US20030139382A1 - Method of treating middle ear infections - Google Patents

Method of treating middle ear infections Download PDF

Info

Publication number
US20030139382A1
US20030139382A1 US10/243,341 US24334102A US2003139382A1 US 20030139382 A1 US20030139382 A1 US 20030139382A1 US 24334102 A US24334102 A US 24334102A US 2003139382 A1 US2003139382 A1 US 2003139382A1
Authority
US
United States
Prior art keywords
dexamethasone
ciprofloxacin
ciprodex
ear
aqueous suspension
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.)
Abandoned
Application number
US10/243,341
Other languages
English (en)
Inventor
G. Wall
Peter Conroy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Inc
Original Assignee
Alcon Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23261416&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030139382(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US10/243,341 priority Critical patent/US20030139382A1/en
Application filed by Alcon Inc filed Critical Alcon Inc
Assigned to ALCON, INC. reassignment ALCON, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CONROY, PETER J., WALL, G. MICHAEL
Publication of US20030139382A1 publication Critical patent/US20030139382A1/en
Priority to US10/946,792 priority patent/US20050059674A1/en
Priority to US12/119,185 priority patent/US20080214513A1/en
Priority to US12/357,697 priority patent/US8846650B2/en
Priority to US14/468,257 priority patent/US9149486B2/en
Priority to US14/838,637 priority patent/US9345714B2/en
Priority to US15/142,225 priority patent/US9402805B1/en
Priority to US15/223,338 priority patent/US20160361324A1/en
Abandoned legal-status Critical Current

