EP1117406A1 - Antibiotic compositions for treatment of the eye, ear and nose - Google Patents
Antibiotic compositions for treatment of the eye, ear and noseInfo
- Publication number
- EP1117406A1 EP1117406A1 EP99950008A EP99950008A EP1117406A1 EP 1117406 A1 EP1117406 A1 EP 1117406A1 EP 99950008 A EP99950008 A EP 99950008A EP 99950008 A EP99950008 A EP 99950008A EP 1117406 A1 EP1117406 A1 EP 1117406A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- otic
- ophthalmic
- alkyl
- nasal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- 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.
- quinolone antibiotics to treat infections represents the current state of the art in the field of ophthalmic pharmaceutical compositions and methods of treatment.
- a topical ophthalmic composition containing the quinolone ciprofloxacin is marketed by Alcon Laboratories, Inc. under the name CILOXANTM (Ciprofloxacin 0.3%) Ophthalmic Solution.
- CILOXANTM Ciprofloxacin 0.3%) Ophthalmic Solution.
- the following quinolones have also been utilized in ophthalmic antibiotic compositions:
- 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, which are primarily useful against gram negative pathogens; and bacitracin, gramicidin, and erythromycin, which are primarily active against gram positive pathogens.
- Ophthalmic, otic and nasal infections are frequently accompanied by inflammation of the infected ophthalmic, otic and nasal tissues and perhaps even surrounding tissues.
- ophthalmic, otic and nasal surgical procedures that create a risk of microbial infections frequently also cause inflammation of the affected tissues.
- ophthalmic, otic and nasal pharmaceutical compositions 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 composition.
- 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 surgery procedures to prevent or alleviate post-surgical infections.
- 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 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.
- compositions of the present invention examples 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.
- otic conditions examples include otitis externa and 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.
- 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
- the antibiotics used in the compositions and methods of the present invention have the following formula:
- Rl is a cyclopropyl which may be substituted by 1 to 3 of substituents selected from the group consisting of a C C 6 alkyl and a halogen atom, a phenyl which may be substituted by 1 to 3 of substituents selected from the group consisting of C r C 6 alkoxy, a halogen atom and hydroxy, a C C 6 alkyl which may be substituted by a halogen atom, a C 2 -C 6 alkanoyloxy or hydroxy, a C 2 -C 6 alkenyl or thienyl;
- R2 is a member selected from the group consisting of a 1 -piperazinyl group which may have 1 to 3 substituents selected from the group consisting of a C,-C 6 alkyl group, a C r C 6 alkanoyl group, a phenyl (C C 6 ) alkyl group, and a 2-oxo-l,3- dioxolenemethyl group which may be substituted by a phenyl group or a C r C 6 alkyl group; a 1 -pyrrolidinyl group which may have 1 to 3 substituents selected from the group consisting of an amino group which can have 1 or 2 substituents selected from a C r C 6 alkyl group and a (C r C 6 )alkooxy-carbonyl group, an amino(C C 6 )alkyl group which may have 1 to 2 substituents selected from C r C 6 alkyl group and a (C C 6 )alkoxy-carbonyl group on the amino
- R3 is a C,-C 6 alkyl
- R is hydrogen atom or a C C 6 alkyl
- X is a halogen atom, or a pharmaceutically acceptable salt thereof.
- Grepafloxacin has the following structure:
- 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 antibiotic selected.
- the antimicrobial activity of antibiotics is generally expressed as the minimum concentration required to inhibit the growth of a specified pathogen. This concentration is also referred to as the "minimum inhibitory concentration" or "MIC”.
- 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”.
- MBC minimum bactericidal concentration
- the minimum inhibitory concentration of Grepafloxacin for several bacteria commonly associated with ophthalmic, otic and nasal infections are provided in the following table:
- the appropriate antibiotic concentration for ophthalmic compositions will generally be an amount of one or more antibiotics of formula (I) sufficient to provide a concentration 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 compounds of formula (I) in a concentration of from about 0.1 to about 1.0 percent by weight (“wt. %”) of the compositions.
- compositions of the present invention may also 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 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.
- dexamethasone derivatives described in U.S. Patent No. 5,223,493 are also preferred steroidal anti-inflammatory agents, particularly with respect to compositions for treating ophthalmic inflammation.
- the following compounds are especially preferred:
- 21 -ether derivatives of dexamethasone are referred to herein as "21 -ether derivatives of dexamethasone".
- the 21-benzyl ether derivative i.e.. compound AL-2512
- 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 IN inhibitors such as ariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline, CG-1088, N-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004, and roflumilast
- inhibitors of cytokine production
- 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 sufficient 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 containe one or more anti-inflammatory agents in an amount of from about 0.01 to about 1.0 wt.%.
- compositions are typically administered to the affected ophthalmic, otic or 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.
- the compositions may also be formulated as irrigating solutions 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 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 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.
- polyquaternium- 1 as the antimicrobial preservative is preferred.
- 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.
- co-solvents include polysorbate 20, 60, and 80, polyoxyefhylene/poiyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art.
- co-solvents are employed at a level of from 0.01% to 2% by weight.
- 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.
- 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.
- Example 1 The following examples are provided to further illustrate the ophthalmic, otic and nasal compositions of the present invention.
- Example 1
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10251098P | 1998-09-30 | 1998-09-30 | |
US10251198P | 1998-09-30 | 1998-09-30 | |
US102510P | 1998-09-30 | ||
US102511P | 1998-09-30 | ||
PCT/US1999/022625 WO2000018404A1 (en) | 1998-09-30 | 1999-09-29 | Antibiotic compositions for treatment of the eye, ear and nose |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1117406A1 true EP1117406A1 (en) | 2001-07-25 |
Family
ID=26799456
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99950008A Withdrawn EP1117406A1 (en) | 1998-09-30 | 1999-09-29 | Antibiotic compositions for treatment of the eye, ear and nose |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1117406A1 (en) |
JP (1) | JP2002525326A (en) |
AU (1) | AU6275999A (en) |
BR (1) | BR9914158A (en) |
CA (1) | CA2344050A1 (en) |
HK (1) | HK1038692A1 (en) |
WO (1) | WO2000018404A1 (en) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6395746B1 (en) | 1998-09-30 | 2002-05-28 | Alcon Manufacturing, Ltd. | Methods of treating ophthalmic, otic and nasal infections and attendant inflammation |
US6509327B1 (en) * | 1998-09-30 | 2003-01-21 | Alcon Manufacturing, Ltd. | Compositions and methods for treating otic, ophthalmic and nasal infections |
US6716830B2 (en) | 1998-09-30 | 2004-04-06 | Alcon, Inc. | Ophthalmic antibiotic compositions containing moxifloxacin |
BR0014203A (en) | 1999-09-24 | 2002-05-21 | Alcon Inc | Topical suspension formulations containing ciprofloxacin and dexamethasone |
DE19962470A1 (en) | 1999-12-22 | 2001-07-12 | Schulz Hans Herrmann | Use of chemotherapy drugs |
AU2005202737B2 (en) * | 1999-12-22 | 2009-01-22 | Bayer Innovation Gmbh | Use of chemotherapeutic agents |
DE19962353A1 (en) | 1999-12-23 | 2001-07-05 | Henkel Ecolab Gmbh & Co Ohg | Hepatitis A virucide |
US6608078B2 (en) | 2000-05-08 | 2003-08-19 | Wockhardt Limited | Antibacterial chiral 8-(substituted piperidino)-benzo [i,j] quinolizines, processes, compositions and methods of treatment |
US6462033B2 (en) | 2000-07-26 | 2002-10-08 | Alcon Universal Ltd. | Process for manufacturing compositions containing ciprofloxacin and hydrocortisone |
US7098219B2 (en) | 2000-08-01 | 2006-08-29 | Wockhart Limited | Inhibitors of cellular efflux pumps of microbes |
US6878713B2 (en) | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
US6964966B2 (en) * | 2001-04-25 | 2005-11-15 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
US20030139382A1 (en) | 2001-09-21 | 2003-07-24 | Alcon, Inc. | Method of treating middle ear infections |
JP2005511743A (en) * | 2001-12-13 | 2005-04-28 | ウォックハート・リミテッド | A new generation of triple-targeted chiral broad-spectrum antibacterial 7-substituted piperidino-quinolone carboxylic acid derivatives, methods for their preparation, compositions, and pharmaceutical use |
US6664267B1 (en) | 2002-05-28 | 2003-12-16 | Wockhardt Limited | Crystalline fluoroquinolone arginine salt form |
CA2508762A1 (en) * | 2002-12-06 | 2004-06-24 | Arriva Pharmaceuticals, Inc. | Methods and compositions for treatment of otitis media |
ATE366734T1 (en) | 2003-09-04 | 2007-08-15 | Wockhardt Ltd | BENZOQUINOLICIN 2-CARBONIC ACID ARGININE SALT TETRAHYDRATE |
US20090042936A1 (en) * | 2007-08-10 | 2009-02-12 | Ward Keith W | Compositions and Methods for Treating or Controlling Anterior-Segment Inflammation |
US20140219949A1 (en) * | 2011-06-22 | 2014-08-07 | Jiangsu Deda Pharmaceuticals Co. Ltd | Pharmaceutical compositions comprising iodine and steroid and uses thereof for sinus diseases |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4551456A (en) * | 1983-11-14 | 1985-11-05 | Merck & Co., Inc. | Ophthalmic use of norfloxacin and related antibiotics |
JP2549285B2 (en) * | 1987-02-02 | 1996-10-30 | 第一製薬株式会社 | Nasal spray |
US5563138A (en) * | 1987-04-16 | 1996-10-08 | Otsuka Pharmaceutical Company, Limited | Benzoheterocyclic compounds |
WO1990001933A1 (en) * | 1988-08-26 | 1990-03-08 | Alcon Laboratories, Inc. | Combination of quinolone antibiotics and steroids for topical ophthalmic use |
DK0782448T3 (en) * | 1995-06-06 | 2002-07-08 | Bayer Ag | Non-irritating, non-sensitizing, non-ototoxic antibacterial ear preparations |
JPH10130148A (en) * | 1996-09-04 | 1998-05-19 | Senju Pharmaceut Co Ltd | Composition for nebulizer |
-
1999
- 1999-09-29 CA CA002344050A patent/CA2344050A1/en not_active Abandoned
- 1999-09-29 JP JP2000571922A patent/JP2002525326A/en active Pending
- 1999-09-29 AU AU62759/99A patent/AU6275999A/en not_active Abandoned
- 1999-09-29 WO PCT/US1999/022625 patent/WO2000018404A1/en not_active Application Discontinuation
- 1999-09-29 BR BR9914158-2A patent/BR9914158A/en not_active IP Right Cessation
- 1999-09-29 EP EP99950008A patent/EP1117406A1/en not_active Withdrawn
-
2002
- 2002-01-02 HK HK02100004.2A patent/HK1038692A1/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0018404A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2002525326A (en) | 2002-08-13 |
CA2344050A1 (en) | 2000-04-06 |
BR9914158A (en) | 2001-06-26 |
WO2000018404A1 (en) | 2000-04-06 |
AU6275999A (en) | 2000-04-17 |
HK1038692A1 (en) | 2002-03-28 |
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