(12) United States Patent
`Cagle et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,716,830 B2
`Apr. 6, 2004
`
`US006716830B2
`
`(54)
`
`(75)
`
`OPHTHALMIC ANTIBIOTIC
`COMPOSITIONS CONTAINING
`MOXIFLOXACIN
`
`Inventors: Gerald Cagle, Fort Worth, TX (US);
`Robert L. Abshire, Fort Worth, TX
`(US); David W. Stroman, Irving, TX
`(US); John M. Yanni, Burleson, TX
`(US)
`
`(73)
`
`Assignee: Alcon, Inc., Hunenberg (CH)
`
`(*)
`
`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)
`
`(22)
`
`(65)
`
`(63)
`
`(60)
`
`(51)
`(52)
`
`(58)
`
`(56)
`
`Appl. No.: 10/200,868
`
`Filed:
`
`Jul. 22, 2002
`Prior Publication Data
`
`US 2002/0193370 A1 Dec. 19, 2002
`
`Related U.S. Application Data
`
`Continuation of application No. 09/646,797, filed as appli-
`cation No. PCT/US99/22622 on Sep. 29, 1999, now aban-
`doned.
`Provisional application No. 60/102,506, filed on Sep. 30,
`1998, and provisional application No. 60/102,504, filed on
`Sep. 30, 1998.
`
`Int. Cl.7 ....................... .. A61K 31/58; A61K 31/44
`U.S. Cl.
`............... .. 514/171; 514/230.2; 514/230.5;
`514/300; 514/312; 514/913
`Field of Search ......................... .. 514/230.2, 230.5,
`514/312, 300, 913, 171
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,474,751 A
`4,551,456 A
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`4,980,470 A
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`
`10/1984 Haslam et al.
`11/1985 Katz
`6/1987 Grohe et al.
`12/1987 Bodor
`3/1988 Bondi et al.
`7/1989 Grohe
`4/1990 Domagala et al.
`12/1990 Masuzawa et al.
`2/1991 Petersen et al.
`2/1991 Bodor
`10/1991 Petersen et al.
`9/1992 Cagle et al.
`11/1992 Brighty
`2/1993 Fujii et al.
`6/1993 Boltralik
`5/1995 Petersen et al.
`1/1996 Petersen et al.
`7/1996 Guy et al.
`10/1996 Ueda et al.
`1/1997 Bergamini et al.
`3/1997 Petersen et al.
`5/1997 Cagle et al.
`9/1997 Robertson et al.
`10/1997 Bergamini et al.
`12/1998 Grunenberg et al.
`12/1998 Hallenbach et al.
`6/1999 Bussell
`
`CA
`EP
`ES
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`
`2086914
`0 982 031
`08320
`WO 90/01933
`WO 96/39146
`WO 98/06435
`WO 99/15172
`W0 00/18386
`W0 00/18387
`W0 00/18388
`W0 00/18404
`
`7/1993
`3/2000
`4/1993
`3/1990
`12/1996
`2/1998
`4/1999
`4/2000
`4/2000
`4/2000
`4/2000
`
`OTHER PUBLICATIONS
`
`Blondeau, Joseph M., A review of the comparative in—vitro
`activities of 12 antimicrobial agents, with focus on five new
`‘respiratory quinolones’, Journal of Antimicrobial Chemo-
`therapy, vol. 43, Suppl. B, pp. 1-11 (1999).
`Elies, W., “Novel fluoroquinolones in the treatment of ENT
`infections”, Chemotherapie Journal, 7/3, pp. 93-97 (1998)
`(no translation); XP000892813.
`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).
`Gootz et al., “Fluoroquinolone antibacterials: SAR mecha-
`nism of action, resistance, and clinical aspects”, Medicinal
`Research Reviews, vol. 16, pp. 433-486 (1996).
`Kaw et al., “The penetration of trovafloxacin into the eye
`and CSF of rabbits”, IOVS, vol. 40, no. 4, p. S88 (Mar. 15,
`1999); XP-000892619.
`Kraseman et al., “Efficacy of Moxifloxacin against Staphy-
`lococcus aureus in respiratory tract and skin and skin
`structure infections”, Jornal Of Antimicrobial Chemo-
`therapy, vol. 44, no. Suppl. A, pp 150 (7/99); XP000892776.
`McLeod et al., “The effect of topical trovafloxacin in a rabbit
`streptococcus pneumoniae keratitis model”, IOVS vol. 40,
`no. 4, p. S689 (Mar. 15, 1999) XP-000892625.
`NCCLS Document M7-A4, “Methods for Dilution Antimi-
`crobial Susceptability Tests for Bacteria That Grow Aero-
`bically”, 4th Edition.
`“New Antimicrobial Agents Approved by the U.S. Food and
`Drug Administration in 1997 and New Indications for Pre-
`viously Approved Agents” Antimicrobial Agents and Che-
`motherapy, vol. 42, No. 4, pp. 987-988 (Apr. 1, 1998);
`XP000872060.
`
`Ng et al., “Treatment of experimental staphylococcus epi-
`dermidis endophthalmitis with oral trovafloxacin”American
`Journal of Ophthalmology, vol. 216 (2), pp. 278-287 (Aug.
`1998).
`
`(List continued on next page.)
`
`Primary Examiner—Zohreh Fay
`(74) Attorney, Agent, or Firm—Gregg C. Brown
`
`(57)
`
`ABSTRACT
`
`Ophthalmic, otic and nasal compositions containing a new
`class of antibiotics (e.g., moxifloxacin) are disclosed. The
`compositions preferably also contain one or more anti-
`inflammatory agents. The compositions may be utilized to
`treat ophthalmic, otic and nasal conditions by topically
`applying the compositions to the affected tissues.
`
`14 Claims, No Drawings
`
`APOTEX 1001
`
`

`
`US 6,716,830 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Patent Abstracts of Japan, vol. 1998, No. 10 (Aug. 31, 1998),
`JP 10 130148 May 19, 1998 abstract.
`Patent Abstracts of Japan, vol. 012, No. 472 (Dec. 9, 1988),
`JP 63 190826 Aug. 8, 1988 abstract.
`Pediatric Research, 104th Annual Meeting of the American
`Pediatric Society and the 63rd Annual meeting of the
`Society for Pediatric Research, vol. 35, No. 4, Part 2, p.
`191A, Seattle, Washington (May 2-5, 1994).
`Senturia, Ben, “Etiology Of External Otitis”, Larynyoscope,
`vol. 55, pp. 277-293 (1945).
`Tillotson, G. S., “Quinolones: structure-activity relation-
`ships and future predictions”, J. of Medical Microbiology,
`vol. 44, pp. 320-324 (1996).
`
`Vincent et al., “Pharmacokinetics and safety of trovafloxacin
`in healthy male volunteers following administration of
`single intravenous doses of the prodrug, alatrofloxacin”,
`Journal ofAntimicrobial Chemotherapy, vol. 39, Suppl. B,
`pp. 75-80 (Jan. 1, 1997).
`
`Weiss, Lee R., “Therapeutic Pathways for Antimicrobial
`Use: General Overview”, The American Journal Of Man-
`aged Care, vol. 4, No. 10, Sup., pp. S543-S549 (1988).
`
`Wentland, Mark P., “Structure-activity relationships of fluo-
`roquinolones”, The New Generation of Quinolones,
`(Siporin, C., Heifetz, C. L. & Domagala, J. M., Eds), pp.
`1-43, Marcel Dekker, New York (1990).
`
`

`
`US 6,716,830 B2
`
`1
`OPHTHALMIC ANTIBIOTIC
`COMPOSITIONS CONTAINING
`MOXIFLOXACIN
`
`This application is a continuation of U.S. application Ser.
`No. 09/646,797 filed Sep. 22, 2000 now abandoned, which
`is the National Stage of International Application No. PCT/
`US99/22622, filed Sep. 29, 1999, which claims the benefit
`under 35 U.S.C. §119(e) of U.S. Provisional Application
`Nos. 60/102,504 and 60/102,506 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
`
`Product
`
`Manufacturer
`
`Ofloxacin
`Norfloxacin
`Lomefloxacin
`
`OCUFLOX TM
`CHIBROXIN TM
`LOMEFLOX TM
`
`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
`
`2
`more antibiotics with the anti-inflammatory activity of one
`or more steroid or non-steroid agents in a single composi-
`tion.
`
`SUMMARY OF THE INVENTION
`
`The invention is based on the use of a potent new class of
`antibiotics to treat ophthalmic, otic and nasal infections, as
`well as the 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 infection.
`The compositions preferably also contain one or more
`anti-inflammatory agents to treat inflammation associated
`with infections of ophthalmic, otic or nasal tissues. The
`anti-inflammatory component of the compositions is also
`useful
`in treating inflammation associated with physical
`trauma to ophthalmic, otic or nasal tissues, including inflam-
`mation resulting from surgical procedures. The composi-
`tions of the present
`invention are therefore particularly
`useful in treating inflammation associated with trauma to
`ophthalmic, otic or nasal tissues wherein there is either an
`infection or a risk of an infection resulting from the trauma.