Links

Images

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
    • A61K31/573—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 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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 or sparfloxacin
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0046—Ear
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the use of formulations of ciprofloxacin and dexamethasone to treat otic infections. Specifically, the invention relates to the topical use of such a fixed combination to treat middle ear infections in humans.
  • External ear infections known as acute otitis externa (“AOE”)
  • AOE acute otitis externa
  • An example of an oral antibiotic product used to treat AOE is AUGMENTIN® (amoxicillin and clavulanic acid).
  • An example of a single-entity antibiotic product approved for topical use in treating AOE is FLOXIN® (ofloxacin).
  • Examples of combination products approved for this use include CORTISPORIN® (hydrocortisone, neomyciri sulfate, and polymyxin b sulfate) and CIPRO®HC (ciprofloxacin and hydrocortisone).
  • SOFRADEX gramicidin, framycetin and hydrocortisone
  • SOFRADEX gramicidin, framycetin and hydrocortisone
  • External ear infections typically involve bacteria of the following types: Pseudomonas aeruginosa, Staphylococcus aureus. Staphylococcus sp. and Coryneforms.
  • middle ear infections known as otitis media (“OM”) typically involve bacteria of the following types: S. pneumonia, H. influenzae and M. catarrhalis.
  • Patients with chronic or severe middle ear infections may have their ear drums (tympanic membranes) intentionally punctured and drainage tubes, often referred to as a tympanostomy tubes, implanted.
  • tympanic membranes may rupture.
  • open tympanic membranes allow the bacteria characteristic of AOE and OM to mix.
  • the present invention provides a method of topically treating OM in human patients who have open tympanic membranes.
  • the method involves the topical application of a fixed combination of ciprofloxacin and dexamethasone as an aqueous suspension product.
  • the dosing regimen may vary depending on the age and weight of the patient, as well as the severity of the infection, in most cases, the combination product would be applied twice a day.
  • Each application would involve topically administering three or four drops into the ear canal, preferably pumping the tragus to force product through the opening in the tympanic membrane and to the site of the infection/inflammation in the middle ear.
  • the present invention is based on the finding that an aqueous combination of ciprofloxacin and dexamethasone was not statistically more effective than ciprofloxacin alone in the treatment of AOE, but was surprisingly statistically more effective that ciprofloxacin alone in the treatment of OM in patients with an open tympanic membrane.
  • FIG. 1 shows the average number of days to time of cessation of ear pain in a human clinical study comparing a ciprofloxacin/dexamethasone combination product to a ciprofloxacin single-entity product.
  • FIG. 2 shows the average number of days to cessation of otorrhea in a human clinical study comparing a ciprofloxacin/dexamethasone combination product to a ciprofloxacin single-entity product.
  • the methods of the present invention involve diagnosing a human patient as having OM and an open tympanic membrane.
  • Open tympanic membrane means that the membrane has been intentionally punctured, with or without tympanostomy tube implantation, or has accidentally ruptured.
  • the method of the present invention involves topically administering to the ear canal of the patient's affected ear an aqueous suspension formulation of a fixed combination of ciprofloxacin and dexamethasone.
  • OM includes, but is not limited to, acute otitis media and chronic supprative otitis media.
  • Dexamethasone can be present in any ophthalmically or otically acceptable form having poor water solubility such that the resulting formulation is a suspension formulation. Suitable forms of dexamethasone include dexamethasone alcohol (alcohol form of dexamethasone), dexamethasone acetate and dexamethasone phosphate. Dexamethasone alcohol is the preferred form of dexamethasone.
  • the average particle size (mean volume basis) of the dexamethasone ingredient should be less than 10 ⁇ m to avoid irritation or discomfort The average particle size is preferably less than 6 ⁇ m and most preferably less than 3 ⁇ m.
  • Dexamethasone particles can be sized using known techniques, such as ball-milling, microfluidization and sonication.
  • the ciprofloxacin ingredient can be any otically acceptable form such that the ciprofloxacin ingredient is in solution in the final formulation.
  • a preferred form of ciprofloxacin is ciprofloxacin hydrochloride, monohydrate.
  • the dexamethasone ingredient will comprise about 0.01-0.5% and the ciprofloxacin ingredient will comprise about 0.1-0.4% of the aqueous suspension formulations administered according to the present invention.
  • the preferred amounts of dexamethasone and ciprofloxacin in the formulations used in the present invention are 0.1% and 0.3%, respectively.
  • the suspension formulations used in the present invention contain a tonicity agent.
  • the tonicity agent may be ionic (e.g., NaCl) or nonionic (e.g., mannitol).
  • the tonicity agent is preferably NaCl.
  • the amount of NaCl will depend on the desired tonicity for the final formulation, but will generally range from 0.1-0.9%.
  • the suspension formulations of the present invention preferably contain an amount of tonicity agent sufficient to cause the formulations to have an osmolality of about 250-350 mOsm.
  • the suspension formulations also contain a nonionic polymer as a suspending agent.
  • a nonionic polymer as a suspending agent.
  • Many otically acceptable nonionic polymers are known. These polymers include hydroxyethyl cellulose; hydroxypropylmethyl cellulose; methyl cellulose; carboxymethyl cellulose; polyvinyl pyrrolidone and polyvinyl alcohol.
  • the preferred nonionic polymer is hydroxyethyl cellulose.
  • the nonionic polymer will be present in the formulations of the present invention in an amount of about 0.1-0.5%. In the case of hydroxyethyl cellulose, the preferred concentration of nonionic polymer is 0.2%.
  • the formulations of the present invention also contain a nonionic surfactant in an amount from about 0.01-0.2%.
  • a nonionic surfactant in an amount from about 0.01-0.2%.
  • Suitable nonionic surfactants include tyloxapol; polyoxyethylene sorbitan esters, such as polysorbate 20, polysorbate 60, and polysorbate 80; polyethoxylated castor oils, such as Cremaphor EL; polyethoxylated hydrogenated castor oils, such as HCO-40; and poloxamers.
  • the preferred surfactant is tyloxapol.
  • the formulations may contain a quaternary ammonium halide as a preservative.
  • Suitable quaternary ammonium halides include polyquaternium-1 and benzalkonium halides.
  • Preferred benzalkonium halides are benzalkonium chloride (“BAC”) and benzalkonium bromide.
  • BAC benzalkonium chloride
  • the amount of the preservative ingredient will range from about 0.005-0.3%. In the preferred case where the preservative is BAC, it is preferably present at a concentration of 0.01%.
  • a chelating agent may also be present in the suspension formulations used in the methods of the present invention.
  • Suitable chelating agents include edetate disodium (“EDTA”); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate. Most preferred is EDTA.
