(12) United States Patent
`Cagle et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,440,964 B1
`Aug. 27, 2002
`
`US006440964B1
`
`(54) COMPOSITIONS AND METHODS FOR
`TREATING OPHTHALMIC AND OTIC
`INFECTIONS
`
`................................. .. 514/230.05; 514/912
`(52) U.S. Cl.
`(58) Field of Search ........................... .. 514/230.05, 912
`
`(75)
`
`Inventors: Gerald Cagle; Robert L. Abshire, both
`of Fort Worth; David W. Stroman,
`Irving; Celeste H. McLean, Fort
`Worth; Linda L. Clark, Grandview;
`John M. Yanni, Burleson, all of TX
`(US)
`
`(73) Assignee: Alcon Manufacturing, Ltd., Fort
`W0fth, TX (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U‘S'C' 154(b) by 0 days’
`
`(21) APPL N05 09/8879771
`<2»
`Jun
`Related U_S_ Application Data
`
`(63) C0ntinuati0n_in_part of application No. 09/577,262, filed as
`application No. PCT/US99/22622 on Sep. 29, 1999.
`Provisional application No‘. 6Q/102,504, filed on Sep. 30,
`1998, and provisional application No. 60/102,506, filed on
`Sep. 30, 1998.
`
`(60)
`
`(56)
`
`References Cited
`
`Us’ PATENT DOCUMENTS
`6,174,878 B1 *
`1/2001 Camache et al.
`.... .. 514/211.12
`
`wo
`
`FOREIGN PATENT DOCUMENTS
`wo 90/01933
`*
`3/1990
`
`* Cited by examiner
`Primary Examiner—Zohreh Fay
`(74) Attorney, Agent, or Firm—Gregg C. Brown
`
`ABSTRACT
`(57)
`Ophthalmic, otic and nasal compositions containing a new
`class of antibiotics (e.g., moxifloxacin) are disclosed. The
`compositions preferably also contain one or more anti-
`i?ii“;‘3§iE2lH?{%f’“2i;§‘:Z§°,‘3E§f12§EZi{?oiib§y“i%§§lii§
`applying the compositions to the ‘affected tissues. The com-
`positions and methods of the invention are particularly
`useful in the treatment of acute otitis externa infections and
`ophthalmic infections attributable to one or both of two
`newly identified Microbacterium species, Microbacterium
`on-n-dis and Microbacterium alcomle.
`
`(51)
`
`Int. Cl.7 ............................................ .. A61K 31/353
`
`6 Claims, 1 Drawing Sheet
`
`Page 1 of 8
`
`LUPIN EX 1073
`
`LUPIN EX 1073
`
`Page 1 of 8
`
`

`
`
`
`U.S. PatentU.S. Patent
`
`
`
`Aug. 27, 2002Aug. 27, 2002
`
`
`
`US 6,440,964 B1US 6,440,964 B1
`
`
`
`Page 2 of 8Page 2 of 8
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`Page 2 of 8
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`

`
`US 6,440,964 B1
`
`1
`COMPOSITIONS AND METHODS FOR
`TREATING OPHTHALMIC AND OTIC
`INFECTIONS
`
`The present application is a continuation-in-part of U.S.
`application Ser. No. 09/577,262 filed May 19, 2000, which
`is a 371 of International Application No. PCT/US99/22622
`filed on Sep. 29, 1999, which U.S. Provisional Application
`Ser. No. 60/102,504 and 60/102,506 filed on Sep. 30, 1998.
`BACKGROUND OF THE INVENTION
`
`invention is directed to the provision of
`The present
`topical antibiotic pharmaceutical compositions for the treat-
`ment 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 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.
`Quinolone antibiotics have been previously utilized to
`treat ophthalmic and otic infections. For example, a topical
`ophthalmic composition containing the quinolone ciprof-
`loxacin is marketed by Alcon Laboratories, Inc. under the
`name CILOXANTM (Ciprofloxacin 0.3%) Ophthalmic
`Solution, and a topical otic composition containing a com-
`bination of ciprofloxacin and hydrocortisone is marketed by
`Alcon Laboratories, Inc. under the name CIPROTM HC. The
`following quinolones have also been utilized in ophthalmic
`antibiotic compositions:
`
`Quinolone
`
`Ofloxacin
`Norfloxacin
`Lomefloxacin
`
`Product
`
`Manufacturer
`
`OCUFLOX TM
`CHIBROXIN TM
`LOMEFLOX TM
`
`Allergan
`Merck
`Senju
`
`Ofloxacin has also been utilized to treat otic infections.
`
`The foregoing quinolone antibiotic compositions are gen-
`erally effective in treating ophthalmic infections, and have
`distinct advantages over prior ophthalmic antibiotic
`compositions, particularly those having relatively limited
`spectrums of antimicrobial activity, such as: neomycin,
`polymyxin B, gentamicin and tobramycin, which are prima-
`rily useful against gram negative pathogens; and bacitracin,
`gramicidin, and erythromycin, which are primarily active
`against gram positive pathogens. However, despite the gen-
`eral efficacy of the ophthalmic quinolone therapies currently
`available, there is a need for improved compositions and
`methods of treatment based on the use of antibiotics that are
`
`more effective than existing antibiotics against key oph-
`thalmic pathogens, and less prone to the development of
`resistance by those pathogens.
`There is an even greater need for effective topical com-
`positions and methods for treating otic and nasal infections,
`particularly bacterial infections. The use of oral antibiotics
`to treat otic infections in children has limited efficacy, and
`creates a serious risk of pathogen resistance to the orally
`administered antibiotics. Although ciprofloxacin has proven
`to be an effective agent in treating otic infections, there is a
`need for a better understanding of the etiology of these
`infections and a corresponding need for
`therapies that
`address the causes of these infections more directly and
`effectively.
`infections are frequently
`Ophthalmic, otic and nasal
`accompanied by inflammation of the infected ophthalmic,
`
`2
`otic and nasal tissues and perhaps even surrounding tissues.
`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 com-
`positions 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 composi-
`tion.
`
`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 use of these antibiotics prior to surgery to sterilize
`the surgical field and prophylactically following surgery or
`other trauma to ophthalmic, otic or nasal tissues to minimize
`the risk of infection. The compositions of the present inven-
`tion may also be administered to the affected tissues during
`ophthalmic, otic or nasal surgical procedures to prevent or
`alleviate post-surgical infection. As utilized herein, the terms
`“treat”, “treating” and derivations thereof are intended to
`include both treatments of existing infections and treatments
`to prevent or reduce the risk of infections.
`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 inflam-
`mation resulting from surgical procedures. The composi-
`tions of the present
`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 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.
`
`Examples of otic conditions that may be treated with the
`compositions of the present invention include otitis extema
`and otitis media. With respect to the treatment of otitis
`media, the compositions of the present invention are prima-
`rily 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, such as tympanostomy, or to
`prevent such infections.
`The compositions and methods of the present invention
`are particularly useful in the treatment of acute infections of
`the external ear canal, which are commonly referred to as
`“acute otitis extema” or “AOE”. The present invention is
`based in part on the isolation of two bacterial species that
`have not previously been identified as pathogens relative to
`acute otitis externa infections. These bacterial species,
`which have been named “Microbacterium otitidis” and
`
`“Microbacterium alconae”, are described in greater detail
`below. The present invention is also based in part on a
`finding that the antibiotics utilized in the present invention,
`particularly Moxifloxacin, have a very high level of antimi-
`crobial activity against these newly discovered pathogens,
`and therefore are particularly useful in the treatment of acute
`otitis externa infections involving these pathogens.
`The two bacterial species that have been identified as
`being associated with acute otitis extema infections have
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
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`65
`
`Page 3 of 8
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`Page 3 of 8
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`

`
`US 6,440,964 B1
`
`3
`also been discovered to be associated with ophthalmic
`infections. As indicated above, the antibiotics utilized in the
`present invention have a high level of antimicrobial activity
`against these newly discovered ophthalmic pathogens, and
`as a result, the compositions of the present invention are
`particularly useful in treating ophthalmic infections involv-
`ing these species.
`
`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 application to ophthalmic, otic and nasal
`tissues, including tissues that have been compromised as the
`result of preexisting disease, trauma, surgery or other physi-
`cal conditions.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`The sole FIGURE of drawings is an automated ribotyping
`chart showing the relationships between two newly identi-
`fied bacterial species and other, known species.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The antibiotics used in the compositions and methods of
`the present invention have the following formula:
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-continued
`
`N
`
`N
`
`HIIn H and
`
`R4N
`
`Y
`
` nIIH
`
`R4N
`
`Y
`
`wherein:
`
`Y is O or CH2;
`R3 is C2-C3 alkoxyl, CH2—CO—C6H3, CH2CH2CO2R‘,
`R‘O2C—CH=C—CO2R‘,
`CH=CH—CO2R‘ or CH2CH2—CN,
`wherein:
`
`R‘ is H or C1 to C3 alkyl;
`R4 is H, C1 to C3 alkyl, C2‘C3 alkoxyl, CH2—CO—C6H3,
`CH2CH2CO2R‘,
`R‘O2C—CH=C—CO2R‘, CH=CH—CO2R‘,
`CH2CH2—CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-
`methyl,
`wherein:
`
`R‘ is H or C1 to C3 alkyl; and their pharmaceutically
`useful hydrates and salts.
`The compound Moxifioxacin is most preferred. Moxifioxa-
`cin has the following structure:
`
`x1
`
`0
`
`COOR2
`
`(1)
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Further details regarding the structure, preparation, and
`physical properties of Moxifioxacin and other compounds of
`formula (I) are provided in U.S. Pat. No. 5,607,942. The
`contents of U.S. Pat. No. 5,607,942 relating to the structure,
`physical properties, and preparation of the compounds of
`formula (I) are hereby incorporated in the present specifi-
`cation by reference.
`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 antibi-
`otic selected. The antimicrobial activity of antibiotics is
`generally expressed as the minimum concentration required
`to inhibit the growth of a specified pathogen. This concen-
`tration is also referred to as the “minimum inhibitory con-
`centration” 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 bacteria is referred to as the “minimum bactericidal
`concentration” or “MBC”. The minimum inhibitory concen-
`tration of Moxifioxacin for several bacteria commonly asso-
`ciated with ophthalmic, otic and nasal infections are pro-
`vided in the following table:
`
`F
`
`B
`
`wherein:
`
`TR1
`
`A is CH, CF, CCl, C—OCH3, or N;
`
`X1 is H, halogen, NH2, or CH3;
`R1 is C1 to C3 alkyl, FCH2CH2, cyclopropyl or phenyl,
`optionally mono-, di- or tri-substituted by halogen, orA
`and R1 together can form a bridge of formula C—O—
`CH2—CH(CH3);
`
`R2 is H, C1 to C3 alkyl (optionally substituted by OH,
`halogen or NH2), or 5-methyl-2-oxo-1,3-dioxol-4-yl-
`methyl; and
`B is a selected from the group consisting of:
`
`L
`
`L
`
`Y
`R3N
`\_/
`
`Y
`R4N
`\_/
`
` u...
`
`N
`
`R4
`
`Page 4 of 8
`
`Page 4 of 8
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`

`
`US 6,440,964 B1
`
`5
`
`Microorganism
`S. aureus/methicillin sensitive
`S. aureus/methicillin resistant
`S. aureus/quinolone resistant
`S. epidermidis/methicillin sensitive
`S. epidermidis/methicillin resistant
`S. pneumoniae/penicillin sensitive
`S. pneumoniae/penicillin resistant
`R aemginosa
`H. influenzae/[5-lactamase positive
`H influenzae/[5lactamase negative
`M. otitidis
`M. alconae
`
`MIC90
`0.13
`4.0
`4.0
`0.25
`4.0
`0.25
`0.25
`8.0
`0.06
`0.06
`2.0
`0.25
`
`All of the foregoing concentrations are expressed as micro-
`grams per milliliter (“mcg/ml”).
`As indicated above, the present invention is based in part
`on the identification of two bacterial species that are
`believed to act as pathogens in acute otitis externa
`infections, Microbacterium otitidis and Microbacterium
`alconae. These bacteria belong to the class known as
`“coryneforms” or “diphtheroids”. Bacteria belonging to this
`class have been previously identified as being present both
`in healthy ears and in ears afflicted with acute otitis externa
`infections. However, prior to the present invention, there had
`been no species-level identification of the coryneform bac-
`teria present either in healthy ears or infected ears, nor had
`there been any attempt to eradicate the pathogenic species
`present
`in acute otitis externa infections with antibiotic
`therapy keyed to those species. The present inventors have
`now identified two species of coryneform bacteria as being
`present in acute otitis externa infections, and have deter-
`mined that
`the compounds of formula (I), particularly
`Moxifloxacin, are very effective in eradicating these species.
`Microbacterium otitidis and Microbacterium alconae
`
`have also been discovered to be pathogens in infections of
`ophthalmic tissues, such as conjunctivitis and blepharitis.
`The compositions of the present invention are therefore
`particularly useful in treating ophthalmic infections involv-
`ing one or both of these species.
`The bacterial species referred to above were identified as
`a result of research conducted on specimens obtained from
`2,122 ears afflicted with acute otitis extema infections and
`82 healthy ears. Coryneform bacteria of some type were
`isolated from 10 to 30% of these ears overall; the incidence
`of finding this class of bacteria present varied depending on
`the season when the specimen was taken. Although coryne-
`form bacteria have been identified previously in both healthy
`and infected ears, the present inventors have discovered that
`the coryneform bacteria present in healthy ears and in acute
`otitis externa ears are different. In the acute otitis extema
`
`ears, 80% of the coryneform bacteria identified belong to the
`genus Microbacterium, while in the healthy ears, 90% of is
`the coryneform bacteria identified belong to the genus
`Turicella.
`
`the
`inventors have also discovered that
`The present
`coryneform bacteria found in acute otitis externa patients
`include two species that have not previously been identified.
`These species are now identified as Microbacterium sp. nov.
`otitidis and Microbacterium sp. nov. alcomze. These names
`for the species have been assigned by the inventors, but have
`not yet been officially published. The names utilized for
`these species below are “Microbacterium otitidis”
`(sometimes abbreviated as “M. 0titia'is”) and “Microbacte-
`rium alconae” (sometimes abbreviated as “M. alcomze”),
`respectively.
`
`6
`In two thirds of the cases where M. otitidis or M. alconae
`
`isolates were identified as being present, these species were
`the only type of bacteria recovered. Moreover, these species
`were not recovered from healthy ears. These findings lead to
`the conclusion that M. otitidis and M. alcomze are pathogens
`in acute otitis externa. That is, these species were either
`largely or totally responsible for the acute otitis externa
`infections in the ears from which they were isolated. The
`above-cited findings are believed to represent the first fre-
`quent association of the genus Microbacterium with a
`human infectious disease, namely, acute otitis externa. The
`two new Microbacterium species that have been discovered
`to be pathogens in acute otitis externa are described in
`greater detail below.
`Both new species can be distinguished from the 27
`recognized species of Microbacterium phenotypically and
`genetypically. Genetypically, M. otitidis is most closely
`related to M. hominis, while M. alcomze is most closely
`related to M. maritypicum and M. liquefaciens.
`The two new Microbacterium species have been charac-
`terized for taxomonic purposes using DNA methods as well
`as phenotypic methods. The sequencing of the 16S rRNA
`gene showed that both sets of strains belonged to the genus
`Microbacterium, although the sequence differences from
`established Microbacterium species were significant enough
`to suggest novel species. Automated ribotyping patterns
`further clarified the relationships (similarities and
`differences) with known Microbacterium species. These
`relationships are shown in FIG. 1. The above-cited analyses
`support the categorization of these bacteria as new species.
`Both species of Microbacterium grow optimally at
`28—30° C. The M. otitidis isolates grow up to 37° C., while
`the M. alcomze isolates grow up to 35° C. The optimal
`growth temperature at 28—30° C. is typical for bacteria that
`are normally found in water and soil.
`Phenotypically,
`the M. otitidis isolates are most easily
`distinguished from M. hominis by their inability to metabo-
`lize: 1) N-acetyl-D-glucosamine, 2) 3-methyl glucose, 3)
`alaninamide, or 4) L-serine. The isolates of M. alcomze can
`be distinguished from M.
`liquefaciens by their ability to
`metabolize: 1) amygdalin, 2) D-mannitol, 3) D-melezitose,
`4) palatinose, 5) D-psicose, 6) salicin, 7) D-sorbitol, 8)
`D-Xylose, or 9) p-hydoxyphenyl acetic acid. Also, M. alco-
`nae can be distinguished from M. maritypicum by their
`ability to metabolize: 1) amygdalin or 2) D-Xylose, and can
`be distinguished from M. maritypicum by their inability to
`metabolize: 1) L-fucose.
`Analysis of cellular fatty acids for the M. otitidis isolates
`showed the three major fatty acids to be: 1) 17:0 anteiso-
`60%, 2) 15:0 anteiso-26%, and 3) 16:0 iso-11%. Analysis of
`the M. alconae isolates showed the three major fatty acids to
`be: 1) 15:0 anteiso-55%, 2) 17:0 anteiso-23%, and 3) 16:0
`iso-11%.
`The appropriate antibiotic concentration for ophthalmic
`compositions will generally be an amount of one or more
`antibiotics of formula (I) sufficient to provide a concentra-
`tion in the aqueous humor and lacrimal fluid of the eye equal
`to or greater than 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 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
`
`10
`
`15
`
`20
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`25
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`30
`
`35
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`40
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`45
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`
`US 6,440,964 B1
`
`7
`antimicrobial effective amount”. The compositions of the
`present invention will typically contain one or more com-
`pounds of formula (I) in a concentration of from about 0.1
`to about 1.0 percent by weight (“wt. %”) of the composi-
`tions.
`
`invention may also
`The compositions of the present
`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 pre-
`ferred steroidal anti-inflammatory agents are glucocorti-
`coids.
`
`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, flunisolide, triamcinolone and
`budesonide.
`The dexamethasone derivatives described in U.S. Pat. No.
`
`5,223,493 (Boltralik) are also preferred steroidal anti-
`inflammatory agents, particularly with respect to composi-
`tions for treating ophthalmic inflammation. The following
`compounds are especially preferred:
`
`AL—1529
`
`AL—25 12
`
`
`
`
`These compounds are referred to herein as “21-ether deriva-
`tives of dexamethasone”. The 21-benzyl ether derivative
`(i.e., compound AL-2512) is particularly preferred.
`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, nabumetome, etodolac,
`phenylbutazone, aspirin, oxyphenbutazone, NCX-4016,
`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 ariflo,
`torbafylline, rolipram, filaminast, piclamilast, cipamfylline,
`CG-1088, V-11294A, CT-2820, PD-168787, CP-293121,
`DWP-205297, CP-220629, SH-636, BAY-19-8004, and rof-
`lumilast; inhibitors of cytokine production, such as inhibi-
`
`8
`tors of the NFkB transcription factor; or other anti-
`inflammatory agents known to those skilled in the art.
`The concentrations of the anti-inflammatory agents con-
`tained 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 suf-
`ficient 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-inflammatory effective amount”. The
`compositions of the present invention will typically contain
`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 nasal tissues by topically apply-
`ing 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 solu-
`tions 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 com-
`positions will typically have a pH in the range of 4.5 to 8.0.
`The ophthalmic compositions must also be formulated to
`have osmotic values that are compatible with the aqueous
`humor of the eye and 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.
`Ophthalmic, otic and nasal pharmaceutical products are
`typically packaged in multidose form. Preservatives are thus
`required to prevent microbial contamination during use.
`Suitable preservatives include: polyquaternium-1, benzalko-
`nium chloride, thimerosal, chlorobutanol, methyl paraben,
`propyl paraben, phenylethyl alcohol, edetate disodium, sor-
`bic acid, or other agents known to those skilled in the art.
`The use of polyquaternium-1 as the antimicrobial preserva-
`tive 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 compo-
`sitions 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 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 increase ocular 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 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Page 6 of 8
`
`Page 6 of 8
`
`

`
`US 6,440,964 B1
`
`EXAMPLE 1
`
`EXAMPLE 4
`
`Ophthalmic[Otic[Nasal Solution
`
`5
`
`Ingredient
`
`Amount (wt. %)
`
`Ophthalmic Ointment
`T
`
`Ingredient
`
`Amount (wt. %)
`
`Moxifloxacin
`Sodium Acetate
`Acetic Acid
`Mannitol
`EDTA
`Benzalkonium Chloride
`Water
`
`0-35
`0.03
`0.04
`4.60
`0.05
`0-006
`q.s. 100
`
`EXAMPLE 2
`
`Ophthalmic[Otic[Nasal Suspension
`
`_
`Ingredlem
`Moxifloxacin
`Dexamethasone, Micronized USP
`Benzalkonium Chloride
`Edetate Disodium, USP
`Sodium Chloride, USP
`Sodium Sulfate, USP
`Tyloxapol, USP
`Hydroxyethylcellulose
`Sulfuric Acid and/or
`Sodium Hydroxide, NF
`Purified Water, USP
`
`Amount (Wt 0/”)
`0.3
`0.10
`0.01
`0.01
`0.3
`1.2
`0.05
`0.25
`q.s. for pH adjustment to 5.5
`
`q.s. to 100
`
`EXAMPLE 3
`
`O hthalmic Ointment
`
`Ingredient
`Moxifloxacin
`M1n_eTa1 011» U_5P
`White petrolatium, USP
`
`Am°“m(Wt'%)
`o_35
`2-0
`q.s 100
`
`15
`
`20
`
`25
`
`30
`
`10
`
`Moxifloxacin
`
`Fluorometholone Acetate, USP
`Chlorobutanol, Anhydrous, NF
`Mineral Oil, USP
`White Petrolatum, USP
`
`0.3
`
`0.1
`0.5
`5
`q.s. 100
`
`The following example is provided to illustrate the activ-
`ity of the compounds of formula (I) against the new Micro-
`bacterium species described above.
`
`EXAMPLE 5
`
`The in vitro activity of Moxifloxacin against Microbac-
`terium otitidis and Microbacterium alconae was determined
`
`using conventional agar and broth dilution methods, such as
`35 those described in NCCLS Document M7-A4, entitled
`“Methods for Dilution Antimicrobial Susceptability Tests
`for Bacteria That Grow Aerobically” (4’h Edition). The
`activity levels were determined as MIC (minimum inhibi-
`.
`.
`.
`tory concentration) values. In order to compare the activity
`40 of the compounds of the present
`invention to other
`antibiotics, MIC values for representatives quinolones,
`aminoglycosides, [3-lactams and other types of antibiotics
`were also determined. The results of these determinations
`are set forth in the table below:
`
`Activity of Moxifloxacin and Other Selected Antibiotics Against New Microbacterium Species
`Microbacterium otitidis
`Microbacterium alconae
`
`Isolate Number—> MCC
`Antibiotic J
`10647
`
`MCC
`10810
`
`MCC
`10990
`
`MCC
`11495
`
`MCC
`11676
`
`MCC
`11316
`
`MCC
`11558
`
`MCC
`11639
`
`MCC
`11653
`
`MCC
`11699
`
`Quinolone
`
`Ciprofloxacin
`Moxifloxacin
`Ofloxacin
`Aminoglycosides
`
`Tobramycin
`Gentamicin
`Neomycin
`B-Lactams
`
`Oxacillin
`
`32
`2.0
`16
`
`32
`8.0
`8.0
`
`2.0
`
`32
`2.0
`32
`
`32
`2.0
`8.0
`
`4.0
`4.0
`2.0
`
`4.0
`
`4.0
`4.0
`2.0
`
`2.0
`
`32
`2.0
`16
`
`4.0
`16
`8.0
`
`32
`2.0
`8.0
`
`16
`4.0
`2.0
`
`1.0
`0.25
`4.0
`
`1.0
`0.25
`4.0
`
`1.0
`0.25
`4.0
`
`2.0
`0.25
`4.0
`
`2.0
`0.25
`4.0
`
`16
`2.0
`1.0
`
`16
`2.0
`1.0
`
`16
`2.0
`1.0
`
`16
`2.0
`1.0
`
`16
`2.0
`1.0
`
`4.0
`
`2.0
`
`8.0
`
`16
`
`32
`
`32
`
`32
`
`Page 7 of 8
`
`Page 7 of 8
`
`

`
`11
`
`12
`
`US 6,440,964 B1
`
`-continued
`
`Activity of Moxifloxacin and Other Selected Antibiotics Against New Microbacterium Species
`Microbacterium otitidis
`Microbacterium alcomze
`
`Isolate Number—> MCC
`Antibiotic t
`10647
`Other Antibiotics
`
`MCC
`10810
`
`MCC
`10990
`
`MCC
`11495
`
`MCC
`11676
`
`MCC
`11316
`
`MCC
`11558
`
`MCC
`11639
`
`MCC
`11653
`
`MCC
`11699
`
`Erythromycin
`Clindamycin
`Tetracycline
`Chloramphenicol
`Polymyxin B
`
`0.03
`0.03
`1.0
`1.0
`1040
`
`0.03
`0.03
`1.0
`1.0
`260
`
`0.03
`0.03
`1.0
`1.0
`260
`
`0.03
`0.03
`1.0
`1.0
`1040
`
`0.03
`0.03
`1.0
`1.0
`16
`
`1.0
`4.0
`1.0
`16
`32.5
`
`2.0
`4.0
`1.0
`16
`32.5
`
`2.0
`4.0
`1.0
`16
`16
`
`0.50
`4.0
`1.0
`16
`16
`
`0.50
`4.0
`1.0
`16
`16
`
`The letters “MCC” in the table above stand for “Micro-
`biology Culture Collection”. The MCC numbers (e.g.,
`“MCC 10647”) represent separate clinical isolates of the two
`.
`.
`.
`.
`Microbacterium species tested. The figures set forth in the
`table are the minimum inhibitory concentrations for each
`
`20
`
`B is a selected from the group consisting of:
`
`N
`
`N
`
`compound, relative to the respective isolates of the two
`Microbacterium species, expressed as micrograms per mil-
`liliter.
`
`25
`
`R3N
`\
`
`Y,
`;
`
`H
`R4N
`\
`
`The invention has been described herein by reference to
`certain preferred embodiments. However, as obvious varia-
`tions thereon will become apparent to those skilled in the art, 30
`the invention is not to be considered as limited thereto.
`
`L
`
`Hlln...
`
`H’
`
`and
`
`H
`
`..nII|H
`
`Y
`
`H
`
`’
`
`1
`
`What is claimed is:
`.
`.
`.
`.
`.
`1. Atopical pharmaceutical composition for treating acute
`otitis externa infections or ophthalmic infections attributable
`to a Microbacterium species selected from the group con-
`sisting of Microbacterium otitidis and Microbacterium
`alcomze, comprising of one or more compounds of the 40
`following formula in an amount effective to eradicate said
`Microbacterium species:
`
`35
`
`F
`
`13
`
`X1
`
`0
`
`COOR2
`
`|
`
`N
`I
`R1
`
`(1)
`
`45
`
`50
`
`55
`
`wherein.
`Y is 0 er CH2;
`R 3
`is C 2— C 5 alk o x y 1 , C H 2— C O — C 6 H 5 ,
`C H 2 C H 2 C 0 2 R ' , R ' 0 2 C — C H= C —C 0 2 R ' ,
`h C.H=CH—CO2R‘ or CH2CH2—CN>
`w erein:
`R‘ is H or C1 to C3 alkyl;
`R4 is H, C2 to C3 alkyl, C2—C3 alkoxyl, CH2—CO—
`C6H3, CH2CH2CO2R‘, R‘O2C—CH=C—CO2R‘,
`CH=CH—CO2R‘, CH2CH2—CN or 5-methyl-2-
`oXo-1,3-dioxol-4-yl-methyl,
`wherein:
`R‘ is H or C1 to C3 alkyl; and their pharmaceutically
`useful hydrates and salts; and a pharmaceutically
`acceptable vehicle therefor.
`2. A composition according to claim 1, wherein the
`composition further comprises an effective amount of an
`antiinflammatory compound.
`3. A composition according to claim 1, wherein the
`composition comprises Moxifloxacin.
`4. A composition according to claim 3, wherein the
`composition further comprises an effective amount of an
`antiinflammatory compound.
`5. A composition according to claim 4, wherein the
`Ais CH, CF, CCl, C—OCH3, or N;
`antiinflammator
`a ent com rises dexamethasone.
`1 .
`6. A method clif t%eating acI:)ute otitis externa infections or
`X 1S H’ halogen’ NH2’ or CH3;
`60 ophthalmic infections attributable to a Microbacterium spe-
`R1 is C1 to C3 alkyl, FCH2CH2, cyclopropyl or phenyl,
`cies. selected from the group consisting of icrobacterium
`optionally mono—, di— or tri—substituted by halogen, or A
`otztidzs and Mzcrobqcterzum alcomze, which comprises
`and R1 together Can form a bridge of formula C_Q_
`instilling a therapeutically effective amount a composition
`CH2_CH(CH3).
`according to any one of claims 1 to 5 in the affected ear or
`.
`.
`2 .
`R 1S H, C1 to C3 alkyl (optionally substituted by OH, 55 eye.
`halogen or NH2), or 5-methyl-2-oxo-1,3-dioXol-4-yl-
`methyl; and
`
`wherein:
`
`Page 8 of 8
`
`*
`
`*
`
`*
`
`*
`
`*
`
`Page 8 of 8