositions and
i s methods of the invention are based on the use of a new class of
antibiotics. The
compositions of the present invention may also contain one or more anti-
inflammatory
agents.
The use of quinolone antibiotics to treat infections represents the current
state of
2o the art in the field of ophthalmic pharmaceutical compositions and methods
of treatment.
For example, a topical ophthalmic composition containing the quinolone
ciprofloxacin is
marketed by Alcon Laboratories, Inc. under the name CILOXANTM lC.'lnr~finxa~in
0.3%) Ophthalmic Solution. The following quinolones have also been utilized in
ophthalmic antibiotic compositions:
uinolone Product Manufacturer
Ofloxacin OCUFLOXTM Allergan
Norfloxacin CHIBROXINTM Merck
Lomefloxacin LOMEFLOXTM Senju
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The foregoing quinolone antibiotic compositions are generally effective in
treating
ophthalmic infections, and have distinct advantages over prior ophthalmic
antibiotic
compositions, particularly those having relatively limited spectrums of
antimicrobial
s activity, such as: neomycin, polvmvxin B. ~entam;~;n a"~t tmhro,~.,....;..,
...L.:..t. ..-_
primarily useful against gram negative pathogens; and bacitracin, gramicidin,
and
erythromycin, which are primarily active against gram positive pathogens.
However,
despite the general efficacy of the ophthalmic quinolone therapies currently
available,
there is a need for improved compositions and methods of treatment based on
the use of
jo antibiotics that are more effective than existing antibiotics against key
ophthalmic
pathogens, and less prone to the development of resistance by those pathogens.
There is an even greater need for effective topical compositions and methods
for
treating otic and nasal infections, particularly bacterial infections. The use
of oral
~s antibiotics to treat otic infections in children has limited efficacy, and
creates a serious
risk of pathogen resistance to the orally administered antibiotics.
Ophthalmic, otic and nasal infections are frequently accompanied by
inflammation
of the infected ophthalmic, otic and nasal tissues and perhaps even
surrounding tissues.
2o Similarly, ophthalmic, otic and nasal surgical procedures that create a
risk of microbial
infections frequently also cause inflammation of the affected tissues. Thus,
there is also a
need for ophthalmic, otic and nasal pharmaceutical compositions that combine
the anti-
infective activity of one or more antibiotics with the anti-inflammatory
activity of one or
more steroid or non-steroid agents in a single composition.
2s
Summary of the Invention
The invention is based on the use of a potent new class of antibiotics to
treat
ophthalmic, otic and nasal infections, as well as the prophylactic use of
these antibiotics
3o following surgery or other trauma to ophthalmic, otic or nasal tissues. The
compositions
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of the present invention may also be administered to the affected tissues
during
ophthalmic, otic or nasal surgery procedures to prevent or alleviate post-
surgical
infections.
s The compositions preferably also contain one or more anti-inflammatory
agents to
treat inflammation associated with infections of ophthalmic, otic or nasal
tissues. The
anti-inflammatory component of the compositions is also useful in treating
inflammation
associated with physical trauma to ophthalmic, otic or nasal tissues,
including
inflammation resulting from surgical procedures. The comn~sitinnc ~f rhP
.,..o~o.,f
io invention are therefore particularly useful in treating inflammation
associated with trauma
to ophthalmic, otic or nasal tissues wherein there is either an infection or a
risk of an
infection resulting from the trauma.
Examples of ophthalmic conditions that may be treated with the compositions of
~s the present invention include conjunctivitis, keratitis, blepharitis,
dacyrocystitis,
hordeolum and corneal ulcers. The compositions of the invention may also be
used
prophylactically in connection with various ophthalmic surgical procedures
that create a
risk of infection.
2o Examples of otic conditions that may be treated with the compostions of the
present invention include otitis externa and otitis media. With respect to the
treatment of
otitis media, the compositions of the present invention are primarily useful
in cases where
the tympanic membrane has ruptured or tympanostomy tubes have been implanted.
The
compositions may also be used to treat infections associated with otic
surgical procedures,
2s such as tympanostomy, or to prevent such infections.
The compositions of the present invention are specially formulated for topical
application to ophthalmic, otic and nasal tissues. The compositions are
preferably sterile,
and have physical properties (e.g., osmolality and pH) that are specially
suited for
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application to ophthalmic, otic and nasal tissues, including tissues that have
been
compromised
Detailed Description of the Invention
s
The antibiotics used in the compositions and methods of the present invention
have the following formula:
(I)
R3 O
COOR
'~ J
R2
I
to R1
wherein
~s R1 is a cyclopropyl which may be substituted by 1 to 3 of substituents
selected
from the group consisting of a C,-C6 alkyl and a halogen atom, a phenyl which
may be substituted by 1 to 3 of substituents selected from the group
consisting of
C~-C6 alkoxy, a halogen atom and hydroxy, a C,-Cb alkyl which may be
substituted by a halogen atom, a C2-C6 alkanoyloxy or hydroxy, a CZ-C6 alkenyl
or
2o thienyl;
R2 is a member selected from the group consisting of a 1-piperazinyl group
which
may have 1 to 3 substituents selected from the group consisting of a C,-C6
alkyl
group, a C,-C6 alkanoyl group, a phenyl (C,-C6) alkyl group, and a 2-oxo-1,3-
zs dioxolenemethyl group which may be substituted by a phenyl group or a C,-C6
alkyl group; a 1-pyrrolidinyl group which may have 1 to 3 substituents
selected
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from the group consisting of an amino group which can have 1 or 2 substituents
selected from a C,-C6 alkyl group and a (C,-C6)alkooxy-carbonyl group, an
amino(C,-C6)alkyl group which may have 1 to 2 substituents selected from C~-C6
alkyl group and a (C,-C6)alkoxy-carbonyl group on the amino moiety, and a C,-
C6
s alkyl group; a morphoIino group which may have 1 to 3 substituents of C~-C6
alkyl
groups; a 1-piperidinyl group which may have 1 to 3 substituents selected from
the
group consisting of a C,-C6 alkyl group, hydroxy, a halogen atom and oxo
group;
and a 1,4-diazobicyclo[4.3.0]nonan-4-yl group;
io R3 is a C,-C6 alkyl;
R is hydrogen atom or a C,-C6 alkyl; and
X is a halogen atom, or a pharmaceutically acceptable salt thereof.
is
The compound Grepafloxacin is most preferred. Grepafloxacin has the following
structure:
CH3 O
2o F ~ COOH
'~ J
N N
NJ
2s
Further details regarding the structure, preparation, and physical properties
of
Grepafloxacin and other compounds of formula (I} are provided in U. S. Patent
No.
5,563,138.
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The concentrations of the antibiotics of formula (I) in the compositions of
the
present invention will vary depending on the intended use of the compositions
(e.g.,
treatment of existing infections or prevention of post-surgical infections),
and the relative
antimicrobial activity of the specific antibiotic selected. The antimirrnh;ai
artiv,itm "f
s antibiotics is generally expressed as the minimum concentration required to
inhibit the
growth of a specified pathogen. This concentration is also referred to as the
"minimum
inhibitory concentration" or "MIC". The term "MIC90" refers to the minimum
concentration of antibiotic required to inhibit the growth of ninety percent
(90%) of the
strains of a species. The concentration of an antibiotic required to totally
kill a specified
io bacteria is referred to as the "minimum bactericidal concentration" or
"MBC". The
minimum inhibitory concentration of Grepafloxacin for several bacteria
commonly
associated with ophthalmic, otic and nasal infections are provided in the
following table:
Microor anism MIC 90
is S. aureus/methicillin sensitive 0.13
S. aureus/methicillin resistant 0.13
S. aureus/quinolone resistant 0.13
S. epidermidis/methicillin sensitive 0.13
S. epidermidis/methicillin resistant 0.13
2o S. pneumoniae/penicillin sensitive 0.25
S. pneumoniae/penicillin resistant 0.25
P. aeruginosa g,0
H. influenzae/(3-lactamase positive 0.008
H influenzae/(3lactamase negative 0.008
2s
All of the foregoing concentrations are expressed as micrograms per milliliter
("mcg/ml")
The appropriate antibiotic concentration for ophthalmic compositions will
generally be an amount of one or more antibiotics of formula (I) sufficient to
provide a
so concentration in the aqueous humor and lacrimal fluid of the eye equal to
or greater than
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the MIC90 level for the selected antibiotic(s), relative to gram-negative and
gram-positive
organisms commonly associated with ophthalmic infections. The appropriate
concentration for otic and nasal compositions will generally be an amount of
one or more
antibiotics of formula (I) sufficient to provide a concentration in the
infected tissues equal
s to or greater than the MIC90 level for the selected antibiotic(s), relative
to gram-negative
and gram-positive organisms commonly associated with otic or nasal infections.