  • the chelating agent if any, will typically be present in an amount from about 0.001-0.1%. In the case of EDTA, the chelating agent is preferably present at a concentration of 0.01%.
  • the suspension formulations of the present invention may contain boric acid in an amount from 0.1-1.5%.
  • the formulations administered according to the present invention have a pH from 3-6, preferably 4.5. pH can be adjusted with NaOH/HCl.
  • the preferred buffering system for these formulations is a combination of sodium acetate and acetic acid.
  • the concentration of sodium acetate will generally range from 0.015-0.06%, and will preferably be about 0.03%.
  • the concentration of acetic acid will generally range from 0.02-0.08, and will preferably be about 0.04%.
  • the ciprofloxacin/dexamethasone combination products administered according to the present invention will generally be administered twice a day.
  • Each administration will typically involve placing 3-4 drops (with a typical drop volume of 30-35 ⁇ L) of the suspension product in the affected ear.
  • the patient will pump the tragus of the affected ear to force the administered product through the opening in the tympanic membrane and to the site of the infection/inflammation in the middle ear.
  • the present invention relates to a ciprofloxacin/dexamethasone aqueous suspension composition that is packaged with directions for use that indicate the composition may be used to treat otitis media in patients with an open tympanic membrane.
  • directions for use includes information contained in product labeling, package inserts and cartons or other packaging materials that accompany the ciprofloxacin/dexamethasone aqueous suspension composition of the present invention.
  • a B C D E Ingredients % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) Ciprofloxacin HCl, 0.35* 0.35 0.35 0.35 0.35 0.35 Monohydrate Dexamethasone Alcohol 0.1 0.1 0.1 0.1 0.1 Hydroxyethyl Cellulose 0.2 0.2 0.2 0.2 0.2 Benzalkonium Chloride 0.01 0.01 0.01 0.01 0.01 0.01 Sodium Acetate (Trihydrate) 0.03 0.03 0.03 0.03 0.03 0.03 Acetic Acid 0.04 0.04 0.04 0.04 0.04 Sodium Chloride 0.25 0.25 0.80 0.53 — Edetate Disodium 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Tyloxapol 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Glycerin 1.5 — — — 2.35 Boric Acid — — — 0.6 — NaOH/HCl
  • (4) prepare an aqueous solution containing the remaining requirement of tyloxapol and the required amounts of all remaining ingredients (e.g., in the case of Formulation D, the remaining ingredients are ciprofloxacin hydrochloride monohydrate, benzalkonium chloride, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium, and purified water;
  • the remaining ingredients are ciprofloxacin hydrochloride monohydrate, benzalkonium chloride, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium, and purified water;
  • (6) combine the sterile slurry obtained in step 3 to the sterile solution obtained in step 5 by aseptically pouring the slurry through a sterile sieve (to remove the beads) into the solution obtained in step 5;
  • (5) prepare an aqueous solution containing the required amounts of the remaining ingredients (e.g., in the case of Formulation D, the remaining ingredients are ciprofloxacin hydrochloride, monohydrate benzalkonium chloride, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium and purified water;
  • the remaining ingredients are ciprofloxacin hydrochloride, monohydrate benzalkonium chloride, sodium acetate, acetic acid, sodium chloride, hydroxyethylcellulose, boric acid, edetate disodium and purified water;
  • a clinical study with a primary objective of demonstrating superiority of a ciprofloxacin/dexamethasone combination product (“ciprofloxacin 0.3%, dexamethasone 0.1%; Formulation D above) (“CIPRODEX”) relative to the marketed CILOXAN® single-agent (ciprofloxacin 0.3%; Alcon Laboratories, Inc.) product for time to cessation of ear pain in patients with moderate to severe acute otitis externa (AOE) was conducted.
  • a summary of the study details for this AOE study is provided below. Summary of AOE Study CIPRODEX (Ciprofloxacin 0.3%) Suspension vs.
  • CILOXAN (Ciprofloxacin 0.3%) Solution vs. CORTISPORIN Suspension (Neomycin 0.35%, Polymyxin B 10,000 IU/mL, Hydrocortisone 1.0%) for Topical Treatment of patients with moderate to severe Acute Otitis Externa (AOE).
  • Study Design Phase III multicenter, randomized, single-blind, active controlled, parallel group study. Study Primary objectives of the study were to demonstrate: Objectives: Superiority of CIPRODEX combination relative to CILOXAN single agent for time to cessation of ear pain. Therapeutic non-inferiority of CIPRODEX combination relative to CILOXAN single agent based on clinical response at the test of cure (TOC) visit (Day 18).
  • Study Visits Day 1, Day 3, Day 8 (End of Therapy, EOT), and Day 18 (TOC).
  • Evaluation Physician evaluation of signs and symptoms of AOE, including inflammation, tenderness, edema, and otic discharge by visit.
  • Microbiology Microbiology outcomes were based on presumed or confirmed bacterial eradication.
  • Efficacy Cessation of ear pain was defined as the first day where the patient dairy Criteria: pain score was zero, with no analgesics used in the prior 24 hours, and the ear pain score remained zero for all subsequent entries.
  • CILOXAN treatments i.e., no contribution of elements.
  • CIPRODEX is non-inferior to CILOXAN for clinical cures and microbiological eradication.
  • CIPRODEX produces more clinical cures than CORTISPORIN and is non-inferior for microbiological eradication.
  • CILOXAN is superior to CORTISPORIN for clinical response in culture positive patients, and non-inferior for microbial eradication.
  • CIPRODEX and CILOXAN are safe and well tolerated in pediatric and adult patients with AOE.
  • Study Visits Day 1, Day 3, Day 8 (End of Therapy, EOT), and Day 14 (Test of Cure, TOC).
  • Physician evaluation of signs and symptoms of AOMT including presence of otorrhea, characteristics of otorrhea, presence of granulation tissue, tube patency, and overall clinical response by visit.
  • Microbiology Microbiology outcomes were based on presumed or confirmed bacterial eradication.
  • CIPRODEX is statistically significantly more effective than CILOXAN for Physician's Clinical Impression at the Day 3 Visit, but not at the Day 8 or Day 14 Visits (using Cochran-Mantel-Haenszel Rank Scores Test). No statistically significant differences were detected between CIPRODEX and CILOXAN for Microbiological Eradication Rates at the Test of Cure Visit (using Fisher's Exact Test). CIPRODEX and CILOXAN are safe and well tolerated in pediatric with AOMT.
  • the results of this study for the MITT population are presented in Table 2 and FIG. 2.
  • the MITT population is defined as the population that received study drug, met inclusion criteria, participated in at least one on-therapy visit, and was culture positive for bacteria on Day 1.
  • the MITT population for this study comprised 87 patients for CIPRODEX and 80 patients for CILOXAN.
  • Study Design Phase III, randomized, evaluator-masked, active-controlled, parallel-group study.
  • Patient Population Approximately 500 pediatric patients with AOMT and post-tympanostomy tube otorrhea (250/arm) were planned. A total of 599 patients were enrolled.
  • Duration of Treatment Patients were required to undergo treatment for either seven (7) days if randomized to receive CIPRODEX or ten (10) days if randomized to receive FLOXIN.
