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`Cagle et al.
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`(10) Patent N0.:
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`(45) Date of Patent:
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`US006395746B1
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`
`
`US 6,395,746 B1
`
`
`May 28, 2002
`
`Ernst et al., “Levofloxacin and trovafloxacin: The next
`
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`
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`generation of fluoroquinolones?”, Clinical Review, Am. J.
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`Gootz et al., “Fluoroquinolone antibacterials: SAR mecha-
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`nism of action, resistance, and clinical aspects”, Medicinal
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`Research Reviews, vol. 16, pp. 433-486 (1996).
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`Kaw et al., “The penetration of trovafloxacin into the eye
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`and CSF of rabbits”, IOVS, vol. 40, No. 4, p. S88 (Mar. 15,
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`1999); XP-000892619.
`Kraseman et al., “Efficacy of Moxifloxacin against Staphy-
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`
`lococcus aureus in respiratory tract and skin and skin
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`
`structure infections”, Jornal of Antimicrobial Chemo-
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`therapy, vol. 44, No. Suppl. A, pp. 150 (Jul. 1999);
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`XP000892776.
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`McLeod et al., “The effect of topical trovafloxacin in a rabbit
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`streptococcus pneumoniae keratitis model”, IOVS vol. 40,
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`No. 4, p. S689 (Mar. 15, 1999) XP-000892625.
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`NCCLS Document M7-A4, “Methods for Dilution Antimi-
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`
`crobial Susceptability Tests for Bacteria That Grow Aero-
`
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`
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`
`
`bically”, 4th Edition, 1997.
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`
`“New Antimicrobial Agents Approved by the U.S. Food and
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`
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`Drug Administration in 1997 and New Indications for Pre-
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`
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`
`
`
`
`
`
`
`viously Approved Agents” Antimicrobial Agents and Che-
`
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`motherapy, vol. 42, No. 4, pp. 987-988 (Apr. 1, 1998);
`XP000872060.
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`NG et al., “Treatment of experimental staphylococcus epi-
`
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`dermidis endophthalmitis with oral trovafloxacin”American
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`
`Journal of Ophthalmology, vol. 216 (2), pp. 278-287 (Aug.
`1998).
`Patent Abstracts of Japan, vol. 1998, No. 10 (Aug. 31, 1998),
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`
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`
`JP 10 130148 May 19, 1998 abstract.
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`
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`Patent Abstracts of Japan, vol. 012, No. 472 (Dec. 9, 1988),
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`JP 63 190826 Aug. 8, 1988 abstract.
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`Pediatric Research, 104th Annual Meeting of the American
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`Pediatric Society and the 63rd Annual meeting of the
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`Society for Pediatric Research, vol. 35, No. 4, Part 2, p.
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`191A, Seattle, Washington (05/02-05/94).
`Tillotson, G, S., “Quinolones: structure-activity relation-
`
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`ships and future predictions”, J. of Medical Microbiology,
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`vol. 44, pp. 320-324 (1996).
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`
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`single intravenous doses of the prodrug, alatrofloxacin”,
`
`
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`
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`
`Journal ofAntimicrobial Chemotherapy, vol. 39, Suppl. B,
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`
`
`
`
`pp. 75-80. (Jan. 1, 1997).
`
`
`
`
`
`(List continued on next page.)
`
`
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`
`Primary Examiner—William R. A. Jarvis
`
`
`
`(74) Attorney, Agent, or Firm—Gregg C. Brown
`
`
`
`
`
`
`ABSTRACT
`
`(57)
`
`
`
`
`
`Methods of treating or preventing ophthalmic, otic, and
`
`
`
`
`
`
`
`nasal infections and attendant inflammation are described.
`
`
`
`
`
`
`
`The methods utilize ophthalmic, otic, and nasal composi-
`
`
`
`
`
`
`
`
`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-
`
`
`
`
`
`
`positions are utilized to treat ophthalmic, otic, and nasal
`
`
`
`
`
`
`
`
`
`conditions by topically applying the compositions to the
`
`
`
`
`
`
`
`affected tissues.