`Examples of ophthalmic conditions that may be treated
`with the compositions of the present
`invention include
`conjunctivitis, keratitis, blepharitis, dacyrocystitis,
`hordeolum and corneal ulcers. The compositions of the
`invention may also be used prophylactically in connection
`with various ophthalmic surgical procedures that create a
`risk of infection.
`
`Examples of otic conditions that may be treated with the
`compositions of the present invention include otitis 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
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`The antibiotics used in the compositions and methods of
`the present invention have the following formula:
`
`50
`
`55
`
`60
`
`65
`
`x1
`
`0
`
`COOR2
`
`(1)
`
`TR1
`
`F
`
`B
`
`wherein:
`A is CH, CF, CCl, C—OCH3, or N;
`X1 is H, halogen, NH2, or CH3;
`R1 is C1 to C3 alkyl, FCH2CH2, cyclopropyl or phenyl,
`optionally mono-, di- or tr-substituted by halogen, or
`A R1 together can form a bridge of formula C—O—
`CH2—CH(CH3);
`
`

`
`US 6,716,830 B2
`
`3
`
`R2 is H, C1 to C3 alkyl (optionally substituted by OH,
`halogen or NH2), or 5-methyl-2-oxo-1,3-dioxol-4-
`yl-methyl; and
`B is a selected from the group consisting of:
`
`4
`ciated with ophthalmic, otic and nasal infections are pro-
`vided in the following table:
`
`N
`
`N
`
`R3N
`
`Y
`
`N
`
`
`
`Hm.. H and
`
`R4N
`\_/Y
`
`H
`
`R4N
`
`...n|H
`
`Y
`
`\_/
`
`wherein:
`
`YisOorCH2;
`R3 is C2-C5 alkoxyl, CH2—CO—C6H3,
`CH2CH2CO2R‘, R‘O2C—CH=C—CO2R‘,
`CH=CH—CO2R‘ or CH2CH2—CN,
`wherein:
`
`R‘ is H or C1 to C3 alky;
`R4 is H, C1 to C3 alkyl, C2-C5 alkoxyl, CH2-CO—
`C6H3, CH2CH2CO2R‘, R‘O2C—CH=C—CO2R‘,
`CH=CH—CO2R‘, CH2CH2—CN or 5-methyl-2-
`oxo-1,3dioxol-4-yl-methyl,
`wherein:
`
`R‘ is H or C1 to C3 alkyl; and
`their pharmaceutically useful hydrates and salts.
`The compound Moxifioxacin is most preferred. Moxi-
`fioxacin has the following structure:
`
`Further details regarding the structure, preparation, and
`physical properties of Moxifioxacin and other compounds of
`formula (I) are provided in U.S. Pat. No. 5,607,942.
`The concentrations of the antibiotics of formula (I) in the
`compositions of the present invention will vary depending
`on the intended use of the compositions (e.g., treatment of
`existing infections or prevention of post-surgical infections),
`and the relative antimicrobial activity of the specific antibi-
`otic selected. The antimicrobial activity of antibiotics is
`generally expressed as the minimum concentration required
`to inhibit the growth of a specified pathogen. This concen-
`tration is also referred to as the “minimum inhibitory con-
`centration” or “MIC”. The term “MIC90” refers to the
`
`minimum concentration of antibiotic required to inhibit the
`growth of ninety percent (90%) of the strains of a species.
`The concentration of an antibiotic required to totally kill a
`specified bacteria is referred to as the “minimum bactericidal
`concentration” or “MBC”. The minimum inhibitory concen-
`tration of Moxifioxacin for several bacteria commonly asso-
`
`Microorganism
`S. aureus/methicillin sensitive
`S. aureus/methicillin resistant
`S. aureus/quinolone resistant
`S. epidemtidis/methicillin sensitive
`S. epidemtidis/methicillin resistant
`S. pneumoniae/penicillin sensitive
`S. pneumoniae/penicillin resistant
`R aemginosa
`H. influenzae/[5-lactamase positive
`H influenzae/[filactamase negative
`
`MIC90
`0.13
`4.0
`4.0
`0.25
`4.0
`0.25
`0.25
`8.0
`0.06
`0.06
`
`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
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`
`US 6,716,830 B2
`
`5
`-continued
`
`O
`
`O
`
`AL-2512
`
`
`
`0
`
`These compounds are referred to herein as “21-ether deriva-
`tives of dexamethasone”. The 21-benzyl ether derivative
`(i.e., compound AL-2512) is particularly preferred.
`The preferred non-steroidal anti-inflammatory agents are:
`prostaglandin H synthetase inhibitors (Cox I or Cox II), also
`referred to as cyclooxygenase type I and type II inhibitors,
`such as diclofenac,
`flurbiprofen, ketorolac, suprofen,
`nepafenac, amfenac,
`indomethacin, naproxen,
`ibuprofen,
`bromfenac, ketoprofen, meclofenamate, piroxicam,
`sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin,
`fenoprofen, benoxaprofen, nabumetome, etodolac,
`phenylbutazone, aspirin, oxyphenbutazone, NCX-4016,
`HCT-1026, NCX-284, NCX-456, tenoxicam and carprofen;
`cyclooxygenase type II selective inhibitors, such as NS-398,
`vioxx, celecoxib, P54, etodolac, L-804600 and S-33516;
`PAF antagonists, such as SR-27417, A-137491, ABT-299,
`apafant, bepafant, minopafant, E-6123, BN-50727, nupafant
`and modipafant; PDE IV inhibitors, such as ariflo,
`torbafylline, rolipram, filaminast, piclamilast, cipamfylline,
`CG-1088, V-11294A, CT-2820, PD-168787, CP-293121,
`DWP-205297, CP-220629, SH-636, BAY-19-8004, and rof-
`lumilast; inhibitors of cytokine production, such as inhibi-
`tors of the NFKB transcription factor; or other anti-
`inflammatory agents known to those skilled in the art.
`The concentrations of the anti-inflammatory agents con-
`tained in the compositions of the present invention will vary
`based on the agent or agents selected and the type of
`inflammation being treated. The concentrations will be suf-
`ficient to reduce inflammation in the targeted ophthalmic,
`otic or nasal tissues following topical application of the
`compositions to those tissues. Such an amount is referred to
`herein as “an anti-inflammatory effective amount”. The
`compositions of the present invention will typically contain
`one or more anti-inflammatory agents in an amount of from
`about 0.01 to about 1.0 wt. %.
`The compositions are typically administered to the
`affected ophthalmic, otic or nasal tissues by topically apply-
`ing one to four drops of a sterile solution or suspension, or
`a comparable amount of an ointment, gel or other solid or
`semisolid composition, one to four times per day. However,
`the compositions may also be formulated as irrigating solu-
`tions that are applied to the affected ophthalmic, otic or nasal
`tissues during surgical procedures.
`The ophthalmic, otic and nasal compositions of the
`present invention will contain one or more compounds of
`formula (I) and preferably one or more anti-inflammatory
`agents, in pharmaceutically acceptable vehicles. The com-
`positions will typically have a pH in the range of 4.5 to 8.0.
`The ophthalmic compositions must also be formulated to
`have osmotic values that are compatible with the aqueous
`humor of the eye and ophthalmic tissues. Such osmotic
`values will generally be in the range of from about 200 to
`about 400 milliosmoles per kilogram of water (“mOsm/kg”),
`but will preferably be about 300 mOsm/kg.
`Ophthalmic, otic and nasal pharmaceutical products are
`typically packaged in multidose form. Preservatives are thus
`
`6
`required to prevent microbial contamination during use.
`Suitable preservatives include: polyquaternium-1, benzalko-
`nium chloride, thimerosal, chlorobutanol, methyl paraben,
`propyl paraben, phenylethyl alcohol, edetate disodium, sor-
`bic acid, or other agents known to those skilled in the art.
`The use of polyquaternium-1 as the antimicrobial preserva-
`tive is preferred. Typically such preservatives are employed
`at a level of from 0.001% to 1.0% by weight.
`The solubility of the components of the present compo-
`sitions may be enhanced by a surfactant or other appropriate
`co-solvent
`in the composition. Such co-solvents include
`polysorbate 20, 60, and 80, polyoxyethylene/
`polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and
`P-103), cyclodextrin, or other agents known to those skilled
`in the art. Typically such co-solvents are employed at a level
`of from 0.01% to 2% by weight.
`The use of viscosity enhancing agents to provide the
`compositions of the invention with viscosities greater than
`the viscosity of simple aqueous solutions may be desirable
`to increase ocular absorption of the active compounds by the
`target tissues or increase the retention time in the eye, ear or
`nose. Such viscosity building agents include, for example,
`polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,
`hydroxy propyl methylcellulose, hydroxyethyl cellulose,
`carboxymethyl cellulose, hydroxy propyl cellulose or other
`agents know to those skilled in the art. Such agents are
`typically employed at a level of from 0.01% to 2% by
`weight.
`The following examples are provided to further illustrate
`the ophthalmic, otic and nasal compositions of the present
`invention.
`
`EXAMPLE 1
`
`Ophthalmic/Otic/Nasal Solution
`
`Ingredient
`Moxifloxacin
`Sodium Acetate
`Acetic Acid
`Mannitol
`EDTA
`Benzalkonium Chloride
`Water
`
`q.s.
`
`Amount (wt. %)
`0.35
`0.03
`0.04
`4.60
`0.05
`0.006
`100
`
`EXAMPLE 2
`
`Ophthalmic/Otic/Nasal Suspension
`
`Ingredient
`Moxifloxacin
`Dexamethasone, Micronized USP
`Benzalkonium Chloride
`Edetate Disodium, USP
`Sodium Chloride, USP
`Sodium Sulfate, USP
`Tyloxapol, USP
`Hydroxyethylcellulose
`Sulfuric Acid and/or
`Sodium Hydroxide, NF
`Purified Water, USP
`
`Amount (wt. %)
`0.3
`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
`
`

`
`US 6,716,830 B2
`
`7
`EXAMPLE 3
`
`Ophthalmic Ointment
`
`Ingredient
`Moxifloxacin
`Mineral Oil, USP
`White petrolatium, USP
`
`q.s
`
`Amount (wt. %)
`0.35
`2.0
`100
`
`EXAMPLE 4
`
`Ophthalmic Ointment
`
`Ingredient
`Moxifloxacin
`Fluorometholone Acetate, USP
`Chlorobutanol, Anhydrous, NF
`Mineral Oil, USP
`White Petrolatum, USP
`
`q.s.
`
`Amount (wt. %)
`0.3
`0.1
`0.5
`5
`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. Atopical ophthalmic pharmaceutical composition com-
`prising moxifloxacin or a pharmaceutically useful hydrate or
`salt
`thereof in a concentration of 0.1 to 1.0 wt % and
`pharmaceutically acceptable vehicle therefor.
`2. An ophthalmic composition according to claim 1,
`wherein the composition further comprises an anti-
`inflammatory effective amount of a steroidal or non-
`steroidal glucocorticoid.
`3. An ophthalmic composition according to claim 2,
`wherein the anti-inflammatory agent comprises a steroidal
`agent.
`
`8
`4. An ophthalmic composition according to claim 3,
`wherein the steroidal agent comprises a glucocorticoid.
`5. An ophthalmic composition according to claim 4,
`wherein the glucocorticoid is selected from the group con-
`sisting of dexamethasone,
`rimexolone, prednisolone,
`fluorometholone, hydrocortisone, mometasone, fluticasone,
`beclomethasone, flunisolide, triamcinolone and budesonide.
`6. An ophthalmic composition according to claim 4,
`wherein the glucocorticoid comprises dexamethasone.
`7. An ophthalmic composition according to claim 4,
`wherein the glucocorticoid comprises a 21-ether derivative
`of dexamethasone.
`
`10
`
`15
`
`8. An ophthalmic composition according to claim 4,
`wherein the glucocorticoid comprises a 21-benzyl ether
`derivative of dexamethasone.
`
`20
`
`25
`
`30
`
`35
`
`9. An ophthalmic composition according to claim 2,
`wherein the anti-inflammatory agent comprises a non-
`steroidal agent selected from the group consisting of pros-
`taglandin H synthetase inhibitors, cyclooxygenase type II
`selective inhibitors, PAF antagonists, and PDE IV inhibitors.
`10. An ophthalmic composition according to claim 9,
`wherein the non-steroidal agent comprises a prostaglandin H
`synthetase inhibitor.
`11. An ophthalmic composition according to claim 10,
`wherein the prostaglandin H synthetase inhibitor comprises
`nepafenac.
`12. An ophthalmic composition according to claim 10,
`wherein the prostaglandin H synthetase inhibitor comprises
`ketorolac.
`
`13. An ophthalmic composition according to claim 10,
`wherein the prostaglandin H synthetase inhibitor comprises
`diclofenac.
`
`14. An ophthalmic composition according to claim 9,
`wherein the non-steroidal agent comprises a cyclooxygenase
`type II selective inhibitor.