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WO2005000307A1 - Composition ophtalmique contenant des quinolones et procede d'utilisation - Google Patents

Composition ophtalmique contenant des quinolones et procede d'utilisation Download PDF

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Publication number
WO2005000307A1
WO2005000307A1 PCT/US2004/020448 US2004020448W WO2005000307A1 WO 2005000307 A1 WO2005000307 A1 WO 2005000307A1 US 2004020448 W US2004020448 W US 2004020448W WO 2005000307 A1 WO2005000307 A1 WO 2005000307A1
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WIPO (PCT)
Prior art keywords
composition
concentration
polyhydric alcohol
levofloxacin
quinolone compound
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.)
Ceased
Application number
PCT/US2004/020448
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English (en)
Inventor
Paul A. Laskar
Shawn D. Hickok
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.)
Daiichi Pharmaceutical Co Ltd
Santen Pharmaceutical Co Ltd
Original Assignee
Daiichi Pharmaceutical Co Ltd
Santen Pharmaceutical Co Ltd
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
Priority claimed from US10/877,280 external-priority patent/US20050009836A1/en
Application filed by Daiichi Pharmaceutical Co Ltd, Santen Pharmaceutical Co Ltd filed Critical Daiichi Pharmaceutical Co Ltd
Priority to JP2006517670A priority Critical patent/JP4758893B2/ja
Publication of WO2005000307A1 publication Critical patent/WO2005000307A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

Definitions

  • the present invention relates to ophthalmic compositions containing quinolones and to methods for using such solutions for treating infections and preserving solutions.
  • Eye infections account for a large proportion of the workload in ophthalmic centers. These infections may be vision- or life-threatening, and prompt treatment of patients with these infections is essential.
  • a number of antibiotic components including quinolones, are currently used in ocular application to control, manage or prevent ocular infections (Schwab, I.R., et al. (2003) Ophthalmology 110(3):457-65).
  • a topical ophthalmic composition containing the quinolone ciprofloxacin is marketed by Alcon Laboratories, Inc.
  • a topical otic composition containing a combination of ciprofloxacin and hydrocortisone is marketed by Alcon Laboratories, Inc.
  • Ofloxacin, norfloxacin and lomefloxacin, levofloxacin, moxifloxacin, gatifloxacin have also been utilized in ophthalmic antibiotic compositions.
  • These 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.
  • the invention includes an ophthalmic composition consisting essentially of a quinolone compound and an aqueous carrier vehicle.
  • the quinolone compound is levofloxacin, moxifloxacin, gatifloxacin, or ofloxacin, in an amount effective as an antibiotic when the composition is placed in the eye.
  • the aqueous carrier vehicle contains a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic.
  • the composition is characterized by: (i) having a pH between 6 and 7, (ii) lacking an antimicrobial preservative component other than that possessed by the quinolone compound, (iii) being sufficiently self-preserved to pass the
  • the quinolone compound may be levofloxacin, at a concentration between 0.3 and 4.0 %w/v, preferably between 1.0 and 3.0 %w/v.
  • the polyhydric alcohol may be one or more of the alcohols, glycerin, propylene glycol, polyethylene glycol having an average molecular weight less than 1000 daltons, mannitol or sorbitol.
  • the polyhydric alcohol includes glycerin at a concentration of about 2.3 v/v percent, propylene glycol, at a concentration of about 2 v/v percent, polyethylene glycol having an average molecular weight between 200 and 1500 daltons and a concentration between about 2 and 8 % w/v, mannitol, at a concentration of about 4 % w/v, or sorbitol, at a concentration of about 4 % w/v.
  • the composition is used, in another aspect of the invention, in treating an ophthalmic infection, by placing the composition in the affected eye, e.g., in droplet form.
  • the invention includes an improvement for enhancing the self-preservative property of a self-preserved ophthalmic composition containing a quinolone compound in an aqueous carrier vehicle containing an isoosmotic amount of physiologically acceptable salt, and substantially lacking in any preservative component other than the quinolone compound.
  • the improvement which includes substituting for the physiologically acceptable salt, a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic, is effective to render the composition sufficiently self-preserved to pass the European Pharmacopoeia Efficacy of Antimicrobial Preservation, Criteria B and A, except for A niger, as well as the corresponding tests in the USP & JP.
  • the invention is directed to a method of preserving an aqueous solution of a quinolone compound, for use in treating an ophthalmic infection, without any exogenous antimicrobial preservative component and sufficient to pass the European Pharmacopoeia Efficacy of Antimicrobial Preservation, Criteria B and A, except for A niger.
  • Figs. 1A-1 D show preferred quinolones: levofloxacin (Fig. 1A), moxifloxacin (Fig. 1 B,), gatifloxacin (Fig. 1 C,) and ofloxacin (Fig. 1 D);
  • Fig. 2 shows the results for the test formulation containing 1.5% levofloxacin plus 2.2% glycerin versus six microorganisms;
  • Fig. 3 shows A.
  • Fig. 4 shows C. albicans APE testing log reduction values versus time for formulations containing varying levels of levofloxacin
  • Fig. 5 shows A. niger APE testing log reduction values versus time for formulations containing 1.5% levofloxacin
  • Fig. 6 shows C. albicans APE testing log reduction values versus time for formulations containing 1.5% levofloxacin
  • Fig. 7 shows A. niger APE testing log reduction values versus time for formulations containing various excipients
  • Fig. 8 shows C. albicans APE testing log reduction values versus time for formulations containing various excipients
  • Figs. 9-12 show human keratocyte bioassay results from various compositions prepared according to certain embodiments of the invention.
  • ophthalmic composition refers to a substance which can be used for the treatment or prevention of eye diseases or disorders, such as infections.
  • ophthalmic infections refers to inflammation of or around the eye, e.g. conjunctiva (conjunctivitis) and cornea (conjunctivitis), caused by microorganisms such as staphylococci, streptococci and/or enterococci.
  • ophthalmically acceptable refers to a material which, at the concentration or amount in question, is compatible with ocular tissue.
  • an ophthalmically acceptable component does not cause significant or undue detrimental effects when brought into contact with ocular tissue.
  • quinolone is meant an antibiotic having a naphthyridine nucleus or quinoline nucleus with different side chains as understood in the art (DaSilva, AD, et al. (2003) Biological activity and synthetic methodologies for the preparation of fluoroquinolones, a class of potent antibacterial agents, Curr Med Chem 10(1 ):21-39; and Yao, J. D. C. et al. (1995) In: Murray, P. R.
  • Quinolones include, but are not limited to, oxolinic acid, cinoxacin, flumequine, miloxacin, rosoxacin, pipemidic acid, norfloxacin, enoxacin, moxifloxacin, gatifloxacin, ciprofloxacin, ofloxacin, lomefloxacin, temafloxacin, fleroxacin, pefloxacin, amifloxacin, sparfloxacin, levofloxacin, clinafloxacin and nalidixic acid.
  • “in amounts effective”, “an amount effective”, or “an effective amount”, refer to the amount of antibiotic administered which is effective to reduce the rate of microbial infection, microbial growth and/or the symptoms associated with microbial infection.
  • “Treatment of or “treating" a subject is any type of intervention provided as a means to alter the natural course of the subject. Treatment includes, but is not limited to, administration of e.g., a pharmaceutical composition, and may be performed either prophylactically, or subsequent to the initiation of a pathologic event or contact with an etiologic agent.
  • the related term "improved therapeutic outcome" relative to a patient diagnosed as infected with a particular microbe refers to a slowing or diminution in the growth of the microbe, or detectable symptoms associated with infection by that particular microbe.
  • lacking an antimicrobial preservative component as used herein means present in quantities that have less than a material effect on, or confer less than a material advantage to, the pharmaceutical composition.
  • toxicity refers to any adverse and/or side effect of a composition on the metabolism of a cell or an ophthalmic tissue. The amount of toxicity associated with a composition may vary with several conditions including, but not limited to, the amount of composition present, the formulation of the drug and the environmental conditions of the affected cell, organ and/or subject.
  • preservative efficacy or “preservative effectiveness”, as used herein, means that the composition satisfies the preservative standards as defined in the protocols European Pharmacopoeia Efficacy of Antimicrobial Preservation, Criteria B and A, except for A. niger (PhEur, 4 th ed, 4.4).
  • Except A. niger in the context of European Pharmacopoeia Efficacy of Antimicrobial Preservation, Criteria B and A, means that the preservative criteria A of the European Pharmacopoeia Efficacy of Antimicrobial Preservation is not met for the mold, A niger.
  • subject refers to a mammal, preferably a human.
  • Ophthalmic Composition The invention provides, in one aspect, an ophthalmic composition. It has been discovered that an ophthalmic, preservative-free quinolone composition having specific components, as described below, is effective to reduce the risk of formation of microbial infections and/or to reduce the severity of inflammation or pain caused by such infections.
  • composition lacks an antimicrobial preservative component other than that possessed by the quinolone compound, the composition is sufficiently self- preserved to pass Criteria B and A, except for A niger, of the European Pharmacopoeia Efficacy of Antimicrobial Preservation. Considered below are the components of the composition of the invention.
  • A. Quinolone Compound The antibiotics utilized in the composition of the present invention are classified as quinolones. These compositions include an antibiotically effective amount of the quinolone component. Such amounts may vary over a relatively broad range depending, for example, on the specific form of the composition being used, the specific quinolone component being used, the specific application for the composition, the frequency of use of the composition and the like factors.
  • the present compositions include a quinolone component in an amount in a range of about 0.3% w/v or less to about 4% w/v or more.
  • the quinolone component is in an amount in the range of about 1.0% w/v to about 3.0% w/v.
  • the quinolone compound is present in an amount effective as an antibiotic when the composition is placed in a mammalian eye, preferably a human eye.
  • An effective amount provides one or more benefits to the subject treated, such as prevention, control or management of microbial infections, and/or reduction in inflammation and/or pain.
  • the quinolone compound is levofloxacin at a concentration between about 0.1 and about 6.0 % w/v, preferably between about 0.3 and 4.0 % w/v, and more preferably between about 1.0 and about 3.0 % w/v.
  • Preferred fluorinated quinolones are second generation quinolones, such as ofloxacin, ciprofloxacin, grepafloxacin, and the next generation quinolones, such as levofloxacin, moxifloxacin and gatifloxacin.
  • These quinolones offer advantages over earlier fluoroquinolones, possessing a broader-spectrum bactericidal activity and excellent bioavailability. In addition, they do not appear to promote the development of resistant strains. See, e.g., Higgins P. G., et al. (2003) Fluoroquinolones: structure and target sites, Curr Drug Targets 4(2): 181 - 90; Blondeau, J. M.
  • Quinolones structure-activity relationships and future predictions, J. of Medical Microbiology, 44, 320-4; Gootz, T. D. and Brighty, K. E. (1996) Fluoroquinolone antibacterials: SAR mechanism of action, resistance, and clinical aspects, Medicinal Research Reviews 16, 433-86; and Wentland, M. P. (1990) Structure- activity relationships of fluoroquinolones, In the New Generation of Quinolones, (Siporin, C, Heifetz, C. L. & Domagala, J. M., Eds), pp. 1 -43, Marcel Dekker, New York; each of which is incorporated herein by reference.
  • quinolones are levofloxacin (Fig. 1A), moxifloxacin (Fig. 1 B), gatifloxacin (Fig. 1 C) and ofloxacin (Fig. 1 D). Details regarding the structure, preparation, and physical properties of moxifloxacin and related compounds are provided in U.S. Pat. No. 5,607,942, which is incorporated by reference herein. Details regarding the structure, preparation, and physical properties of gatifloxacin and related compounds are provided in U.S. Pat. No. 4,980,470, which is incorporated by reference herein. Additional methods for the preparation of quinolones may be found in DaSilva, AD, et; al.
  • the ophthalmic composition of the invention contains an aqueous carrier vehicle for administration.
  • the carrier is a polyhydric alcohol that is at a concentration that renders the composition substantially isoosmotic with physiological fluids.
  • the composition is adjusted to have an osmolarity of between about 230 to about 450 mOsm, preferably 260-320 mOsm.
  • Suitable polyhydric alcohols include ethylene glycol, propylene glycol-
  • the polyhydric alcohol is glycerol, propylene glycol, polyethylene glycol having an average molecular weight less than 1000 daltons, mannitol and/or sorbitol.
  • the polyhydric alcohol includes glycerin at a concentration of about 2.3 v/v %.
  • the polyhydric alcohol includes propylene glycol at a concentration of about 2 v/v %.
  • An exemplary polyhydric alcohol includes polyethylene glycol having an average molecular weight between 200 and 1500 daltons and a concentration between about 2 and 8 % w/v.
  • the polyhydric alcohol includes mannitol, at a concentration of about 4 % w/v.
  • the polyhydric alcohol includes sorbitol, at a concentration of about 4 % w/v.
  • the quinolone compound is levofloxacin, present at a concentration between 1.0 and 2.0 % w/v
  • the polyhydric alcohol is glycerin, present at a concentration of between 2 and 2.5 v/v%.
  • the ophthalmic composition of the present invention is advantageously adjusted to a pH range generally employed for eye solutions, which, in one embodiment is from about 3 to 8, preferably from about 4 to 7.5, and more preferably between about 6 and 7.
  • a pH range generally employed for eye solutions which, in one embodiment is from about 3 to 8, preferably from about 4 to 7.5, and more preferably between about 6 and 7.
  • various ophthalmically acceptable acids and/or bases may be used.
  • Acids optionally useful in the present compositions include boric acid, hydrochloric acid, acetic acid, other acids which are ophthalmically acceptable in the concentrations used, and the like.
  • Bases which may be included in the present compositions include, but are not limited to, sodium and/or potassium hydroxides, other alkali and/or alkaline earth metal hydroxides, organic bases, other bases which are ophthalmically acceptable in the concentrations used, and the like.
  • the ophthalmic composition of the invention lacks an antimicrobial preservative component other than that possessed by the quinolone compound, but is still sufficiently self-preserved.
  • the antimicrobial effectiveness of the ophthalmic composition of the present invention may be determined using an organism challenge test according to the methods described in the United States Pharmacopia (USP), European Pharmacopoeia (Ph. Eur.), and/or Japanese Pharmacopia (JP), each of which is incorporated herein by reference.
  • these tests involve inoculating samples with known levels of gram-positive (e.g., Staphylococcus aureus) and gram-negative (e.g., Pseudomonas aeruginosa and Escherichia coli) vegetative bacteria, yeast (e.g., Candida albicans) and mold (e.g., Aspergillus niger).
  • the inoculated samples are tested at specified intervals to determine if the antimicrobial preservative system is capable of killing or inhibiting the propagation of organisms purposely introduced into the formulation.
  • the rate or level of antimicrobial activity determines compliance with the USP, Ph. Eur. and/or JP preservative efficacy standard for ophthalmic preparations.
  • the composition is sufficiently self-preserved to pass the European Pharmacopoeia Efficacy of Antimicrobial Preservation Criteria B and A, except for A. niger.
  • the composition is sufficiently self- preserved to pass the European Pharmacopoeia Efficacy of Antimicrobial Preservation Criteria B and A, except for A. niger, as well as the corresponding tests in the USP and/or JP.
  • Exemplary formulations containing preservative-free compositions that are capable of passing at least the USP Antimicrobial Effectiveness testing are given in Examples B, D and E below.
  • E. Toxicity A variety of test models and protocols may be used in the invention as in vitro screens for assessing ocular toxicity or irritation. See, e.g., Booman, K.A. et al. (1988) In vitro methods for estimating eye irritancy of cleaning products, Phase I: Preliminary assessment, J. Toxicol. Cut & Ocular Toxicol. 7:173- 185, which is incorporated herein by reference. Cell cultures used in conjunction with quantifiable, objective endpoints for assessing cytotoxicity have shown good correlation to in vivo data sets. Bruner, L.H, et al. (1991) Evaluation of seven in vitro alternatives for ocular safety testing, Fund. Appl. Toxicol.
  • a preferred method for assessment involves adding the composition to a cell culture of human corneal keratocytes to a final concentration corresponding to an ocular composition having a concentration of about 5% to 15%, preferably about 10%, and observing substantial lack of toxicity.
  • An exemplary human keratocyte bioassay method for assessing toxicity is described in Example F, below. Additional methods for testing toxicity contemplated by the invention include the in vitro cornea equivalent model as disclosed in U.S. Patent No. 5,827,641 , which is incorporated herein by reference. Toxicity in vivo is primarily manifested by allergic reactions to excipients or active ingredients in topical antibacterial preparations (Robert P.Y. and Adenis J.P. (2001 ) Comparative review of topical ophthalmic antibacterial preparation, Drugs 61 (2): 175-185).
  • the invention provides, in one aspect, a method of treating an ophthalmic condition in a subject.
  • the method includes administering one or more of the foregoing compositions to a subject so as to provide one or more of the desired benefits.
  • benefits include prevention, control or management of ocular microbial infections and/or the symptoms associated therewith, e.g. inflammation and/or pain.
  • the method includes topical administration of the composition in the subject's eye.
  • Such administration may include, but is not limited to, topical application to the eye, installation into the eye, placing an insert into the cul-de-sac (space) between the eyeball and the eyelid and the like.
  • Other conventional methods of administering ophthalmic compositions to the eye may be employed and are well known to those of skill in the art.
  • the dosage level of the foregoing compositions may depend on a number of factors, including, but not limited to, the particular application involved, the particular quinolone component employed, the concentration of the quinolone component in the composition, the severity of the infection and/or the subject's response to the treatment. Such dosage can be easily determined by routine and well known techniques to achieve the desired result in the subject being treated. Physicians may adjust the number of doses per day, the time between doses, and the length of treatment with the composition. Techniques for administration of pharmaceutical ophthalmic compositions may be found in Remington's Pharmaceutical Sciences (1995) 19th Ed., Williams & Wilkins, which is incorporated by reference herein, and are well known to those skilled in the art.
  • Ophthalmic conditions contemplated for treatment include conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum, and corneal ulcers.
  • Bacterial conjunctivitis is the most common form of infectious conjunctivitis and bacterial keratitis accounts for 65-90% of all bacterial corneal infections.
  • Additional conditions contemplated for treatment include infection or a risk of infection resulting from trauma to ophthalmic tissue. Trauma associated with contamination by vegetative material, contact lens wear and longierm corticosteroid use are common risk factors.
  • the method may also include prophylactic treatment in connection with various ophthalmic surgical procedures that create a risk of infection.
  • preseptal cellulitis peripheral cellulitis
  • orbital cellulitis which is an infectious inflammation of the tissues anterior to the orbital septum, more often encountered in children with upper respiratory infections
  • orbital cellulitis which is an infectious inflammatory process involving the orbital tissues posterior to the orbital septum
  • mucormycosis which is a fulminant usefulisitic fungal infection caused by fungi of, the class Zygomycetes.
  • the infection typically begins in the paranasal sinuses and spreads to the orbit.
  • the large, nonseptate hyphae cause vascular occlusion. This causes ischemia and infarction of tissue.
  • Efficacy of the method of treatment may be conveniently measured by any of the standard indicators of reduced or eliminated ophthalmic infection.
  • the present methods may be curative and/or preventative when applied.
  • the method may be utilized presurgically and/or post-traumatically.
  • the method may be applied prior to a microbial infection, or before inflammation and/or pain is apparent, or following such infection.
  • Use of the method is effective to reduce the risk of the formation of such infections.
  • synergistic and optimized doses of the present invention are established by determining the concentrations of components that provide the desired effect in a test system, such as the cell systems described herein, or in other suitable in vitro or in vivo model systems.
  • efficacious doses for administration to human (or other animal) subjects can be determined, for example, based on known or routinely ascertainable pharmacokinetics of the specific compound in humans (See, e.g., Benet, L. Z., et al. (1996), in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Ed., Hardman, J. G., et al., eds., McGraw-Hill, San Francisco; Wagner, J. G., (1993)
  • the invention includes, in another aspect, a method of preserving an aqueous solution of a quinolone compound without any exogenous antimicrobial preservative component.
  • the preserved solution is preferably used for treating an ophthalmic infection, as discussed above.
  • the method includes adding to the solution an amount of a polyhydric alcohol sufficient to render the solution substantially isoosmotic.
  • the quinolone compound is selected from the group consisting of levofloxacin, moxifloxacin, gatifloxacin and ofloxacin
  • said polyhydric alcohol is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol having an average molecular weight less than 1000 daltons, mannitol and sorbitol.
  • APE results for formulations containing 1.5% levofloxacin plus or minus 2.2% glycerin versus a BAK control sample (see Table 3) against A. niger and C. albicans are shown in Figs. 5 and 6.
  • the results shown in Figs. 5 and 6 indicate that formulations containing levofloxacin and glycerin give enhanced APE performance versus formulations containing levofloxacin alone.
  • HCK corneal keratocyte
  • HCE endothelial cells
  • CSM chondroitin sulfate medium
  • fetal bovine serum Hyclone, Logan, UT, USA
  • test or control solutions were obtained from Daiichi Pharmaceutical Company Ltd., Japan, and ciprofloxacin, moxifloxacin and gatifloxacin were purchased from LKT Laboratories, Inc., MN) for 15 minutes, 30 minutes, 1 hour, and 4 hours. Test solutions were applied at concentrations of
  • Calcein AM Fluorescent Quantitative Bioassay Live cells are distinguished by the presence of ubiquitous intracellular 30 esterase activity, determined by the enzymatic conversion of the virtually non- fluorescent cell permeant calcein AM to the intensely fluorescent calcein. The polyanionic calcein is well retained within live cells, producing an intense uniform green (530 nm) fluorescence in live cells. This can be expressed as: Calcein AM (Non-Fluorescent) + Esterases Calcein (Fluorescent Product) After exposure to test and control materials, cells were incubated with 100 ⁇ l/well of 2 ⁇ M Calcein AM solution (Molecular Probes, Inc. Eugene, OR, USA) and immediately read on a Millipore CytoFluorTM 2,300 Fluorescence

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Abstract

L'invention concerne une composition ophtalmique destinée à traiter des infections oculaires. Cette composition comprend un composé quinolone en dose efficace en tant qu'antibiotique lorsqu'elle est instillée dans l'oeil. Ladite composition est rendue isoosmotique à l'aide d'un polyalcool. Ladite composition peut servir à traiter des états ophtalmiques par application topique sur les tissus affectés.
PCT/US2004/020448 2003-06-26 2004-06-25 Composition ophtalmique contenant des quinolones et procede d'utilisation Ceased WO2005000307A1 (fr)

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JP2006517670A JP4758893B2 (ja) 2003-06-26 2004-06-25 キノロンを含む眼科用組成物及びその使用の方法

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US60/483,295 2003-06-26
US10/877,280 US20050009836A1 (en) 2003-06-26 2004-06-24 Ophthalmic composition containing quinolones and method of use
US10/877,208 2004-06-24

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070413A1 (fr) * 2005-12-12 2007-06-21 Allergan, Inc. Traitement d'ulcères cornéens avec un topique à la gatifloxacine
WO2008044734A1 (fr) * 2006-10-12 2008-04-17 Kyorin Pharmaceutical Co., Ltd. Préparation liquide aqueuse comprenant de la gatifloxacine
WO2008085913A1 (fr) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Procédés pour traiter, prévenir, ou réduire le risque d'infections ophtalmiques, otiques, et nasales
RU2407491C1 (ru) * 2009-09-29 2010-12-27 Эрнест Витальевич Бойко Способ лечения внутриглазных инфекций
CN102770141A (zh) * 2010-02-25 2012-11-07 参天制药株式会社 含有左氧氟沙星或其盐、或者它们的溶剂合物的眼感染症治疗用滴眼剂，眼感染症的治疗方法，左氧氟沙星或其盐、或者它们的溶剂合物及其使用
US8741930B2 (en) 2008-10-24 2014-06-03 Bridge Pharma, Inc. Treating xerophthalmia with norketotifen
US8765787B2 (en) 2008-11-21 2014-07-01 Bridge Pharma, Inc. Methods of treatment of xerophthalmia with self-preserving ocular formulations of norketotifen
EP2886130A1 (fr) * 2013-12-23 2015-06-24 Rafarm S.A. Composition pharmaceutique ophtalmique et son procédé de préparation
RU2595837C2 (ru) * 2014-09-29 2016-08-27 Открытое Акционерное Общество "Татхимфармпрепараты" Состав и способ получения глазных капель

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070413A1 (fr) * 2005-12-12 2007-06-21 Allergan, Inc. Traitement d'ulcères cornéens avec un topique à la gatifloxacine
WO2008044734A1 (fr) * 2006-10-12 2008-04-17 Kyorin Pharmaceutical Co., Ltd. Préparation liquide aqueuse comprenant de la gatifloxacine
WO2008085913A1 (fr) * 2007-01-04 2008-07-17 Rib-X Pharmaceuticals, Inc. Procédés pour traiter, prévenir, ou réduire le risque d'infections ophtalmiques, otiques, et nasales
US8741930B2 (en) 2008-10-24 2014-06-03 Bridge Pharma, Inc. Treating xerophthalmia with norketotifen
US8765787B2 (en) 2008-11-21 2014-07-01 Bridge Pharma, Inc. Methods of treatment of xerophthalmia with self-preserving ocular formulations of norketotifen
US8969385B2 (en) 2008-11-21 2015-03-03 Bridge Pharma, Inc. Ocular formulations of norketotifen
RU2407491C1 (ru) * 2009-09-29 2010-12-27 Эрнест Витальевич Бойко Способ лечения внутриглазных инфекций
CN102770141A (zh) * 2010-02-25 2012-11-07 参天制药株式会社 含有左氧氟沙星或其盐、或者它们的溶剂合物的眼感染症治疗用滴眼剂，眼感染症的治疗方法，左氧氟沙星或其盐、或者它们的溶剂合物及其使用
TWI488627B (zh) * 2010-02-25 2015-06-21 參天製藥股份有限公司 左氧氟沙星或其鹽或該等之溶劑合物之用途
EP2886130A1 (fr) * 2013-12-23 2015-06-24 Rafarm S.A. Composition pharmaceutique ophtalmique et son procédé de préparation
RU2595837C2 (ru) * 2014-09-29 2016-08-27 Открытое Акционерное Общество "Татхимфармпрепараты" Состав и способ получения глазных капель

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