`
`
`
`11 Claims, N0 Drawings
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`
`
`
`
`SENJU EXHIBIT 2086
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`LUPIN V. SENJU
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`IPR2015-01100
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`(54) METHODS OF TREATING OPHTHALMIC,
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`
`OTIC AND NASAL INFECTIONS AND
`
`
`
`
`
`ATTENDANT INFLAMMATION
`
`
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`
`(75)
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`
`Inventors: Gerald Cagle; Robert L. Abshire, both
`
`
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`of Fort Worth; David W. Stroman,
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`Irving; John M. Yanni, Burleson, all of
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`TX (US)
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`(73) Assignee: Alcon Manufacturing, Ltd., Fort
`Worth, TX (US)
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`( * ) Notice:
`
`
`
`
`
`
`(21) Appl. No.:
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`(22) PCT Filed:
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`Subject to any disclaimer, the term of this
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`patent is extended or adjusted under 35
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`
`
`U.S.C. 154(b) by 0 days.
`
`09/646,799
`
`Sep. 9, 1999
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`
`
`PCT/US99/22624
`
`
`(86) PCT No.:
`
`
`
`§ 371 (C)(1),
`
`
`
`
`
`
`
`
`
`Sep. 22, 2000
`(2), (4) Date:
`(87) PCT Pub. No.: WO00/18388
`
`
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`
`PCT Pub. Date: Apr. 6, 2000
`
`
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`(60)
`
`
`
`(51)
`
`
`
`Related U.S. Application Data
`
`
`
`
`Provisional application No. 60/102,508, filed on Sep. 30,
`
`
`
`
`
`
`
`
`1998, and provisional application No. 60/102,509, filed on
`
`
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`Sep. 30, 1998.
`
`
`
`Int. Cl.7 ...................... .. A61K 31/44; A61K 31/58;
`
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`A61K 31/56; A61K 31/40; A61K 31/65
`
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`..................... .. 514/300; 514/174; 514/179;
`
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`514/180; 514/181; 514/413; 514/619
`
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`
`
`(58) Field of Search ............................... .. 514/300, 174,
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`514/179, 180, 181, 413, 619
`
`
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`
`
`
`(52) U.S. Cl.
`
`
`
`(56)
`
`
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`SENJU EXHIBIT 2086
`LUPIN v. SENJU
`IPR2015-01100
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`
`
`US 6,395,746 B1
`Page 2
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`
`6/1999 Bussell
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`Werss, Lee R., Therapeutrc Pathways for Ant1m1cr0b1al
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`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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`
`
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`(S1p0r1n, C., Herfetz, C. L. & Domagala, J. M., Eds), pp.
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`
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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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`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.
`
`
`
`2/1991 Bodor
`
`
`10/1991 Petersen et 211.
`
`
`9/1992 Cagle et al.
`
`
`
`11/1992 Brighty
`
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`2/1993 Fujiietal.
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`
`
`6/1993 Boltralik
`
`
`5/1995 Petersen et al.
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`
`
`
`
`1/1996 Petersen et al.
`
`
`
`7/1996 Guy et a1.
`10/1996 Ueda et a1.
`
`
`
`
`
`
`1/1997 Befgamini ‘*4 a1~
`
`
`
`3/1997 Petersen et 31-
`
`
`
`E:%1;t:):1;)/t al
`
`
`
`’
`.
`.
`10/1997 Bergamrnr et al.
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`
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`
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`
`12/1993 Gnmenberg et a1.
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`
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`
`4,920,120 A
`
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`4,990,517 A
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`4,996,335 A
`
`5,059,597 A
`
`5,149,694 A
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`
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`
`5,480,879 A
`
`5,540,930 A
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`
`
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`
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`2
`
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`
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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
`
`2
`
`SUMMARY OF THE INVENTION
`
`
`
`
`
`The invention is based on the use of a potent new class of
`
`
`
`
`
`
`
`
`antibiotics to treat ophthalmic, otic and nasal infections, as
`
`
`
`
`
`
`
`
`well as the prophylactic use of these antibiotics following
`
`
`
`
`
`
`
`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
`
`
`
`
`
`in treating inflammation associated with physical
`useful
`
`
`
`
`
`
`
`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 externa
`
`
`
`
`
`
`
`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 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.
`
`
`DETAILED DESCRIPTION OF THE
`
`
`INVENTION
`
`
`The antibiotics used in the compositions and methods of
`
`
`
`
`
`
`
`the present invention have the following formula:
`
`
`
`
`
`
`
`
`
`
`W
`
`
`
`O
`
`
`
`(1)
`
`
`
`COR
`
`
`
`1
`
`2
`
`
`| N
`|
`/
`
`
`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;
`
`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
`
`
`
`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.
`
`
`
`
`The use of quinolone antibiotics to treat infections rep-
`
`
`
`
`
`
`
`
`resents the current state of the art in the field of ophthalmic
`
`
`
`
`
`
`
`
`
`pharmaceutical compositions and methods of treatment. For
`
`
`
`
`
`
`
`
`
`
`
`
`example, a topical ophthalmic composition containing the
`quinolone ciprofloxacin is marketed by Alcon Laboratories,
`
`
`
`
`
`Inc. under the name CILOXANTM (Ciprofloxacin 0.3%)
`
`
`
`
`
`
`
`Ophthalmic Solution. The following quinolones have also
`
`
`
`
`
`
`
`been utilized in ophthalmic antibiotic compositions:
`
`
`
`
`
`
`Quinolone
`
`
`Ofloxacin
`Norfloxacin
`
`
`Lomefloxacin
`
`
`Product
`
`
`OCUFLOX TM
`CHIBROXIN TM
`
`
`LOMEFLOX TM
`
`
`Manufacturer
`
`
`Allergan
`Merck
`
`
`Senju
`
`
`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.
`
`
`infections are frequently
`Ophthalmic, otic and nasal
`
`
`
`
`
`
`
`accompanied by inflammation of the infected ophthalmic,
`
`
`
`
`
`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.
`
`
`5
`
`10
`
`
`
`15
`
`
`
`20
`
`
`
`25
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`
`
`45
`
`
`
`50
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`Page 3 of 7
`
`Page 3 of 7
`
`
`
`
`
`US 6,395,746 B1
`
`4
`
`associated with ophthalmic, otic and nasal infections are
`
`
`
`
`
`
`
`provided in the following table:
`
`
`
`
`
`
`
`
`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
`
`
`R25
`
`
`R7
`
`
`
`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, 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.
`
`
`
`
`
`invention also
`The antibiotics utilized in the present
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`The compound Trovafloxacin is most preferred. Trova-
`
`
`
`
`
`
`floxacin has the following structure:
`
`
`
`
`
`
`H
`
`
`
`F
`
`
`
`N
`
`
`
`NH2
`
`
`
`H
`
`
`
`\
`
`/
`
`
`N
`
`
`
`0
`
`
`
`O
`
`
`On
`
`F
`
`
`N
`
`
`
`F
`
`
`
`10
`
`
`
`
`
`20
`
`
`
`25
`
`
`
`30
`
`
`
`35
`
`
`
`40
`
`45
`
`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),
`
`
`
`
`
`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 Trovafloxacin for several bacteria commonly
`
`
`
`
`
`
`
`
`50
`
`
`
`55
`
`
`
`60
`
`
`
`65
`
`
`
`Page 4 of 7
`
`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/[filactamase negative
`
`
`
`
`
`
`
`
`MIC90
`0.03
`2.0
`
`4.0
`
`0.06
`4.0
`
`0.25
`0.25
`2.0
`
`0.03
`0.03
`
`
`
`
`
`
`
`
`
`All of the foregoing concentrations are expressed as micro-
`
`
`
`
`
`
`
`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-
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`tors of the NFkB transcription factor; or other anti-
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`inflammatory agents known to those skilled in the art.
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`The concentrations of the anti-inflammatory agents con-
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`tained in the compositions of the present invention will vary
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`based on the agent or agents selected and the type of
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`inflammation being treated. The concentrations will be suf-
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`ficient to reduce inflammation in the targeted ophthalmic,
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`otic or nasal tissues following topical application of the
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`compositions to those tissues. Such an amount is referred to
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`herein as “an anti-inflammatory effective amount”. The
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`compositions of the present invention will typically contain
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`one or more anti-inflammatory agents in an amount of from
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`about 0.01 to about 1.0 wt.%.
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`The compositions are typically administered to the
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`affected ophthalmic, otic or nasal tissues by topically apply-
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`ing one to four drops of a sterile solution or suspension, or
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`a comparable amount of an ointment, gel or other solid or
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`semisolid composition, one to four times per day. However,
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`the compositions may also be formulated as irrigating solu-
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`tions that are applied to the affected ophthalmic, otic or nasal
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`tissues during surgical procedures.
`The ophthalmic, otic, and nasal compositions of the
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`present invention will contain one or more compounds of
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`formula (I) and preferably one or more anti-inflammatory
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`agents, in pharmaceutically acceptable vehicles. The com-
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`positions will typically have a pH in the range of 4.5 to 8.0.
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`The ophthalmic compositions must also be formulated to
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`have osmotic values that are compatible with the aqueous
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`humor of the eye and ophthalmic tissues. Such osmotic
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`values will generally be in the range of from about 200 to
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`about 400 milliosmoles per kilogram of water (“mOsm/kg”),
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`but will preferably be about 300 mOsm/kg.
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`Ophthalmic, otic, and nasal products are typically pack-
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`aged in multidose form. Preservatives are thus required to
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`Page 5 of 7
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`Page 5 of 7
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`7
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`EXAMPLE 3
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`Ophthalmic Ointment
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`Ingredient
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`Trovafloxacin
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`Mineral Oil, USP
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`White petrolatium, USP
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`Amount (wt. %)
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`0.35
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`2.0
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`q.s 100
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`US 6,395,746 B1
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`R2 is
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`R25
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`R7
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`10
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`15
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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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`50
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`55
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`EXAMPLE 4
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`Ophthalmic Ointment
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`Ingredient
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`Trovafloxacin
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`Fluorometholone Acetate, USP
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`Chlorobutanol, Anhydrous, NF
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`Mineral Oil, USP
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`White Petrolatum, USP
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`Amount (wt. %)
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`0.3
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`0.1
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`0.5
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`5
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`q.s. 100
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`The invention has been described herein by reference to
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`certain preferred embodiments. However, as obvious varia-
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`tions thereon will become apparent to those skilled in the art,
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`the invention is not to be considered as limited thereto.
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`What is claimed is:
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`1. A method of treating or preventing ophthalmic, otic or
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`nasal infections and attendant inflammation, which com-
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`prises topically applying a therapeutically effective amount
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`of a topical ophthalmic, otic or nasal pharmaceutical com-
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`position to the affected tissues, said composition comprising
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`one or more compounds of the 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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`| \
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`1
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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;
`W is hydrogen, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy,
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`NH2 or NHCH3;
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`A is CH, CF, CCl, 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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`Page 6 of 7
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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, CHZNHCH3 or
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`CH2NHC2H5, and R5, R6, R7, and R9 may also
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`independently be NH2, NHCH3 or NHC2H5, provided
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`that not more than three of R3, R4, R5, R6, R7, R9, R10
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`and R25 are other than hydrogen, and if three of these
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`substituents are not hydrogen, at least one of them is
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`methyl; or
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`a prodrug of a compound of formula (I) having a free
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`amino group, or a pharmaceutically useful hydrate or
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`salt of a compound of formula (I);
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`an anti-inflammatory effective amount of a steroidal or
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`non-steroidal anti-inflammatory agent; and
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`a pharmaceutically acceptable vehicle therefor.
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`2. A method according to claim 1, wherein the ant-
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`inflammatory agent comprises a glucocorticoid.
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`3. Atopical composition according to claim 2, wherein the
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`glucocorticoid is selected from the group consisting of
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`dexamethasone, AL1529, AL25 12,
`rimexolone,
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`prednisolone,
`fluorometholone, hydrocortisone,
`mometasone, fluticasone, beclomethasone, flunisolide, tri-
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`amcinolone and budesonide.
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`4. Atopical composition according to claim 1, wherein the
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`anti-inflammatory agent comprises a non-steroidal