AU2003248033B2

AU2003248033B2 - Antibiotic Compositions for Treatment of the Eye, Ear and Nose

Info

Publication number: AU2003248033B2
Application number: AU2003248033A
Authority: AU
Inventors: Robert L. Abshire; Gerald Cagle; David W. Stroman; John M. Yanni
Original assignee: Alcon Laboratories Inc
Current assignee: Alcon Vision LLC
Priority date: 1998-09-30
Filing date: 2003-09-15
Publication date: 2007-01-18
Anticipated expiration: 2019-09-29
Also published as: AU2003248033A1

Description

4*; S&FRef: 546455D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Alcon Laboratories, Inc.

6201 South Freeway Mail Code Q-148 Fort Worth Texas 76134-2099 United States of America Gerald Cagle Robert L. Abshire David W. Stroman John M. Yanni Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Antibiotic Compositions for Treatment of the Eye, Ear and Nose The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c ANTIBIOTIC COMPOSITIONS FOR TREATMENT OF THE EYE, EAR AND NOSE Background of the Invention The present invention is directed to the provision of topical antibiotic pharmaceutical compositions for the treatment 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 represents 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 Ophthalmic Solution. The following quinolones have also been utilized in ophthalmic antibiotic compositions: Quinolone Product Manufacturer Ofloxacin OCUFLOX T M Allergan Norfloxacin CHIBROXINTM Merck Lomefloxacin LOMEFLOXTM Senju The foregoing quinolone antibiotic compositions are generally 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, -1 Cwhich are primarily useful against gram negative pathogens; and bacitracin, gramicidin, and erythromycin, which are primarily active against gram positive pathogens. However, d despite the general efficacy of the ophthalmic quinolone therapies currently available,

C

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 ophthalmic pathogens, and less prone to the development of resistance by those pathogens.

~There is an even greater need for effective topical compositions and methods for 00 treating otic and nasal infections, particularly bacterial infections. The use of oral r antibiotics to treat otic infections in children has limited efficacy, and creates a serious risk of pathogen resistance to the orally administered antibiotics.

SOphthalmic, otic and nasal infections are frequently accompanied by inflammation of the infected ophthalmic, otic and nasal tissues and perhaps even surrounding tissues.

Similarly, ophthalmic, otic and nasal surgical procedures that create a risk of microbial infections frequently also cause inflammation of the affected tissues. Thus, there is also a is need for ophthalmic, otic and nasal pharmaceutical compositions that combine the antiinfective activity of one or more antibiotics with the anti-inflammatory activity of one or more steroid or non-steroid agents in a single composition.

Summary of the Invention In a first aspect the present invention provides the use of moxifloxacin, or a pharmaceutically useful hydrate or salt thereof in the preparation of a pharmaceutical composition for topically treating or preventing an ophthalmic, otic or nasal infection, wherein the moxifloxacin or the hydrate or salt thereof is at a concentration of 0.1 to wt. In a second aspect the present invention provides a method for topically treating or preventing an ophthalmic, otic or nasal infection in a mammal comprising administering to a mammal in need thereof an effective amount of moxifloxacin, or a pharmaceutically useful hydrate or salt thereof, or a pharmaceutical composition comprising moxifloxacin or a pharmaceutically useful hydrate or salt thereof and a pharmaceutically acceptable vehicle therefore, wherein the moxifloxacin or the hydrate or salt thereof is administered at a concentration of O.1 to 1.0 wt. In a third aspect the present invention provides a pharmaceutical composition comprising moxifloxacin or a pharmaceutically useful hydrate or salt thereof and a pharmaceutically acceptable vehicle therefor for topically treating or preventing an

ID

ophthalmic, otic or nasal infection, wherein the moxifloxacin or the hydrate or salt thereof 0 is at a concentration of O. 1 to 1.0 wt. SThe invention is based on the use of a potent new class of antibiotics to treat ophthalmic infections, as well as the prophylactic use of this antibiotic following surgery or other trauma to ophthalmic tissues. The compositions of the present invention may also be administered to the affected tissues during ophthalmic surgical procedures to prevent or alleviate post-surgical infection.

00 The compositions preferably also contain one or more anti-inflammatory agents to Ntreat inflammation associated with infections of ophthalmic, otic, or nasal tissues. The 0c anti-inflammatory component of the compositions is also useful in treating inflammation associated with physical trauma to ophthalmic, otic or nasal tissues, including inflammation resulting from surgical procedures. The compositions 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 compostions of the present invention include otitis extemrna and otitis media. With respect to the treatment of otitis media, the compositions of the present invention are primarily 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 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 physical conditions.

-3- O Detailed Description of the Invention SThe antibiotic used in the compositions and methods of the present invention is Smoxifloxacin or a pharmaceutically useful hydrate or salt thereof. Moxifloxacin has the following structure:

O

F CO 2

H

CcJ N( N 00 CHO Nr CO Further details regarding the structure, preparation and physical properties of Omoxifloxacin are provided in United States Patent No. 5,607,942.

Other antibiotics disclosed herein which may be used in the compositions and methods of the present invention have the following general formula:

X

1

O

F COOR 2 B A N

R

wherein A is CH, CF, CCI, C-OCH 3 or N; X' is H, halogen, NH 2 or CH 3 R' is Ci to C 3 alkyl, FCH 2 CH, cyclopropyl, or phenyl, optionally mono-, di- or trisubstituted by halogen, or A and R' together can form a bridge of formula CO-CH 2

CH(CH

3

R

2 is H, Ci to C 3 alkyl (optionally substituted by OH, halogen or NH 2 or 2-oxo-1,3-dioxol-4-yl-methyl; and B is selected from the group consisting of: SH H Hi, H H H ,H R3N Y R4N Y R4N Y R4N Y R Y and wherein Y is 0or CH 3 R 3 is C 2

-C

5 alkoxyl, CH 2

-CO-C

6

H

5

CH

2

CH-

2 C0 2 R'0 2

C-CH=C-CO

2

CLH:CH-

CO

2 or CH 2

CI-

2

-CN,

wherein Ris H or C, to C 3 alkyl; 00 R 4is H, C, to C 3 alkyl, C 2 to Cs alkoxyl, CH 2

-CO-C

6

H

5

CH

2

CH

2

CO

2 R'0 2

C-

CH=C-CO

2

CH=CH-CO

2

CI-

2

CH

2 -CN, or 5-methyl-2-oxo- 1,3 -dioxol-4-yl-methyl, wherein R' is as defined above; and their pharmaceutically useful hydrates and salts.

The concentrations of moxifloxacin or a pharmaceutically useful hydrate or salt thereof in the compositions of the present invention is 0.1 to 1.0 wt and will vary depending on the intended use of the compositions treatment of existing infections or prevention of post-surgical infections).

\O

The antimicrobial activity of antibiotics is generally expressed as the minimum U concentration required to inhibit the growth of a specific pathogen. This concentration is also referred to as the "minimum inhibitory concentration" or "MIC". The term refers to the minimum concentration of antibiotics required to inhibit the growth of ninety s percent of the strains of a species. The concentration of an antibiotic required to c totally kill a specified bacteria is referred to as the "minimum bactericidal concentration" 0or "MBC". The minimum inhibitory concentration of Moxifloxacin for several bacteria 00 commonly associated with ophthalmic, otic and nasal infections are provided in the aC following table: O Microorganism MIC 9 0 S.aureus/methicillin sensitive 0.13 S.aureus/methicillin resistant S.aureus/quinolone resistant S.epidermidis/methicillin sensitive 0.25 S.epidermidis/methicillin resistant S.pneumoniae/penicillin sensitive 0.25 S.pneumoniae/penicillin resistant 0.25 P.aeruginosa H.influenzae/P-lactamase positive 0.06 H.influenzae/p-lactamase negative 0.06 All of the foregoing concentrations are expressed as micrograms per millilitre ("mcg/ml").

IO

O The appropriate antibiotic concentration for ophthalmic compositions will generally 0 be an amount of the antibiotic sufficient to provide a concentration in the aqueous humor and lacrimol fluid of the eye equal to or greater than the MIC90 level for the antibiotic, Srelative to gram-negative and gram-positive organisms commonly associated with (Nl ophthalmic infections. The appropriate antibiotic concentration for otic and nasal c compositions will generally be an amount sufficient to provide a conenctration in the infected tissues equal to or greater than the MIC90 level for the antibiotic, relative to gram-negative and gram-positive organisms commonly associated with otic and nasal Sinfections. Such amounts are referred to herein as "an antimicrobial effective amount".

to The compositions of the present invention contain moxifloxacin or a pharmaceutically useful hydrate or salt thereof in a concentration of 0.1 to 1.0 percent by weight ("wt The compositions of the present invention may also contain one or more antiinflammatory agents. The anti-inflammatory agents utilised in the present invention are broadly classified as steroidal or non-steroidal. The preferred steroidal anti-inflammatory agents are glucocorticoids.

The preferred glucocorticoids for ophthalmic and otic use include dexamethasone, loteprednol, rimexolone, prednisolone, fluorometholone, and hydrocortisone. The preferred glucocorticoids for nasal use include mometasone, fluticasone, beclomethasone, flunisolide, triamcinolone and budesonide.

The dexamethasone derivatives described in US Patent No. 5,223,493 (Boltralik) are also preferred steroidal anti-inflammatory agents, particularly with respect to compositions for treating ophthalmic inflammation. The following compounds are especially preferred: *11 *a AL-1529 S""O AL-2512 0_ j I'llI

F

O

These compounds are referred to herein as "21-ether derivatives of dexamethasone". The 21-benzyl ether derivative 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 roflumilast; inhibitors of cytokine production, such as inhibitors of the NFkB transcription factor; or other anti-inflammatory agents known to those skilled in the art.

-8-

IO

0 The concentrations of the anti-inflammatory agents contained in the compositions o of the present invention will vary based on the agent or agents selected and the type of Sinflammation being treated. The concentrations will be sufficient to reduce inflammation 0in 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 antiinflammatory effective amount". The composition of the present invention will typically contain one or more anti-inflammatory agents in an amount of from about 0.01 to about

OO

S1.0 wt%.

SThe compositions are typically administered to the affected ophthalmic, otic or o0 nasal tissues by topically applying 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 solutions that are applied to the affected ophthalmic, nasal or otic tissues during surgical procedures.

The ophthalmic, otic and nasal compositions of the present invention will contain moxifloxacin or a pharmaceutically useful hydrate or salt thereof and preferably one or more anti-inflammatory agents, in pharmaceutically acceptable vehicles. The compositions will typically have a pH in the range of 4.5 to 8.0. The ophthalmic compositions must also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water ("mOsm/kg"), but will preferably be about 300 mOsm/kg.

Ophthalmic, otic and nasal pharmaceutical products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: polyquaternium-1, 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 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 compositions 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 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 to 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 Amount (wt. Moxifloxacin 0.35 Sodium Acetate 0.03 Acetic Acid 0.04 Mannitol 4.60 EDTA 0.05 Benzalkonium Chloride 0.006 Water q.s. 100 Example 2 Ophthalmic/OticfNasal Suspension Ingredient Moxifloxacin Dexamethasone, Micronized USP Benzalkonium Chloride Edetate Disodium, USP Sodium Chloride, USP Sodium Sulfate, USP Tyloxapol, USP Ilydroxyethylcellulose 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 q.s. to 100 Example 3 Ophthalmic Ointment Ingredient Moxifloxacin Mineral Oil, USP White petrolatium, USP Amount 0.35 q.s 100 -1I1I- Example 4 Ophthalmic Ointment Ingredient Moxifloxacin Fluorometholone Acetate, USP Chlorobutanol, Anhydrous, NF Mineral Oil,USP White Petrolatum, USP Amount 0.3 0.1 q.s. 100 The invention has been described herein by reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.

-12-

Claims

2. The use according to claim 1, wherein the composition further comprises a Ssteroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent. oO 0 3. The use according to claim 2, wherein the anti-inflammatory agent comprises go the steroidal agent.
4. The use according to claim 3, wherein the steroidal agent comprises a glucocorticoid. The use according to claim 4, wherein the glucocorticoid is selected from the group consisting of dexamethasone, rimexolone, prednisolone, fluorometholone, hydrocortisone, mometasone, fluticasone, beclormethasone, flunisolide, triamcinolone, is budesonide and combinations thereof.
6. The use according to claim 4, wherein the glucocorticoid comprises dexamethasone, a 21-ether derivative of dexamethasone, or a 21-benzyl ether derivative of dexamethasone.
7. The use according to claim 2, wherein the composition comprises a non- steroidal anti-inflammatory agent.
8. The use according to claim 7, wherein the non-steroidal agent is selected from the group consisting of prostaglandin H synthetase inhibitors, cyclooxygenase type II selective inhibitors, PAF antagonists, PDE IV inhibitors, and combinations thereof.
9. The use according to claim 7, wherein the non-steroidal agent comprises a prostaglandin H synthetase inhibitor. The use according to claim 9, wherein the prostaglandin H synthetase inhibitor comprises nepafenac, ketorolac or diclofenac.
11. The use according to claim 7, wherein the non-steroidal agent comprises a cyclooxygenase type II selective inhibitor.
12. The use according to any one of claims 1 to 11, wherein the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is at a concentration of 0.35 wt. to wt.
13. The use according to any one of claims 1 to 12, wherein the composition is a liquid further comprising sodium chloride. IO
14. The use according to claim 13, wherein the composition further comprises a 0 viscosity enhancing agent and a surfactant. The use according to any one of claims 1 to 19, wherein the composition has a SpH in the range of from 4.5 to s 16. The use according to any one of claims 1 to 14, wherein the composition has a pH in the range of from 5.5 to
17. The use according to any one of claims 1 to 16, wherein the composition has oO an osmotic value from about 200 to about 400 milliosmoles per kilogram of water.
18. The use according to any one of claims 1 to 17, wherein the composition has an osmotic value of about 300 milliosmoles per kilogram of water.
19. The use according to any one of claims 1 to 18, wherein the composition further comprises an antimicrobial preservative at a concentration of 0.001 to 1.0 wt. The use according to any one of claims 1 to 19, wherein the composition is a sterile solution in a multi-dose form. Is 21. The use according to any one of claims 1 to 20, wherein the composition is for treating or preventing an ophthalmic infection.
22. The use according to claim 21, wherein the ophthalmic infection is selected from the group consisting of conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulceration, and combinations thereof.
23. The use according to claim 22, wherein the ophthalmic infection is conjunctivitis.
24. The use according to claim 22, wherein the ophthalmic infection is keratitis. The use according to any one of claims 21 to 24, wherein the composition is for inhibiting growth of at least one pathogen selected from the group consisting of S. aureus, S. epidermidis, S. pneumoniae, and H. influenzae.
26. The use according to any one of claims 21 to 25, wherein the composition inhibits growth of S. aureus and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.13 micrograms per millilitre.
27. The use according to any one of claims 21 to 25, wherein the composition inhibits growth ofS. epidermidis and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 micrograms per millilitre. IO S28. The use according to any one of claims 21 to 25, wherein the composition 0 inhibits growth ofS. pneumoniae and comprises the moxifloxacin or the pharmaceutically Suseful hydrate or salt thereof in an amount sufficient for providing a concentration of the 0moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 micrograms per millilitre. S29. The use according to any one of claims 21 to 25, wherein the composition inhibits growth of H influenzae and comprises the moxifloxacin or the pharmaceutically 00 0 useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.06 micrograms per millilitre. The use according to any one of claims 21 to 25, wherein the composition inhibits growth of P. aeruginosa.
31. The use according to any one of claims 21 to 25, wherein the composition inhibits growth of P. aeruginosa and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 8 micrograms per millilitre.
32. A method for topically treating or preventing an ophthalmic, otic or nasal infection in a mammal comprising administering to a mammal in need thereof an effective amount of moxifloxacin, or a pharmaceutically useful hydrate or salt thereof, or a pharmaceutical composition comprising moxifloxacin or a pharmaceutically useful hydrate or salt thereof and a pharmaceutically acceptable vehicle therefore, wherein the moxifloxacin or the hydrate or salt thereof is administered at a concentration of 0.1 to wt.%.
33. The method according to claim 32, wherein the moxifloxacin is co- administered with a steroidal anti-inflammatory agent or a non-steroidal anti- inflammatory agent.
34. The method according to claim 33, wherein the anti-inflammatory agent comprises a steroidal agent.
35. The method according to claim 34, wherein the steroidal agent comprises a glucocorticoid.
36. The method according to claim 35, wherein the glucocorticoid is selected from the group consisting of dexamethasone, rimexolone, prednisolone, fluorometholone, hydrocortisone, mometasone, fluticasone, beclormethasone, flunisolide, triamcinolone, budesonide and combinations thereof. IO O 37. The method according to claim 36, wherein the glucocorticoid comprises 0 dexamethasone, a 21-ether derivative of dexamethasone, or a 21-benzyl ether derivative Sof dexamethasone.
38. The method according to claim 33, wherein the anti-inflammatory agent comprises a non-steroidal agent.
39. The method according to claim 38, wherein the non-steroidal agent is selected from the group consisting of prostaglandin H synthetase inhibitors, cyclooxygenase type SII selective inhibitors, PAF antagonists, PDE IV inhibitors, and combinations thereof.
40. The method according to claim 39, wherein the non-steroidal agent comprises to a prostaglandin H synthetase inhibitor.
41. The method according to claim 40, wherein the prostaglandin H synthetase inhibitor comprises nepafenac, ketorolac or diclofenac.
42. The method according to claim 39, wherein the non-steroidal agent comprises a cyclooxygenase type II selective inhibitor.
43. The method according to any one of claims 32 to 42, wherein the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is at a concentration of 0.35 wt.% to 1.0 wt.%.
44. The method of any one of claims 32 to 43, wherein the moxifloxacin or pharmaceutically useful hydrate or salt thereof, or composition is administered in connection with a surgical procedure. The method according to any one of claims 32 to 44, wherein the method is for the treatment or prevention of an ophthalmic infection.
46. The method according to claim 45, wherein the ophthalmic infection is selected from the group consisting of conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, corneal ulceration, and combinations thereof.
47. The method according to claim 46, wherein the ophthalmic infection is conjunctivitis.
48. The method according to claim 46, wherein the ophthalmic infection is keratitis.
49. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with at least one pathogen selected from the group consisting of S. aureus, S. epidermidis, S. pneumoniae, and H. influenzae. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with S. aureus and the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is in an amount sufficient for providing a concentration of the IO 0 moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.13 O micrograms per millilitre. S51. The method according to any one of claims 45 to 48, wherein the ophthalmic Sinfection is associated with S. epidermidis and the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is in an amount sufficient for providing a concentration of Cc the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 0micrograms per millilitre. 00
52. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with S. pneumoniae and the moxifloxacin or the pharmaceutically 0lo useful hydrate or salt thereof is in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 micrograms per millilitre.
53. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with H. influenzae and the moxifloxacin or the pharmaceutically s1 useful hydrate or salt thereof is in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.06 micrograms per millilitre.
54. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with P. aeruginosa.
55. The method according to any one of claims 45 to 48, wherein the ophthalmic infection is associated with P. aeruginosa and the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 8 micrograms per millilitre.
56. A pharmaceutical composition comprising moxifloxacin or a pharmaceutically useful hydrate or salt thereof and a pharmaceutically acceptable vehicle therefor for topically treating or preventing an ophthalmic, otic or nasal infection, wherein the moxifloxacin or the hydrate or salt thereof is at a concentration of 0.1 to 1.0 wt.
57. The pharmaceutical composition according to claim 56, further comprising a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent.
58. The pharmaceutical composition according to claim 57, wherein the anti- inflammatory agent comprises a steroidal agent.
59. The pharmaceutical composition according to claim 58, wherein the steroidal agent comprises a glucocorticoid. \O c 60. The pharmaceutical composition according to claim 59, wherein the Sglucocorticoid is selected from the group consisting of dexamethasone, rimexolone, prednisolone, fluorometholone, hydrocortisone, mometasone, fluticasone, Sbeclormethasone, flunisolide, triamcinolone, budesonide and combinations thereof.
61. The pharmaceutical composition according to claim 60, wherein the C glucocorticoid comprises dexamethasone, a 21 -ether derivative of dexamethasone or a 21- Sbenzyl ether derivative of dexamethasone. 00
62. The pharmaceutical composition according to claim 57, wherein the anti- 2C inflammatory agent comprises a non-steroidal agent.
63. The pharmaceutical composition according to claim 62, wherein the non- steroidal agent is selected from the group consisting of prostaglandin H synthetase inhibitors, cyclooxygenase type II selective inhibitors, PAF antagonists, PDE IV inhibitors, and combinations thereof.
64. The pharmaceutical composition according to claim 63, wherein the non- steroidal agent comprises a prostaglandin H synthetase inhibitor. The pharmaceutical composition according to claim 64, wherein the prostaglandin H synthetase inhibitor comprises nepafenac, ketorolac, or diclofenac.
66. The pharmaceutical composition according to claim 63, wherein the non- steroidal agent comprises a cyclooxygenase type II selective inhibitor.
67. The pharmaceutical composition according to any one of claims 56 to 66, wherein the moxifloxacin or the pharmaceutically useful hydrate or salt thereof is at a concentration of 0.35 wt. to 1.0 wt.
68. The pharmaceutical composition according to any one of claims 56 to 67, wherein the composition is a liquid further comprising sodium chloride.
69. The pharmaceutical composition according to claim 68, further comprising a viscosity enhancing agent and a surfactant. The pharmaceutical composition according to any one of claims 56 to 69, wherein the composition has a pH in the range of from 4.5 to
71. The pharmaceutical composition according to any one of claims 56 to 69, wherein the composition has a pH in the range of from 5.5 to
72. The pharmaceutical composition according to any one of claims 56 to 71, wherein the composition has an osmotic value from about 200 to about 400 milliosmoles per kilogram of water. IO
73. The pharmaceutical composition according to any one of claims 56 to 72, Swherein the composition has an osmotic value of about 300 milliosmoles per kilogram of Swater.
74. The pharmaceutical composition according to any one of claims 56 to 73, further comprising an antimicrobial preservative at a concentration of 0.001 to 1.0 wt. C 75. The pharmaceutical composition according to any one of claims 56 to 74, Swherein the composition is a sterile solution in a multi-dose form. 00
76. The pharmaceutical composition according to any one of claims 56 to 75, in aC the form of a topical ophthalmic formulation for treating or preventing an ophthalmic infection.
77. The pharmaceutical composition according to claim 76, wherein the composition is suitable for inhibiting growth of at least one pathogen selected from the group consisting of S. aureus, S. epidermidis, S. pneumoniae, and H. influenzae.
78. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of S. aureus and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.13 micrograms per millilitre.
79. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of S. epidermidis and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 micrograms per millilitre. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of S. pneumoniae and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.25 micrograms per millilitre.
81. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of H. influenzae and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 0.06 micrograms per millilitre.
82. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of P. aeruginosa. S83. The pharmaceutical composition according to claim 76 or 77, wherein the composition inhibits growth of P. aeruginosa and comprises the moxifloxacin or the pharmaceutically useful hydrate or salt thereof in an amount sufficient for providing a concentration of the moxifloxacin in lacrimal fluid and aqueous humor of the eye of at least about 8 micrograms per millilitre. Dated 20 December, 2006 o Alcon Laboratories, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON