(12) United States Patent
`Cagle et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006395746Bl
`US 6,395,746 Bl
`May 28,2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) METHODS OF TREATING OPHTHALMIC,
`OTIC AND NASAL INFECTIONS AND
`ATTENDANT INFLAMMATION
`
`(75)
`
`Inventors: Gerald Cagle; Robert L. Abshire, both
`of Fort Worth; David W. Stroman,
`Irving; John M. Yanni, Burleson, all of
`TX (US)
`
`(73) Assignee: Alcon Manufacturing, Ltd., Fort
`Worth, 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. No.:
`
`09/646,799
`
`(22) PCT Filed:
`
`Sep. 9, 1999
`
`(86) PCT No.:
`
`PCT/US99/22624
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Sep. 22, 2000
`
`(87) PCT Pub. No.: W000/18388
`
`PCT Pub. Date: Apr. 6, 2000
`
`(51)
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/102,508, filed on Sep. 30,
`1998, and provisional application No. 60/102,509, filed on
`Sep. 30, 1998.
`Int. Cl? ........................ A61K 31/44; A61K 31!58;
`A61K 31/56; A61K 31/40; A61K 31/65
`(52) U.S. Cl. ....................... 514/300; 514/174; 514/179;
`514/180; 514/181; 514/413; 514/619
`(58) Field of Search ................................. 514/300, 174,
`514/179, 180, 181, 413, 619
`
`(56)
`
`References Cited
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`Blondeau, Joseph M., A review of the comparative in-vitro
`activities of 12 antimicrobial agents, with focus on five new
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`Elies, W., "Novel fluoroquinolones in the treatment of ENT
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`Ernst et al., "Levofloxacin and trovafloxacin: The next
`generation of fluoroquinolones?", Clinical Review, Am. J.
`Health-Syst. Pharm., vol. 54, pp. 2569-2584 (114/15/97).
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`nism of action, resistance, and clinical aspects", Medicinal
`Research Reviews, vol. 16, pp. 433-486 (1996).
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`and CSF of rabbits", IOVS, vol. 40, No.4, p. S88 (Mar. 15,
`1999); XP-000892619.
`Kraseman et al., "Efficacy of Moxifloxacin against Staphy(cid:173)
`lococcus aureus in respiratory tract and skin and skin
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`structure
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`No. 4, p. S689 (Mar. 15, 1999) XP-000892625.
`NCCLS Document M7-A4, "Methods for Dilution Antimi(cid:173)
`crobial Susceptability Tests for Bacteria That Grow Aero(cid:173)
`bically", 4th Edition, 1997.
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`viously Approved Agents" Antimicrobial Agents and Che(cid:173)
`motherapy, vol. 42, No. 4, pp. 987-988 (Apr. 1, 1998);
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`NG et al., "Treatment of experimental staphylococcus epi(cid:173)
`dermidis endophthalmitis with oral trovafloxacin" American
`Journal of Ophthalmology, vol. 216 (2), pp. 278-287 (Aug.
`1998).
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`Pediatric Research, 104th Annual Meeting of the American
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`191A, Seattle, Washington (05/02-05/94).
`Tillotson, G, S., "Quinolones: structure-activity relation(cid:173)
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`vol. 44, pp. 320-324 (1996).
`Vincent et al., "Pharmacokinetics and safety of trovalfloxa(cid:173)
`cin in healthy male volunteers following administration of
`single intravenous doses of the prodrug, alatrofloxacin",
`Journal of Antimicrobial Chemotherapy, vol. 39, Suppl. B,
`pp. 75-80. (Jan. 1, 1997).
`
`(List continued on next page.)
`
`Primary Examiner-William R. A Jarvis
`(74) Attorney, Agent, or Firm-Gregg C. Brown
`
`(57)
`
`ABSTRACT
`
`Methods of treating or preventing ophthalmic, otic, and
`nasal infections and attendant inflammation are described.
`The methods utilize ophthalmic, otic, and nasal composi(cid:173)
`tions containing a new class of antibiotics (e.g.
`trovafloxacin). The compositions also contain one or more
`anti-inflammatory agents (e.g. dexamethasone). The com(cid:173)
`positions are utilized to treat ophthalmic, otic, and nasal
`conditions by topically applying the compositions to the
`affected tissues.
`
`11 Claims, No Drawings
`
`Page 1 of 7
`
`SENJU EXHIBIT 2086
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`

`
`US 6,395,746 Bl
`Page 2
`
`U.S. PATENT DOCUMENTS
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`5,912,255 A
`
`6/1999 Bussell
`
`4,844,902 A
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`4,996,335 A
`5,059,597 A
`5,149,694 A
`5,164,402 A
`5,185,337 A
`5,223,493 A
`5,416,096 A
`5,480,879 A
`5,540,930 A
`5,563,138 A
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`
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`2/1991 Petersen et a!.
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`9/1992 Cagle et a!.
`11/1992 Brighty
`2/1993 Fujii et a!.
`6/1993 Boltralik
`5/1995 Petersen et a!.
`1!1996 Petersen et a!.
`7/1996 Guy et a!.
`10/1996 Ueda et a!.
`1!1997 Bergamini et a!.
`3/1997 Petersen et a!.
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`12/1998 Grunenberg et a!.
`12/1998 Hallenbach et a!.
`
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`OTHER PUBLICATIONS
`
`Weiss, Lee R., "Therapeutic Pathways for Antimicrobial
`Use: General Overview", The American Journal Of Man(cid:173)
`aged Care, vol. 4, No. 10, Sup., pp. S543-S549 (1988).
`Wentland, Mark P., "Structure-activity relationships of fiuo(cid:173)
`roquinolones", The New Generation of Quinolones,
`(Siporin, C., Heifetz, C. L. & Domagala, J. M., Eds), pp.
`1-43, Marcel Dekker, New York (1990).
`Senturia, Ben, "Etiology Of External Otitis", Larynyoscope,
`vol. 55, pp. 277-293 (1945).
`
`Page 2 of 7
`
`

`
`US 6,395,746 Bl
`
`2
`SUMMARY OF THE INVENTION
`
`1
`METHODS OF TREATING OPHTHALMIC,
`OTIC AND NASAL INFECTIONS AND
`ATTENDANT INFLAMMATION
`
`This application is 371 of PCT/US99/22624, filed Sep.
`29, 1999, which claims priority to provisional application
`Nos. 60/102,508 and 60/102,509, both filed Sep. 30, 1998.
`
`BACKGROUND OF THE INVENTION
`The present invention is directed to the provision of 10
`topical antibiotic pharmaceutical compositions for the treat(cid:173)
`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 15
`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 rep(cid:173)
`resents the current state of the art in the field of ophthalmic 20
`pharmaceutical compositions and methods of treatment. For
`example, a topical ophthalmic composition containing .the
`quinolone ciprofloxacin is marketed by Alcon Laboratones,
`Inc. under the name CILOXAN™ (Ciprofloxacin 0.3%)
`Ophthalmic Solution. The following quinolones have also
`been utilized in ophthalmic antibiotic compositions:
`
`25
`
`Quinolone
`
`Product
`
`Manufacturer
`
`Ofloxacin
`Norfloxacin
`Lomefloxacin
`
`OCUFLOX TM
`CHIBROXIN TM
`LOMEFLOXTM
`
`Allergan
`Merck
`Senju
`
`30
`
`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 following
`5 surgery or other trauma to ophthalmic, otic or nasal tissues.
`The compositions of the present invention may also be
`administered to the affected tissues during ophthalmic, otic
`or nasal surgical procedures to prevent or alleviate post-
`surgical 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(cid:173)
`mation resulting from surgical procedures. The composi(cid:173)
`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 externa
`and otitis media. With respect to the treatment of otitis
`media, the compositions of the present invention are prima(cid:173)
`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 of the present invention are specially
`formulated for topical application to ophthalmic, otic and
`40 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-
`45 cal conditions.
`
`35
`
`The foregoing quinolone antibiotic compositions are gen(cid:173)
`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(cid:173)
`rily useful against gram negative pathogens; and bacitracin,
`gramicidin, and erythromycin, which are primarily active
`against gram positive pathogens. However, despite the gen(cid:173)
`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(cid:173)
`thalmic pathogens, and less prone to the development of
`resistance by those pathogens.
`There is an even greater need for effective topical com(cid:173)
`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 55
`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.
`Similarly, ophthalmic, otic and nasal surgical procedures 60
`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(cid:173)
`positions that combine the anti-infective activity of one or
`more antibiotics with the anti-inflammatory activity of one 65
`or more steroid or non-steroid agents in a single composi-
`tion.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The antibiotics used in the compositions and methods of
`50 the present invention have the following formula:
`
`(I)
`
`wherein
`R1 is hydrogen, a pharmaceutically acceptable cation, or
`(C1-C6) alkyl;
`Y, when taken independently, is ethyl, t-butyl, vinyl,
`cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p(cid:173)
`difluorophenyl;
`
`Page 3 of 7
`
`

`
`US 6,395,746 Bl
`
`4
`associated with ophthalmic, otic and nasal infections are
`provided in the following table:
`
`5
`
`10
`
`15
`
`Microorganism
`
`S. aureus/methicillin sensitive
`S. aureus/methicillin resistant
`S. aureus/quinolone resistant
`S. epidennidis/methicillin sensitive
`S. epidennidis/methicillin resistant
`S. pneumoniae/penicillin sensitive
`S. pneumoniae/penicillin resistant
`P. aernginosa
`H. infiuenzae!i)-lactamase positive
`H. infiuenzae!i)lactamase negative
`
`0.03
`2.0
`4.0
`0.06
`4.0
`0.25
`0.25
`2.0
`0.03
`0.03
`
`3
`W is hydrogen, F, C1, Br, C1-C4 alkyl, C1-C4 alkoxy,
`NH2 or NHCH3;
`A is CH, CF, CC1, COCH3, C-CH3, C-CN or N; or
`A is carbon and is taken together with Y and the carbon
`and nitrogen to which A and Y are attached to form a
`five or six membered ring which may contain oxygen
`or a double bond, and which may have attached thereto
`R8 which is methyl or methylene; and
`R2 is
`
`R2~0 R'N- or
`
`R7
`
`9
`
`R10
`
`wherein:
`R3, R4, R5, R6, R7, R9, R10 and R25 are each indepen(cid:173)
`dently H, CH3, CH2NH2, CH2NHCH3 or CH2NHC2H5,
`and R5, R6, R7 and R9 may also independently be NH2,
`NHCH3 or NHC2H5, provided that not more than three of
`R3, R4, R5, R6, R7, R9, R10 and R25 are other than
`hydrogen, and if three of these substituents are not
`hydrogen, at least one of them is methyl.
`The antibiotics utilized in the present invention also
`include prodrugs of the compounds of formula (I) having a
`free amino group, as well as pharmaceutically useful
`hydrates and salts of the compounds of formula (I).
`The compound Trovafloxacin is most preferred. Trova(cid:173)
`floxacin has the following structure:
`
`F
`
`0
`
`0
`
`0"
`
`N rYF
`y
`
`F
`
`All of the foregoing concentrations are expressed as micro(cid:173)
`grams per milliliter ("mcg/ml").
`The appropriate antibiotic concentration for ophthalmic
`20 compositions will generally be an amount of one or more
`antibiotics of formula (I) sufficient to provide a concentra(cid:173)
`tion in the aqueous humor and lacrimal fluid of the eye equal
`to or greater than the MI C90 level for the selected antibiotic
`25 (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
`30 infected tissues equal to or greater than the MI C90 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
`35 present invention will typically contain one or more com(cid:173)
`pounds of formula (I) in a concentration of from about 0.1
`to about 1.0 percent by weight ("wt. %") of the composi(cid:173)
`tions.
`The compositions of the present invention may also
`40 contain one or more anti-inflammatory agents. The anti(cid:173)
`inflammatory agents utilized in the present invention are
`broadly classified as steroidal or non-steroidal. The pre(cid:173)
`ferred steroidal anti-inflammatory agents are glucocorti(cid:173)
`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
`50 budesonide.
`The dexamethasone derivatives described in U.S. Pat. No.
`5,223,493 (Boltralik) are also preferred steroidal anti(cid:173)
`inflammatory agents, particularly with respect to composi(cid:173)
`tions for treating ophthalmic inflammation. The following
`compounds are especially preferred:
`
`45
`
`0
`
`o -
`
`AL-1529
`
`Further details regarding the structure, preparation, and
`physical properties of Trovafloxacin and other compounds
`of formula (I) are provided in U.S. Pat. No. 5,164,402.
`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), 55
`and the relative antimicrobial activity of the specific antibi(cid:173)
`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(cid:173)
`tration is also referred to as the "minimum inhibitory con- 60
`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 65
`concentration" or "MBC". The minimum inhibitory concen(cid:173)
`tration of Trovafloxacin for several bacteria commonly
`
`Page 4 of 7
`
`

`
`US 6,395,746 Bl
`
`5
`-continued
`
`AL-2512
`
`0
`
`10
`
`6
`prevent microbial contamination during use. Suitable pre(cid:173)
`servatives include: polyquaternium-1, benzalkonium
`chloride, thimerosal, chlorobutanol, methylparaben, propyl
`paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
`5 or other agents known to those skilled in the art. The use of
`polyquaternium-1 as the antimicrobial preservative is pre(cid:173)
`ferred. 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
`15 P-103), cyclodextrin, or other agents knoat 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 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, poly-
`vinyl 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.
`
`20
`
`These compounds are referred to herein as "21 -ether
`derivatives of dexamethasone". The 21-benzyl ether deriva(cid:173)
`tive (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; 25
`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, 30
`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(cid:173)
`lumilast; inhibitors of cytokine production, such as inhibi(cid:173)
`tors of the NFkB transcription factor; or other anti- 35
`inflammatory agents known to those skilled in the art.
`The concentrations of the anti-inflammatory agents con(cid:173)
`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 45
`about 0.01 to about 1.0 wt.%.
`The compositions are typically administered to the
`affected ophthalmic, otic or nasal tissues by topically apply(cid:173)
`ing one to four drops of a sterile solution or suspension, or
`a comparable amount of an ointment, gel or other solid or 50
`semisolid composition, one to four times per day. However,
`the compositions may also be formulated as irrigating solu(cid:173)
`tions that are applied to the affected ophthalmic, otic or nasal
`tissues during surgical procedures.
`The ophthalmic, otic, and nasal compositions of the 55
`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(cid:173)
`positions will typically have a pH in the range of 4.5 to 8.0.
`The ophthalmic compositions must also be formulated to 60
`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 products are typically pack(cid:173)
`aged in multidose form. Preservatives are thus required to
`
`40
`
`EXAMPLE 1
`
`Ophthalmic/Otic/Nasal Solution
`
`Ingredient
`
`Amount (wt. %)
`
`Trovafloxacin
`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
`
`Ingredient
`
`Amount (wt. %)
`
`Trovafloxacin
`Dexamethasone, Micronized USP
`Benzalkonium Chloride
`Edetate Disodium, USP
`Sodium Chloride, USP
`Sodium Sulfate, USP
`Tyloxapol, USP
`Hydroxyethylcellulose
`Sulfuric Acid and/or
`Sodium Hydroxide, NF
`65 Purified Water, USP
`
`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
`
`Page 5 of 7
`
`

`
`7
`EXAMPLE 3
`
`US 6,395,746 Bl
`
`R2 is
`
`8
`
`Ophthalmic Ointment
`
`Ingredient
`
`Amount (wt. %)
`
`Trovafloxacin
`Mineral Oil, USP
`White petrolatium, USP
`
`0.35
`2.0
`q.s 100
`
`R2:f;RO "'N- or
`R7
`
`R9
`
`R10
`
`5
`
`10
`
`EXAMPLE 4
`
`wherein:
`
`Ophthalmic Ointment
`
`Ingredient
`
`Amount (wt. %)
`
`Trovafloxacin
`Fluorometholone Acetate, USP
`Chlorobutanol, Anhydrous, NF
`Mineral Oil, USP
`White Petrolatum, USP
`
`0.3
`0.1
`0.5
`5
`q.s. 100
`
`15
`
`20
`
`R3, R4, RS, R6, R7, R9, R10 and R25 are each indepen(cid:173)
`dently H, CH 3 , CH 2 NH 2 , CH 2 NHCH 3 or
`CH2NHC2 H5 , and RS, R6, R7, and R9 may also
`independently be NH2 , NHCH3 or NHC2 H5 , provided
`that not more than three ofR3, R4, RS, R6, R7, R9, RlO
`and R25 are other than hydrogen, and if three of these
`substituents are not hydrogen, at least one of them is
`methyl; or
`a prodrug of a compound of formula (I) having a free
`amino group, or a pharmaceutically useful hydrate or
`salt of a compound of formula (I);
`an anti-inflammatory effective amount of a steroidal or
`non-steroidal anti-inflammatory agent; and
`a pharmaceutically acceptable vehicle therefor.
`2. A method according to claim 1, wherein the ant-
`30 inflammatory agent comprises a glucocorticoid.
`3. A topical composition according to claim 2, wherein the
`glucocorticoid is selected from the group consisting of
`dexamethasone, AL1529, AL2512, rimexolone,
`prednisolone, fluorometholone, hydrocortisone,
`35 mometasone, fluticasone, beclomethasone, flunisolide, tri(cid:173)
`amcinolone and budesonide.
`4. A topical composition according to claim 1, wherein the
`anti-inflammatory agent comprises a non-steroidal agent
`selected from the group consisting of prostaglandin H syn-
`40 thetase inhibitors, PAF antagonists, and PDE IV inhibitors.
`5. A method according to claim 1, wherein the compound
`of formula (I) comprises trovafloxacin.
`6. A method according to any one of claim 2, 3, or 4, or
`wherein the compound of formula (I) comprises trovafloxa-
`em.
`7. A method according to any one of claim 1, 2, 3, 4, or
`5, or wherein the composition is topically applied to the eye
`to treat ophthalmic infections and attendant inflammation.
`8. A method according to any one of claim 1, 2, 3, 4, or
`50 5, wherein the composition is topically instilled in the ear to
`treat otic infections and attendant inflammation.
`9. A method of claim 1 or claim 5, wherein the anti(cid:173)
`inflammatory agent comprises dexamethasone.
`10. A method according to claim 1 or claim 5, wherein the
`55 anti-inflammatory agent comprises nepafenac.
`11. A method according to claim 1 or claim 5, wherein the
`anti-inflammatory agent comprises ketoralac.
`
`The invention has been described herein by reference to 25
`certain preferred embodiments. However, as obvious varia(cid:173)
`tions thereon will become apparent to those skilled in the art,
`the invention is not to be considered as limited thereto.
`What is claimed is:
`1. A method of treating or preventing ophthalmic, otic or
`nasal infections and attendant inflammation, which com(cid:173)
`prises topically applying a therapeutically effective amount
`of a topical ophthalmic, otic or nasal pharmaceutical com(cid:173)
`position to the affected tissues, said composition comprising
`one or more compounds of the formula:
`
`(I)
`
`wherein
`R1 is hydrogen, a pharmaceutically acceptable cation, or
`(C1-C6) alkyl;
`Y, when taken independently, is ethyl, t-butyl, vinyl,
`cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p(cid:173)
`difluorophenyl;
`W is hydrogen, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy,
`NH2 or NHCH3 ;
`A is CH, CF, CCl, COCH3 , C-CH3 , C-CN or N; or
`A is carbon and is taken together with Y and the carbon
`and nitrogen to which A and Y are attached to form a
`five or six membered ring which may contain oxygen
`or a double bond, and which may have attached thereto
`R8 which is methyl or methylene; and
`
`45
`
`* * * * *
`
`Page 6 of 7
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`INVENTOR(S)
`
`: 6,395,746 B1
`: May 28, 2002
`: Gerald Cagle et al.
`
`Page 1 of 1
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is
`hereby corrected as shown below:
`
`Title page,
`Item [22], should read-- PCT Filed: Sep. 29, 1999 --
`
`Signed and Sealed this
`
`Fifteenth Day of April, 2003
`
`JAMES E. ROGAN
`Director of the United States Patent and Trademark Office
`
`Page 7 of 7