  • Criteria for Evaluation Subsequent to the demonstration of non-inferiority, superiority analyses were conducted. Analyses for the determination of superiority were based on the data set of patients who received treatment, had a positive pre-therapy culture and met the inclusion/exclusion criteria for enrollment (modified intent-to-treat, MITT). Analyses were also conducted for the intent-to-treat (ITT), per protocol (PP) and modified per protocol (MPP) data sets.
  • ITT intent-to-treat
  • PP per protocol
  • MPP modified per protocol
  • Safety The safety evaluation was conducted on all patients who were randomized into the study and received at least one dose of study drug. The safety analysis was based on the following; extent of exposure to study drug; adverse events; and audiometry examination.
  • CIPRODEX Otic Suspension is superior to FLOXIN Otic Solution in clinical and microbiological response at the test of cure (TOC) visit;
  • CIPRODEX Otic Suspension is effective and safe for the treatment of pediatric patients with acute otitis media and otorrhea with tympanosotomy tubes (AOMT).
  • AOMT tympanosotomy tubes
  • CIPRODEX was superior to FLOXIN for treatment failure rate (p ⁇ 0.0189).
  • CIPRODEX was superior to FLOXIN for time to cessation of otorrhea for all data sets (p ⁇ 0.018). Clinically, this translates to the cessation of otorrhea in 20 to 33% less time for the CIPRODEX treated patients in comparison to the FLOXIN treated patients (median time of 4 days for CIPRODEX versus 5-6 days for FLOXIN).
  • CIPRODEX is effective in treating acute otitis media with otorrhea in tympanostomy (AOMT) patients and results in 90% patients with clinical cure, 92% patients with microbiological success and a 4-day median time to cessation of otorrhea.
  • CIPRODEX is superior to FLOXIN for clinical cures at the TOC visit.
  • Clinical Cure Rates and 95% Confidence Intervals by Treatment Group (All Data Sets) Treatment CIPRODEX FLOXIN Clinical Cure Clinical Cure No Yes No Yes Data Set N % N % N % N % Delta Lower Upper P-value a ITT 75 25.25 222 74.75 117 38.74 185 61.26 13.49 6.10 20.88 0.0004 MITT 43 20.67 165 79.33 78 36.11 138 63.89 15.44 6.99 23.88 0.0004 PP 28 12.07 204 87.93 50 22.73 170 77.27 10.66 3.71 17.60 0.0027 MPP 18 10.00 162 90.00 37 21.76 133 78.24 11.76 4.17 19.36 0.0025
  • CIPRODEX is superior to FLOXIN for microbiological eradication at the TOC visit.
  • Treatment CIPRODEX FLOXIN Microbiological Microbiological Eradication Eradication Failure Success Failure Success Data Set N % N % N % N % Delta Lower Upper P-value a ITT 128 43.10 169 56.90 154 50.99 148 49.01 7.90 ⁇ 0.07 15.87 0.0529 MITT 41 19.71 167 80.29 72 33.33 144 66.67 13.62 5.33 21.91 0.0015 PP 67 28.88 165 71.12 81 36.82 139 63.18 7.94 ⁇ 0.70 16.58 0.0722 MPP 15 8.33 165 91.67 31 18.24 139 81.76 9.90 2.83 16.97 0.0061
  • CIPRODEX is superior to FLOXIN for treatment failure rate. Discontinuations Due to Treatment Failure by Treatment Group Treatment CIPRODEX FLOXIN Treatment Failure Treatment Failure No Yes No Yes Data Set N % N % N % N % P-value ITT 281 94.61 16 5.39 270 89.40 32 10.60 0.0189 MITT 199 95.67 9 4.33 192 88.89 24 11.11 0.0091 PP 220 94.83 12 5.17 188 85.45 32 14.55 0.0008 MPP 172 95.56 8 4.44 146 85.88 24 14.12 0.0017
  • CIPRODEX is superior to FLOXIN for improvement in clinical response at Days 3, 11 and 18.
  • Clinical Response by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit Clinical Response N % N % P-value a Day 3 Missing 1 0 0 0 ⁇ .000 1 Cured 64 30.92 38 17.59 Improved 130 62.80 134 62.04 Unchanged 9 4.35 35 16.20 Worse 4 1.93 9 4.17 Day 11 Missing 1 0 0 0 ⁇ .0001 Cured 174 84.06 136 62.96 Improved 25 12.08 58 26.85 Unchanged 4 1.93 12 5.56 Worse 4 1.93 10 4.63 Day 18 Missing 1 0 0 0 0.0023 Cured 174 84.06 153 70.83 Improved 20 9.66 38 17.59 Unchanged 6 2.90 12 5.56 Worse 7 3.38 13 6.02
  • CIPRODEX is superior to FLOXIN for time to cessation of otorrhea.
  • Time to Cessation of Otorrhea by Treatment Group (MITT) Treatment CIPRODEX FLOXIN P-value a Mean 6.02 7.10 0.0204 Median 4.00 5.00 Std 4.87 4.68 N 208 216 Min 2 2 Max 21 21
  • CIPRODEX is superior to FLOXIN for absence of otorrhea at Days 3, 11 and 18. Presence/Absence of Otorrhea by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit Otorrhea N % N % P-value a Day 1 Present 208 100.00 216 100.00 Day 3 Absent 67 32.21 40 18.52 0.0012 Present 141 67.79 176 81.48 Day 11 Absent 176 84.62 137 63.43 ⁇ .0001 Present 32 15.38 79 36.57 Day 18 Missing 1 0 0 0 0.0004 Absent 176 85.02 153 70.83 Present 31 14.98 63 29.17
  • CIPRODEX is superior to FLOXIN for reduction in granulation tissue at Days 11 and 18.
  • Granulation Tissue by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit Granulation Tissue N % N % P-value a Day 1 Absent 159 76.44 175 81.02 0.3449 Mild 30 14.42 21 9.72 Moderate 15 7.21 16 7.41 Severe 4 1.92 4 1.85 Day 3 Missing 1 0 0 0 0.3285 Absent 177 85.51 182 84.26 Mild 24 11.59 22 10.19 Moderate 6 2.90 10 4.63 Severe 0 0.00 2 0.93 Day 11 Missing 1 0 0 0 0.0086 Absent 198 95.65 186 86.11 Mild 8 3.86 22 10.19 Moderate 1 0.48 8 3.70 Day 18 Missing 1 0 0 0 0.0383 Absent 203 98.07 192 88.89 Mild 3 1.45 21 9.72 Moderate 1 0.48 3 1.39
  • CIPRODEX is superior to FLOXIN for reduction in otorrhea volume at Days 3, 11 and 18.
  • Volume by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit Volume N % N % P-value a Day 1 Scant 17 8.17 14 6.48 0.3195 Moderate 104 50.00 99 45.83 Copious 87 41.83 103 47.69 Day 3 Missing 1 0 0 0 ⁇ .0001 Absent 66 31.88 39 18.06 Scant 98 47.34 84 38.89 Moderate 34 16.43 77 35.65 Copious 9 4.35 16 7.41 Day 11 Missing 1 0 0 0 ⁇ .0001 Absent 175 84.54 136 62.96 Scant 19 9.18 42 19.44 Moderate 7 3.38 26 12.04 Copious 6 2.90 12 5.56 Day 18 Missing 2 0 0 0 0.0003 Absent 175 84.95 153 70.83 Scant 14 6.80 21 9.72 Moderate 8 3.88 27 12.50 Copious 9 4.
  • CIPRODEX is superior to FLOXIN for absence of otorrhea color and less purulent otorrhea at Day 3, and absence of otorrhea color and less mucoid otorrhea at Days 11 and 18.
  • SRT mean change of speech reception threshold
  • CIPRODEX administered twice daily in the affected ear(s) is safe and well tolerated in pediatric patients with acute otitis media with tympanostomy tubes, based upon a review of adverse events and an assessment of audiometry parameters.
  • CIPRODEX administered twice daily in the affected ear(s) is safe and well tolerated in pediatric patients with acute otitis media with tympanostomy tubes, based upon a review of adverse events and an assessment of audiometry parameters.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
US10/243,341 2001-09-21 2002-09-13 Method of treating middle ear infections Abandoned US20030139382A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US10/243,341 US20030139382A1 (en) 2001-09-21 2002-09-13 Method of treating middle ear infections
US10/946,792 US20050059674A1 (en) 2001-09-21 2004-09-22 Method of treating middle ear infections
US12/119,185 US20080214513A1 (en) 2001-09-21 2008-05-12 Method of treating middle ear infections
US12/357,697 US8846650B2 (en) 2001-09-21 2009-02-13 Method of treating middle ear infections
US14/468,257 US9149486B2 (en) 2001-09-21 2014-08-25 Method of treating middle ear infections
US14/838,637 US9345714B2 (en) 2001-09-21 2015-08-28 Method of treating middle ear infections
US15/142,225 US9402805B1 (en) 2001-09-21 2016-04-29 Method of treating middle ear infections
US15/223,338 US20160361324A1 (en) 2001-09-21 2016-07-29 Method of treating middle ear infections

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32395101P 2001-09-21 2001-09-21
US10/243,341 US20030139382A1 (en) 2001-09-21 2002-09-13 Method of treating middle ear infections

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/946,792 Division US20050059674A1 (en) 2001-09-21 2004-09-22 Method of treating middle ear infections

Publications (1)

Publication Number Publication Date
US20030139382A1 true US20030139382A1 (en) 2003-07-24

Family

ID=23261416

Family Applications (8)

Application Number Title Priority Date Filing Date
US10/243,341 Abandoned US20030139382A1 (en) 2001-09-21 2002-09-13 Method of treating middle ear infections
US10/946,792 Abandoned US20050059674A1 (en) 2001-09-21 2004-09-22 Method of treating middle ear infections
US12/119,185 Abandoned US20080214513A1 (en) 2001-09-21 2008-05-12 Method of treating middle ear infections
US12/357,697 Expired - Lifetime US8846650B2 (en) 2001-09-21 2009-02-13 Method of treating middle ear infections
US14/468,257 Expired - Fee Related US9149486B2 (en) 2001-09-21 2014-08-25 Method of treating middle ear infections
US14/838,637 Expired - Fee Related US9345714B2 (en) 2001-09-21 2015-08-28 Method of treating middle ear infections
US15/142,225 Expired - Fee Related US9402805B1 (en) 2001-09-21 2016-04-29 Method of treating middle ear infections
US15/223,338 Abandoned US20160361324A1 (en) 2001-09-21 2016-07-29 Method of treating middle ear infections

Family Applications After (7)

Application Number Title Priority Date Filing Date
US10/946,792 Abandoned US20050059674A1 (en) 2001-09-21 2004-09-22 Method of treating middle ear infections
US12/119,185 Abandoned US20080214513A1 (en) 2001-09-21 2008-05-12 Method of treating middle ear infections
US12/357,697 Expired - Lifetime US8846650B2 (en) 2001-09-21 2009-02-13 Method of treating middle ear infections
US14/468,257 Expired - Fee Related US9149486B2 (en) 2001-09-21 2014-08-25 Method of treating middle ear infections
US14/838,637 Expired - Fee Related US9345714B2 (en) 2001-09-21 2015-08-28 Method of treating middle ear infections
US15/142,225 Expired - Fee Related US9402805B1 (en) 2001-09-21 2016-04-29 Method of treating middle ear infections
US15/223,338 Abandoned US20160361324A1 (en) 2001-09-21 2016-07-29 Method of treating middle ear infections

Country Status (19)

Country Link
US (8) US20030139382A1 (enExample)
EP (1) EP1429780B1 (enExample)
JP (1) JP2005504804A (enExample)
KR (1) KR20040035760A (enExample)
CN (1) CN1231218C (enExample)
AT (1) ATE313328T1 (enExample)
AU (1) AU2002333671B2 (enExample)
BR (1) BR0212898A (enExample)
CA (1) CA2459930C (enExample)
CY (1) CY1104988T1 (enExample)
DE (1) DE60208216T2 (enExample)
DK (1) DK1429780T3 (enExample)
ES (1) ES2250739T3 (enExample)
FR (1) FR13C0012I2 (enExample)
MX (1) MXPA04002576A (enExample)
PL (1) PL212457B1 (enExample)
RU (1) RU2295346C2 (enExample)
WO (1) WO2003026671A1 (enExample)
ZA (1) ZA200401847B (enExample)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070098679A1 (en) * 2002-11-27 2007-05-03 Regents Of The University Of Minnesota Methods and Compositions for Applying Pharmacologic Agents to the Ear
US20070110788A1 (en) * 2005-11-14 2007-05-17 Hissong James B Injectable formulation capable of forming a drug-releasing device
US20070264310A1 (en) * 2006-05-10 2007-11-15 Medtronic, Inc. Solvating system and sealant for medical use in the middle or inner ear
US20070264342A1 (en) * 2006-05-10 2007-11-15 Medtronic, Inc. Solvating system and sealant for medical use in the sinuses and nasal passages
US20070264296A1 (en) * 2006-05-10 2007-11-15 Myntti Matthew F Biofilm extracellular polysachharide solvating system
US20080139545A1 (en) * 2006-05-22 2008-06-12 Won-Taek Choe Formulation to treat ear infection
WO2008085913A1 (en) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Methods for treating, preventing, or reducing the risk of opthalmic, otic, and nasal infections
US20080195037A1 (en) * 2007-02-08 2008-08-14 James Britton Hissong Film forming polymeric sealant for medical use
US20090011045A1 (en) * 2004-12-09 2009-01-08 Bayer Healthcare Ag Pharmaceutical for Hygienic Administration in the Ear
US20100009952A1 (en) * 2008-05-14 2010-01-14 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US20100016450A1 (en) * 2008-07-21 2010-01-21 Otonomy, Inc. Controlled release delivery devices for the treatment of otic disorders
US20100086576A1 (en) * 2008-10-06 2010-04-08 Myntti Matthew F Antimicrobial composition and methods of making and using same
US20100144719A1 (en) * 2008-12-05 2010-06-10 Kabra Bhagwati P Pharmaceutical suspension
US20100227904A1 (en) * 2009-03-03 2010-09-09 Alcon Research, Ltd. Pharmaceutical Composition for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye
US20100226992A1 (en) * 2009-03-03 2010-09-09 Alcon Research, Ltd. Pharmaceutical Composition for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye
US7976873B2 (en) 2006-05-10 2011-07-12 Medtronic Xomed, Inc. Extracellular polysaccharide solvating system for treatment of bacterial ear conditions
WO2011049958A3 (en) * 2009-10-21 2011-09-09 Otonomy, Inc. Modulation of gel temperature of poloxamer-containing formulations
US8784790B2 (en) 2008-06-12 2014-07-22 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US20150119371A1 (en) * 2013-10-30 2015-04-30 Micro Labs Limited Topical pharmaceutical compositions of antibiotics and steroidal anti inflammatory agents
US9205048B2 (en) 2008-07-21 2015-12-08 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
US10653133B2 (en) 2011-05-10 2020-05-19 Next Science IP Holdings Pty Ltd Antimicrobial solid and methods of making and using same

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1429780T3 (da) * 2001-09-21 2006-02-13 Fremgangsmåde til behandling af mellemoreinfektioner
PE20060489A1 (es) * 2004-08-13 2006-06-19 Schering Plough Ltd Formulacion farmaceutica que comprende un antibiotico, un triazol y un corticosteroide
US20090263345A1 (en) * 2008-01-28 2009-10-22 Foresight Biotherapeutics, Inc. Otic compositions for the treatment of infections of the internal and external ear in mammals
AU2009274137B2 (en) * 2008-07-21 2013-10-31 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US20120082627A1 (en) * 2009-06-08 2012-04-05 Otic Pharma Ltd. Otic foam formulations
ES2658995T3 (es) * 2012-12-26 2018-03-13 Otic Pharma Ltd. Composiciones farmacéuticas óticas espumables
CA2954170A1 (en) * 2014-07-03 2016-01-07 Otonomy, Inc. Sterilization of ciprofloxacin composition
US9393243B1 (en) * 2015-07-14 2016-07-19 Nilesh Parikh Topical Ciprofloxacin compositions
EP3512513A4 (en) 2016-09-16 2020-04-15 Otonomy, Inc. OTIC GEL FORMULATIONS FOR THE TREATMENT OF EXTERNAL OTITIS
IT201900005280A1 (it) * 2019-04-05 2020-10-05 Ntc S R L Composizione otologica

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3134718A (en) * 1963-12-12 1964-05-26 Schering Corp Pregna-1,4-dienes and compositions containing same
US4670444B1 (en) * 1980-09-03 1999-02-09 Bayer Ag and-naphthyridine-3-carboxylic acids and antibacte7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-rial agents containing these compounds
US5223493A (en) * 1984-12-28 1993-06-29 Alcon Laboratories, Inc. Anti-inflammatory compounds for ophthalmic use
US4686214A (en) * 1985-10-30 1987-08-11 Alcon Laboratories, Inc. Anti-inflammatory compounds for ophthalmic use
DE3704907A1 (de) * 1987-02-17 1988-08-25 Bayer Ag Topisch anwendbare zubereitungen von gyrase-inhibitoren in kombination mit kortikosteroiden
AU4201189A (en) * 1988-08-26 1990-03-23 Alcon Laboratories, Inc. Combination of quinolone antibiotics and steroids for topical ophthalmic use
SU1811833A1 (ru) * 1989-06-09 1993-04-30 Vladimir I Ivanov Способ введения лекарственных средств в ухо 2
ATE162081T1 (de) * 1991-09-17 1998-01-15 Alcon Lab Inc Chinolan-antibiotika und polystyrolsulfonat enthaltende zusammensetzungen
ES2065846B1 (es) 1993-04-20 1995-10-01 Cusi Lab Formulacion farmaceutica a base de un agente antiinflamatorio esteroidico o no esteroidico y un antibiotico pertenciente al grupo de los inhibidores de la adn girasa para su utilizacion topica oftalmica.
US5540930A (en) * 1993-10-25 1996-07-30 Pharmos Corporation Suspension of loteprednol etabonate for ear, eye, or nose treatment
US5420120A (en) * 1993-12-17 1995-05-30 Alcon Laboratories, Inc. Anti-inflammatory glucocorticoid compounds for topical ophthalmic use
ES2078175B1 (es) 1993-12-31 1996-10-16 Cusi Lab Formulacion farmaceutica conteniendo clobetasona y tobramicina y sus aplicaciones.
ES2079320B1 (es) * 1994-05-17 1996-10-16 Cusi Lab Disolucion oftalmica a base de un diclofenaco y tobramicina y sus aplicaciones.
EP0782448B1 (en) 1995-06-06 2002-03-27 Bayer Aktiengesellschaft Non-irritation, non-sensitizing, non-ototoxic otic antibacterial compositions
US5843930A (en) * 1995-06-06 1998-12-01 Bayer Corporation Method of treating otitis with ciprofloxacin-hydrocortisone suspension
DE19524691A1 (de) * 1995-07-06 1997-01-09 Liedtke Pharmed Gmbh Methode und Zusammensetzung einer topischen Therapie von Innenohr und Labyrinth-Symptomen
ES2106680B1 (es) * 1995-08-03 1998-07-01 Vita Invest Sa Composiciones acuosas conteniendo ciprofloxacino y utilizacion y procedimiento correspondientes.
KR100508227B1 (ko) 1997-03-14 2006-03-23 센주 세이야꾸 가부시키가이샤 로테프레드놀에타보네이트수성현탁액
AR020660A1 (es) 1998-09-30 2002-05-22 Alcon Lab Inc Composiciones antibioticas para el tratamiento de ojos, oidos y nariz
AR020661A1 (es) 1998-09-30 2002-05-22 Alcon Lab Inc Una composicion farmaceutica topica oftalmica, otica o nasal y el uso de la misma para la manufactura de un medicamento
WO2000018404A1 (en) 1998-09-30 2000-04-06 Alcon Laboratories, Inc. Antibiotic compositions for treatment of the eye, ear and nose
US6395746B1 (en) * 1998-09-30 2002-05-28 Alcon Manufacturing, Ltd. Methods of treating ophthalmic, otic and nasal infections and attendant inflammation
PL201130B1 (pl) * 1999-09-24 2009-03-31 Alcon Inc Kompozycje zawiesinowe zawierające ciprofloksacynę i deksametazon do podawania miejscowego do oczu, uszu lub nosa
DK1429780T3 (da) * 2001-09-21 2006-02-13 Fremgangsmåde til behandling af mellemoreinfektioner

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9592196B2 (en) 2002-11-27 2017-03-14 Regents Of The University Of Minnesota Methods and compositions for applying pharmacologic agents to the ear
US8734836B2 (en) * 2002-11-27 2014-05-27 Regents Of The University Of Minnesota Methods and compositions for applying pharmacologic agents to the ear
US20070098679A1 (en) * 2002-11-27 2007-05-03 Regents Of The University Of Minnesota Methods and Compositions for Applying Pharmacologic Agents to the Ear
US20090011045A1 (en) * 2004-12-09 2009-01-08 Bayer Healthcare Ag Pharmaceutical for Hygienic Administration in the Ear
US20070110788A1 (en) * 2005-11-14 2007-05-17 Hissong James B Injectable formulation capable of forming a drug-releasing device
US20070264310A1 (en) * 2006-05-10 2007-11-15 Medtronic, Inc. Solvating system and sealant for medical use in the middle or inner ear
US8691288B2 (en) 2006-05-10 2014-04-08 Medtronic, Inc. Gallium-containing sealant for medical use
US20090258086A1 (en) * 2006-05-10 2009-10-15 Medtronic Xomed, Inc. Biofilm extracellular polysaccharide solvating system
US7993675B2 (en) 2006-05-10 2011-08-09 Medtronic Xomed, Inc. Solvating system and sealant for medical use in the sinuses and nasal passages
US7976875B2 (en) 2006-05-10 2011-07-12 Medtronic Xomed, Inc. Biofilm extracellular polysaccharide solvating system
US7976873B2 (en) 2006-05-10 2011-07-12 Medtronic Xomed, Inc. Extracellular polysaccharide solvating system for treatment of bacterial ear conditions
US7959943B2 (en) 2006-05-10 2011-06-14 Medtronics Xomed, Inc. Solvating system and sealant for medical use in the middle or inner ear
US20070264342A1 (en) * 2006-05-10 2007-11-15 Medtronic, Inc. Solvating system and sealant for medical use in the sinuses and nasal passages
US20070264296A1 (en) * 2006-05-10 2007-11-15 Myntti Matthew F Biofilm extracellular polysachharide solvating system
US20080139545A1 (en) * 2006-05-22 2008-06-12 Won-Taek Choe Formulation to treat ear infection
WO2008085913A1 (en) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Methods for treating, preventing, or reducing the risk of opthalmic, otic, and nasal infections
US8088095B2 (en) 2007-02-08 2012-01-03 Medtronic Xomed, Inc. Polymeric sealant for medical use
US9119896B2 (en) 2007-02-08 2015-09-01 Medtronic Xomed, Inc. Polymeric sealant for medical use
US20080195037A1 (en) * 2007-02-08 2008-08-14 James Britton Hissong Film forming polymeric sealant for medical use
US20110008456A1 (en) * 2008-05-14 2011-01-13 Otonomy, Inc. Controlled Release Corticosteroid Compositions and Methods for the Treatment of Otic Disorders
RU2469726C2 (ru) * 2008-05-14 2012-12-20 Отономи, Инк. Композиции с контролируемым высвобождением на основе кортикостероидов для лечения ушных болезней
US9511020B2 (en) 2008-05-14 2016-12-06 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US20100009952A1 (en) * 2008-05-14 2010-01-14 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8828980B2 (en) 2008-05-14 2014-09-09 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8030297B2 (en) 2008-05-14 2011-10-04 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of OTIC disorders
WO2009139924A3 (en) * 2008-05-14 2010-04-01 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US9744126B2 (en) 2008-05-14 2017-08-29 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
CN102026623B (zh) * 2008-05-14 2013-08-14 奥德纳米有限公司 用于治疗耳部病症的控制释放皮质类固醇组合物和方法
US8546363B2 (en) 2008-05-14 2013-10-01 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8658626B2 (en) 2008-05-14 2014-02-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8680083B2 (en) 2008-05-14 2014-03-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8680082B2 (en) 2008-05-14 2014-03-25 Otonomy, Inc. Controlled release corticosteroid compositions and methods for the treatment of otic disorders
US8784790B2 (en) 2008-06-12 2014-07-22 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US9700344B2 (en) 2008-06-12 2017-07-11 Medtronic Xomed, Inc. Method for treating chronic wounds with an extracellular polymeric substance solvating system
US9205048B2 (en) 2008-07-21 2015-12-08 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9603796B2 (en) 2008-07-21 2017-03-28 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US11369566B2 (en) 2008-07-21 2022-06-28 Alk-Abelló, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US10772828B2 (en) 2008-07-21 2020-09-15 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US9867778B2 (en) 2008-07-21 2018-01-16 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of otic disorders
US20100016450A1 (en) * 2008-07-21 2010-01-21 Otonomy, Inc. Controlled release delivery devices for the treatment of otic disorders
US9233068B2 (en) 2008-07-21 2016-01-12 Otonomy, Inc. Controlled release antimicrobial compositions and methods for the treatment of OTIC disorders
US8940792B2 (en) 2008-10-06 2015-01-27 Next Science, Llc Antimicrobial composition and methods for using same
US20100086576A1 (en) * 2008-10-06 2010-04-08 Myntti Matthew F Antimicrobial composition and methods of making and using same
US9707173B2 (en) 2008-12-05 2017-07-18 Alcon Research, Ltd. Pharmaceutical suspension
US20100144719A1 (en) * 2008-12-05 2010-06-10 Kabra Bhagwati P Pharmaceutical suspension
WO2010065730A2 (en) 2008-12-05 2010-06-10 Alcon Research, Ltd. Pharmaceutical suspension
US20100227904A1 (en) * 2009-03-03 2010-09-09 Alcon Research, Ltd. Pharmaceutical Composition for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye
US20100226992A1 (en) * 2009-03-03 2010-09-09 Alcon Research, Ltd. Pharmaceutical Composition for Delivery of Receptor Tyrosine Kinase Inhibiting (RTKi) Compounds to the Eye
US8912236B2 (en) 2009-03-03 2014-12-16 Alcon Research, Ltd. Pharmaceutical composition for delivery of receptor tyrosine kinase inhibiting (RTKi) compounds to the eye
WO2011049958A3 (en) * 2009-10-21 2011-09-09 Otonomy, Inc. Modulation of gel temperature of poloxamer-containing formulations
US10653133B2 (en) 2011-05-10 2020-05-19 Next Science IP Holdings Pty Ltd Antimicrobial solid and methods of making and using same
US9486405B2 (en) 2013-08-27 2016-11-08 Otonomy, Inc. Methods for the treatment of pediatric otic disorders
US20150119371A1 (en) * 2013-10-30 2015-04-30 Micro Labs Limited Topical pharmaceutical compositions of antibiotics and steroidal anti inflammatory agents