Such
amounts are referred to herein as "an antimicrobial effective amount". The
compositions
of the present invention will typically contain one or more compounds of
formula (I) in a
concentration of from about 0.1 to about 1.0 percent by weight ("wt. %") of
the
~ o compositions.
The compositions of the present invention may also contain one or more anti
inflammatory agents. The anti-inflammatory agents utilized in the present
invention are
broadly classified as steroidal or non-steroidal. The preferred steroidal anti-
inflammatory
i s agents are glucocorticoids.
The preferred glucocorticoids for ophthalmic and otic use include
dexamethasone,
loteprednol, rimexolone, prednisolone, fluorometholone, and hydrocortisone.
The
preferred glucocorticoids for nasal use include mometasone, fluticasone,
beclomethasone,
2o flunisolide, triamcinolone and budesonide.
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The dexamethasone derivatives described in U.S. Patent No. 5,223,493
(Boltralik)
are also preferred steroidal anti-inflammatory agents, particularly with
respect to
compositions for treating ophthalmic inflammation. The following compounds are
especially preferred:
AL-1529
O
O
O O
O ""O r AL-2512
~~~~~ii
F
These compounds are referred to herein as "21-ether derivatives of
dexamethasone". The 21-benzyl ether derivative (i.e., compound AL-2512) is
particularly preferred.
Zo The preferred non-steroidal anti-inflammatory agents are: prostaglandin H
synthetase inhibitors (Cox I or Cox II), also referred to as cyclooxygenase
type I and type
II inhibitors, such as diclofenac, flurbiprofen, ketorolac, suprofen,
nepafenac, amfenac,
indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen, meclofenamate,
piroxicam,
sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen,
benoxaprofen,
~ s nabumetome, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016,
_g_
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HCT-1026, NCX-284, NCX-456, tenoxicam and carprofen; cyclooxygenase type II
selective inhibitors, such as NS-398, vioxx, celecoxib, P54, etodolac, L-
804600 and S-
33516; PAF antagonists, such as SR-27417, A-137491, ABT-299, apafant,
bepafant,
minopafant, E-6123, BN-50727, nupafant and modipafant; PDE IV inhibitors, such
as
s ariflo, torbafylline, rolipram, flaminast, piclamilast, cipamfylline, CG-
1088, V-11294A,
CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004,
and roflumilast; inhibitors of cytokine production, such as inhibitors of the
NFkB
transcription factor; or other anti-inflammatory agents known to those skilled
in the art.
The concentrations of the anti-inflammatory agents contained in the
compositions
of the present invention will vary based on the agent or agents selected and
the type of
inflammation being treated. The concentrations will be sufficient to reduce
inflammation
in the targeted ophthalmic, otic or nasal tissues following topical
application of the
compositions to those tissues. Such an amount is referred to herein as "an
anti-
cs inflammatory effective amount". The compositions of the present invention
will typically
containe one or more anti-inflammatory agents in an amount of from about 0.01
to about
1.0 wt.%.
The compositions are typically administered to the affected ophthalmic, otic
or
2o nasal tissues by topically applying one to four drops of a sterile solution
or suspension, or
a comparable amount of an ointment, gel or other solid or semisolid
composition, one to
four times per day. However, the compositions may also be formulated as
irrigating
solutions that are applied to the affected ophthalmic, otic or nasal tissues
during surgical
procedures.
The ophthalmic, otic and nasal compositions of the present invention will
contain
one or more compounds of formula (I) and preferably one or more anti-
inflammatory
agents, in pharmaceutically acceptable vehicles. The compositions will
typically have a
pH in the range of 4.5 to 8Ø The ophthalmic compositions must also be
formulated to
3o have osmotic values that are compatible with the aqueous humor of the eye
and
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ophthalmic tissues. Such osmotic values will generally be in the range of from
about 200
to about 400 milliosmoles per kilogram of water ("mOsm/kg"), but will
preferably be
about 300 mOsm/kg.
s Ophthalmic, otic and nasal products are typically packaged in multidose
form.
Preservatives are thus required to prevent microbial contamination during use.
Suitable
preservatives include: polyquaternium-l, benzalkonium chloride, thimerosal,
chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate
disodium,
sorbic acid, or other agents known to those skilled in the art. The use of
polyquaternium-
to 1 as the antimicrobial preservative is preferred. Typically such
preservatives are
employed at a level of from 0.001 % to 1.0% by weight.
The solubility of the components of the present compositions may be enhanced
by
a surfactant or other appropriate co-solvent in the composition. Such co-
solvents include
polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants
(e.g., Pluronic
is F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled
in the art.
Typically such co-solvents are employed at a level of from 0.01 % to 2% by
weight.
The use of viscosity enhancing agents to provide the compositions of the
invention
with viscosities greater than the viscosity of simple aqueous solutions may be
desirable to
2o increase absorption of the active compounds by the target tissues or
increase the retention
time in the eye, ear or nose. Such viscosity building agents include, for
example,
polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl
methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy
propyl
cellulose or other agents know to those skilled in the art. Such agents are
typically
zs employed at a level of from 0.01 % to 2% by weight.
The following examples are provided to further illustrate the ophthalmic, otic
and
nasal compositions of the present invention.
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Exa
Oohthalmic/Otic/Nasal Solution
Ingredient Amount (wt. %)
s Grepafloxacin 0.3 5
Sodium Acetate 0.03
Acetic Acid 0.04
Mannitol 4.60
EDTA 0.05
to BenzaIkonium Chloride 0.006
Water q.s. 100
Example Z
is Ophthalmic/Otic/Nasal Suspension
Ingredient Amount (wt. %)
Grepafloxacin 0.3
Dexamethasone, Micronized USP 0.10
2o Benzalkonium Chloride 0.01
Edetate Disodium, USP 0.01
Sodium Chloride, USP 0.3
Sodium Sulfate, USP 1.2
Tyloxapol, USP 0.05
2s Hydroxyethylcellulose 0.25
Sulfuric Acid and/or
Sodium Hydroxide, NF q.s. for pH adjustment
to 5.5
Purified Water, USP q.s. to 100
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Examine 3
Ouhthalmic Ointment
InEredient Amount (wt.%)
Grepafloxacin 0.35
Mineral Oil, USP 2.0
White petrolatium, USP q.s 100
Example 4
Ophthalmic Ointment
Ingredient Amount (wt.%)
Grepafloxacin 0.3
Is Fluorometholone Acetate, USP 0.1
Chlorobutanol, Anhydrous, NF 0.5
Mineral OiI,USP
White Petrolatum, USP q. s. 100
The invention has been described herein by reference to certain preferred
embodiments. However, as obvious variations thereon will become apparent to
those
skilled in the art, the invention is not to be considered as limited thereto.
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