SENJU EXHIBIT 2086
`LUPIN v SENJU
`IPR2015-01105
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`PAGE 1 OF 7
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`US 6,395,746 B1
`Page 2
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`6/1999 Bussell
`5,912,255 A
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`FOREIGN PATENT DOCUMENTS
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`WO 98/06435
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`W0 99/15172
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`WO 00/18386
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`W0 00/18387
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`WO 00/18388
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`WO 00/18404
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`2/1998
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`4/1999
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`4/2000
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`4/2000
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`4/2000
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`4/2000
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`OTHER PUBLICATIONS
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`Werss, Lee R., Therapeutrc Pathways for Ant1m1cr0b1al
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`Use: General OVerV1eW”, The Amerzcan Journal Of Man-
`aged Care, V01. 4, N0. 10, Sup., pp. S543—S549 (1988).
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`Wentland, Mark P., “Structure—actiVity relationships of fluo-
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`roquinolones”, The New Generation of Quinolones,
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`(S1p0r1n, C., Herfetz, C. L. & Domagala, J. M., Eds), pp.
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`1-43, Marcel Dekker, New York (1990).
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`Senturra, Ben, “Et10l0gy Of External Ot1t1s”, Larynyoscope,
`Vol. 55, pp. 277-293 (1945).
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`U.S. PATENT DOCUMENTS
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`7/1989 Gfohe
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`4/1990 Domagala et 211.
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`12/1990 Masuzawa et al.
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`2/1991 Petersen et 211.
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`2/1991 Bodor
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`10/1991 Petersen et 211.
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`9/1992 Cagle et al.
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`11/1992 Brighty
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`2/1993 Fujiietal.
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`6/1993 Boltralik
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`5/1995 Petersen et al.
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`1/1996 Petersen et al.
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`7/1996 Guy et a1.
`10/1996 Ueda et a1.
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`1/1997 Befgamini ‘*4 a1~
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`3/1997 Petersen et 31-
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`E:%1;t:):1;)/t al
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`10/1997 Bergamrnr et al.
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`12/1993 Gnmenberg et a1.
`12/1998 Hallenbach et 211.
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`4,844,902 A
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`4,920,120 A
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`4,980,470 A
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`4,990,517 A
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`4,996,335 A
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`5,059,597 A
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`5,149,694 A
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`5,164,402 A
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`5,185,337 A
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`5,223,493 A
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`5,416,096 A
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`5,480,879 A
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`5,540,930 A
`5,563,138 A
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`595979560 A
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`5509942 A
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`2
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`5,679,665 A
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`5,349,752 A
`5,854,241 A
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`PAGE 2 OF 7
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`PAGE 2 OF 7
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`US 6,395,746 B1
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`2
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`SUMMARY OF THE INVENTION
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`The invention is based on the use of a potent new class of
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`antibiotics to treat ophthalmic, otic and nasal infections, as
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`well as the prophylactic use of these antibiotics following
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`surgery or other trauma to ophthalmic, otic or nasal tissues.
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`The compositions of the present
`invention may also be
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`administered to the affected tissues during ophthalmic, otic
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`or nasal surgical procedures to prevent or alleviate post-
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`surgical infections.
`The compositions preferably also contain one or more
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`anti-inflammatory agents to treat inflammation associated
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`with infections of ophthalmic, otic or nasal tissues. The
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`anti-inflammatory component of the compositions is also
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`in treating inflammation associated with physical
`useful
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`trauma to ophthalmic, otic or nasal tissues, including inflam-
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`mation resulting from surgical procedures. The composi-
`tions of the present
`invention are therefore particularly
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`useful in treating inflammation associated with trauma to
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`ophthalmic, otic or nasal tissues wherein there is either an
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`infection or a risk of an infection resulting from the trauma.
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`Examples of ophthalmic conditions that may be treated
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`with the compositions of the present
`invention include
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`conjunctivitis, keratitis, blepharitis, dacyrocystitis,
`hordeolum and corneal ulcers. The compositions of the
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`invention may also be used prophylactically in connection
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`with various ophthalmic surgical procedures that create a
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`risk of infection.
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`Examples of otic conditions that may be treated with the
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`compositions of the present invention include otitis externa
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`and otitis media. With respect to the treatment of otitis
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`media, the compositions of the present invention are prima-
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`rily useful
`in cases where the tympanic membrane has
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`ruptured or tympanostomy tubes have been implanted. The
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`compositions may also be used to treat infections associated
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`with otic surgical procedures, such as tympanostomy, or to
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`prevent such infections.
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`The compositions of the present invention are specially
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`formulated for topical application to ophthalmic, otic and
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`nasal tissues. The compositions are preferably sterile, and
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`have physical properties (e.g., osmolality and pH) that are
`specially suited for application to ophthalmic, otic and nasal
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`tissues, including tissues that have been compromised as the
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`result of preexisting disease, trauma, surgery or other physi-
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`cal conditions.
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`DETAILED DESCRIPTION OF THE
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`INVENTION
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`The antibiotics used in the compositions and methods of
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`the present invention have the following formula:
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`W
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`O
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`(1)
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`COR
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`1
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`2
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`| N
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`A
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`TY
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`F
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`R2
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`wherein
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`R1 is hydrogen, a pharmaceutically acceptable cation, or
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`(C1-C6) alkyl;
`t-butyl, vinyl,
`is ethyl,
`Y, when taken independently,
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`cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p-
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`difluorophenyl;
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`1
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`METHODS OF TREATING OPHTHALMIC,
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`OTIC AND NASAL INFECTIONS AND
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`ATTENDANT INFLAMMATION
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`This application is 371 of PCT/US99/22624, filed Sep.
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`29, 1999, which claims priority to provisional application
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`Nos. 60/102,508 and 60/102,509, both filed Sep. 30, 1998.
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`BACKGROUND OF THE INVENTION
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`invention is directed to the provision of
`The present
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`topical antibiotic pharmaceutical compositions for the treat-
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`ment of ophthalmic, otic and nasal infections, particularly
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`bacterial infections, and to methods of treating ophthalmic,
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`otic and nasal infections by applying those compositions to
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`the affected tissues. The compositions and methods of the
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`invention are based on the use of a new class of antibiotics.
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`The compositions of the present invention may also contain
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`one or more anti-inflammatory agents.
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`The use of quinolone antibiotics to treat infections rep-
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`resents the current state of the art in the field of ophthalmic
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`pharmaceutical compositions and methods of treatment. For
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`example, a topical ophthalmic composition containing the
`quinolone ciprofloxacin is marketed by Alcon Laboratories,
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`Inc. under the name CILOXANTM (Ciprofloxacin 0.3%)
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`Ophthalmic Solution. The following quinolones have also
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`been utilized in ophthalmic antibiotic compositions:
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`Quinolone
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`Ofloxacin
`Norfloxacin
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`Lomefloxacin
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`Product
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`OCUFLOX TM
`CHIBROXIN TM
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`LOMEFLOX TM
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`Manufacturer
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`Allergan
`Merck
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`Senju
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`The foregoing quinolone antibiotic compositions are gen-
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`erally effective in treating ophthalmic infections, and have
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`distinct advantages over prior ophthalmic antibiotic
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`compositions, particularly those having relatively limited
`spectrums of antimicrobial activity, such as: neomycin,
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`polymyxin B, gentamicin and tobramycin, which are prima-
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`rily useful against gram negative pathogens; and bacitracin,
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`gramicidin, and erythromycin, which are primarily active
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`against gram positive pathogens. However, despite the gen-
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`eral efficacy of the ophthalmic quinolone therapies currently
`available, there is a need for improved compositions and
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`methods of treatment based on the use of antibiotics that are
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`more effective than existing antibiotics against key oph-
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`thalmic pathogens, and less prone to the development of
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`resistance by those pathogens.
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`There is an even greater need for effective topical com-
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`positions and methods for treating otic and nasal infections,
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`particularly bacterial infections. The use of oral antibiotics
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`to treat otic infections in children has limited efficacy, and
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`creates a serious risk of pathogen resistance to the orally
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`administered antibiotics.
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`infections are frequently
`Ophthalmic, otic and nasal
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`accompanied by inflammation of the infected ophthalmic,
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`otic and nasal tissues and perhaps even surrounding tissues.
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`Similarly, ophthalmic, otic and nasal surgical procedures
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`that create a risk of microbial infections frequently also
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`cause inflammation of the affected tissues. Thus, there is also
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`a need for ophthalmic, otic and nasal pharmaceutical com-
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`positions that combine the anti-infective activity of one or
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`more antibiotics with the anti-inflammatory activity of one
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`or more steroid or non-steroid agents in a single composi-
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`tion.
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`PAGE 3 OF 7
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`PAGE 3 OF 7
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`

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`US 6,395,746 B1
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`4
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`associated with ophthalmic, otic and nasal infections are
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`provided in the following table:
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`3
`W is hydrogen, F, C1, Br, C1-C4 alkyl, C1-C4 alkoxy,
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`NH2 or NHCH3;
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`A is CH, CF, CC1, COCH3, C—CH3, C—CN or N; or
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`A is carbon and is taken together with Y and the carbon
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`and nitrogen to which A and Y are attached to form a
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`five or six membered ring which may contain oxygen
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`or a double bond, and which may have attached thereto
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`R8 which is methyl or methylene; and
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`R2 is
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`R25
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`R7
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`R3
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`R6
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`N? or
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`R9
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`R10
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`R25
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`R7
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`R4
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`R6
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`N
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`R3
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`R9
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`R5
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`wherein:
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`R3, R4, R5, R6, R7, R9, R10 and R25 are each indepen-
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`dently H, CH3, CH2NH2, CH2NHCH3 or CH2NHC2H5,
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`and R5, R6, R7 and R9 may also independently be NH2,
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`NHCH3 or NHC2H5, provided that not more than three of
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`R3, R4, R5, R6, R7, R9, R10 and R25 are other than
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`hydrogen, and if three of these substituents are not
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`hydrogen, at least one of them is methyl.
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`invention also
`The antibiotics utilized in the present
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`include prodrugs of the compounds of formula (I) having a
`free amino group, as well as pharmaceutically useful
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`hydrates and salts of the compounds of formula
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`The compound Trovafloxacin is most preferred. Trova-
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`floxacin has the following structure:
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`H
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`F
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`N
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`NH2
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`H
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`\
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`/
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`N
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`0
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`O
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`On
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`F
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`N
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`F
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`10
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`20
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`25
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`30
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`35
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`40
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`45
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`Further details regarding the structure, preparation, and
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`physical properties of Trovafloxacin and other compounds
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`of formula (I) are provided in U.S. Pat. No. 5,164,402.
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`The concentrations of the antibiotics of formula (I) in the
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`compositions of the present invention will vary depending
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`on the intended use of the compositions (e.g., treatment of
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`existing infections or prevention of post-surgical infections),
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`and the relative antimicrobial activity of the specific antibi-
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`otic selected. The antimicrobial activity of antibiotics is
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`generally expressed as the minimum concentration required
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`to inhibit the growth of a specified pathogen. This concen-
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`tration is also referred to as the “minimum inhibitory con-
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`centration” or “MIC”. The term “MIC90” refers to the
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`minimum concentration of antibiotic required to inhibit the
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`growth of ninety percent (90%) of the strains of a species.
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`The concentration of an antibiotic required to totally kill a
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`specified bacteria is referred to as the “minimum bactericidal
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`concentration” or “MBC”. The minimum inhibitory concen-
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`tration of Trovafloxacin for several bacteria commonly
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`50
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`PAGE 4 OF 7
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`Microorganism
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`S. aureus/methicillin sensitive
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`S. aureus/methicillin resistant
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`S. aureus/quinolone resistant
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`S. epidermidis/methicillin sensitive
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`S. epidermidis/methicillin resistant
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`S. pneumoniae/penicillin sensitive
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`S. pneumoniae/penicillin resistant
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`R aemginosa
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`H. influenzae/[5-lactamase positive
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`H. influenzae/[filactamase negative
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`MIC90
`0.03
`2.0
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`4.0
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`0.06
`4.0
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`0.25
`0.25
`2.0
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`0.03
`0.03
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`All of the foregoing concentrations are expressed as micro-
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`
`
`
`
`
`
`grams 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 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
`
`
`
`
`
`
`
`
`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,
`fiuorometholone, and hydrocortisone. The
`
`
`
`
`
`preferred glucocorticoids for nasal use include mometasone,
`
`
`
`
`
`
`
`fluticasone, beclomethasone, fiunisolide, 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
`
`
`
`
`
`PAGE 4 OF 7
`
`

`
`
`
`US 6,395,746 B1
`
`
`6
`prevent microbial contamination during use. Suitable pre-
`
`
`
`
`
`
`
`servatives include: polyquaternium-1, 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-1 as the antimicrobial preservative is pre-
`
`
`
`
`
`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
`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.
`
`
`
`
`
`EXAMPLE 1
`
`
`Ophthalmic/Otic/Nasal Solution
`
`
`Ingredient
`
`Trovafloxacin
`Sodium Acetate
`
`Acetic Acid
`
`Mannitol
`
`EDTA
`
`Benzalkonium Chloride
`
`
`Water
`
`
`
`
`
`
`
`
`
`EXAMPLE 2
`
`
`
`
`
`Amount (wt. %)
`
`
`0.35
`0.03
`
`0.04
`
`4.60
`
`0.05
`
`0.006
`
`
`q.s. 100
`
`
`
`Ophthalmic/Otic/Nasal Suspension
`
`
`
`
`Ingredient
`
`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
`
`
`Purified Water, USP
`
`
`
`
`
`
`
`
`
`Amount (wt. %)
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`
`
`15
`
`
`
`20
`
`
`
`25
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`45
`
`
`
`50
`
`
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`5
`
`-continued
`
`
`
`O
`
`
`O
`
`
`
`AL-2512
`
`
`
`
`0
`
`
`
`These compounds are referred to herein as “21 -ether
`
`
`
`
`
`
`
`
`derivatives of dexamethasone”. The 21-benzyl ether deriva-
`
`
`
`
`
`
`
`
`
`
`
`
`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;
`
`
`
`
`
`
`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-
`
`
`
`
`
`
`
`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 products are typically pack-
`
`
`
`
`
`
`
`
`aged in multidose form. Preservatives are thus required to
`
`
`
`
`
`
`
`
`PAGE 5 OF 7
`
`PAGE 5 OF 7
`
`

`
`7
`
`EXAMPLE 3
`
`
`Ophthalmic Ointment
`
`
`Ingredient
`
`Trovafloxacin
`
`Mineral Oil, USP
`
`
`
`White petrolatium, USP
`
`
`
`
`
`
`Amount (wt. %)
`
`
`0.35
`
`2.0
`
`q.s 100
`
`
`
`
`
`
`US 6,395,746 B1
`
`R2 is
`
`
`R25
`
`
`
`R7
`
`
`
`
`
`10
`
`
`
`15
`
`
`
`20
`
`25
`
`
`
`30
`
`35
`
`
`
`40
`
`45
`
`
`
`50
`
`55
`
`
`
`EXAMPLE 4
`
`
`Ophthalmic Ointment
`
`
`
`
`Ingredient
`
`Trovafloxacin
`
`Fluorometholone Acetate, USP
`
`
`
`Chlorobutanol, Anhydrous, NF
`
`
`Mineral Oil, USP
`
`
`
`White Petrolatum, USP
`
`
`
`
`Amount (wt. %)
`
`
`
`0.3
`
`0.1
`
`0.5
`
`5
`
`q.s. 100
`
`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,
`
`
`
`
`
`
`
`
`
`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-
`
`
`
`
`
`
`
`prises topically applying a therapeutically effective amount
`
`
`
`
`
`
`of a topical ophthalmic, otic or nasal pharmaceutical com-
`
`
`
`
`
`
`
`
`position to the affected tissues, said composition comprising
`
`
`
`
`
`
`
`one or more compounds of the formula:
`
`
`
`
`
`
`W
`
`
`
`O
`
`
`(1)
`
`
`COR
`
`
`
`1
`
`2
`
`
`| \
`|
`1
`
`
`A
`
`TY
`
`
`
`F
`
`
`
`
`R2
`
`wherein
`
`
`R1 is hydrogen, a pharmaceutically acceptable cation, or
`
`
`
`
`
`
`
`(C1-C6) alkyl;
`t-butyl, vinyl,
`is ethyl,
`Y, when taken independently,
`
`
`
`
`
`
`
`
`cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p-
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`PAGE 6 OF 7
`
`R3
`
`
`
`R6
`
`
`
`N? or
`
`
`R9
`
`
`
`R10
`
`
`
`R25
`
`
`
`R7
`
`
`
`R4
`
`
`
`R6
`
`
`
`N
`
`
`
`R3
`
`
`
`R9
`
`
`
`R5
`
`
`
`
`
`wherein:
`
`
`R3, R4, R5, R6, R7, R9, R10 and R25 are each indepen-
`
`
`
`
`
`
`
`
`
`
`
`dently H, CH3, CH2NH2, CHZNHCH3 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; 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-
`
`
`
`
`
`
`
`
`
`inflammatory agent comprises a glucocorticoid.
`
`
`
`
`3. Atopical composition according to claim 2, wherein the
`
`
`
`
`
`
`
`glucocorticoid is selected from the group consisting of
`
`
`
`
`
`
`
`
`dexamethasone, AL1529, AL25 12,
`rimexolone,
`
`
`
`
`
`
`
`prednisolone,
`fluorometholone, hydrocortisone,
`mometasone, fluticasone, beclomethasone, flunisolide, tri-
`
`
`
`
`
`amcinolone and budesonide.
`
`
`
`4. Atopical composition according to claim 1, wherein the
`
`
`
`
`
`
`
`anti-inflammatory agent comprises a non-steroidal agent
`
`
`
`
`
`selected from the group consisting of prostaglandin H syn-
`
`
`
`
`
`
`thetase inhibitors, PAF antagonists, and PDE IV inhibitors.
`
`
`
`
`
`
`
`5. Amethod 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
`
`
`
`
`
`
`
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`wherein the compound of formula (I) comprises trovafloXa-
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`7. A method according to any one of claim 1, 2, 3, 4, or
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`5, or wherein the composition is topically applied to the eye
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`to treat ophthalmic infections and attendant inflammation.
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`8. A method according to any one of claim 1, 2, 3, 4, or
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`5, wherein the composition is topically instilled in the ear to
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`treat otic infections and attendant inflammation.
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`9. A method of claim 1 or claim 5, wherein the anti-
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`inflammatory agent comprises dexamethasone.
`10. A method according to claim 1 or claim 5, wherein the
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`anti-inflammatory agent comprises nepafenac.
`11. Amethod according to claim 1 or claim 5, wherein the
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`anti-inflammatory agent comprises ketoralac.
`*
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`PAGE 6 OF 7
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`

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