Also Published As

Publication number Publication date
FR13C0012I1 (enExample) 2013-04-05
US20140363511A1 (en) 2014-12-11
ATE313328T1 (de) 2006-01-15
KR20040035760A (ko) 2004-04-29
DE60208216T2 (de) 2006-06-29
US20080214513A1 (en) 2008-09-04
US8846650B2 (en) 2014-09-30
US20160243029A1 (en) 2016-08-25
PL212457B1 (pl) 2012-10-31
RU2004111984A (ru) 2005-02-27
WO2003026671A1 (en) 2003-04-03
ES2250739T3 (es) 2006-04-16
EP1429780B1 (en) 2005-12-21
US20160361324A1 (en) 2016-12-15
CN1555267A (zh) 2004-12-15
US20090156566A1 (en) 2009-06-18
US9345714B2 (en) 2016-05-24
US9402805B1 (en) 2016-08-02
CA2459930A1 (en) 2003-04-03
AU2002333671B2 (en) 2006-07-20
US20050059674A1 (en) 2005-03-17
DE60208216D1 (de) 2006-01-26
EP1429780A1 (en) 2004-06-23
JP2005504804A (ja) 2005-02-17
CN1231218C (zh) 2005-12-14
US20150374716A1 (en) 2015-12-31
DK1429780T3 (da) 2006-02-13
RU2295346C2 (ru) 2007-03-20
BR0212898A (pt) 2004-10-13
ZA200401847B (en) 2005-05-25
CA2459930C (en) 2009-11-10
MXPA04002576A (es) 2004-06-18
PL369205A1 (en) 2005-04-18
CY1104988T1 (el) 2009-11-04
US9149486B2 (en) 2015-10-06
FR13C0012I2 (fr) 2014-02-14

Similar Documents

Publication Publication Date Title
US9402805B1 (en) Method of treating middle ear infections
AU2002333671A1 (en) Method of treating middle ear infections
EP1575597B1 (en) Use of rimexolone in the treatment of dry eye
Tracy et al. Intranasal beclomethasone as an adjunct to treatment of chronic middle ear effusion
US20010034339A1 (en) Topical suspension formulations containing ciprofloxacin and dexamethasone
WO2013078998A1 (en) Novel slow-releasing ophthalmic compositions comprising povidone iodine
US9114168B2 (en) Pharmaceutical compositions containing a fluoroquinolone antibiotic drug
BRPI0900723B1 (pt) Composição oftálmica tópica para tratar ou prevenir infecções oftálmicas bacterianas em um paciente humano
AU2006295248A1 (en) Methods for treatment and prevention of otitis media using nonionic surfactants to facilitate transmembrane drug delivery into the middle ear
Nyalazi et al. A Rare Case of Bilateral Post Intravitreal Avastin Endophthalmitis with Bilateral Good Visual Outcome–A Case Report
Theodosiadis et al. Non-inferiority evaluation of preservative-free latanoprost/timolol eye drops solution versus preserved latanoprost/timolol eye drops in patients with high intraocular pressure and open-angle glaucoma
HK1076248B (en) Use of rimexolone in the treatment of dry eye

Legal Events

Date Code Title Description
AS Assignment

Owner name: ALCON, INC., SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WALL, G. MICHAEL;CONROY, PETER J.;REEL/FRAME:013302/0801

Effective date: 20020912

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION