`
`niche
`Patentamt
`European
`Patent Office
`desbrevet
`
`"
`
`(12)
`
`IMIWAAL|MAN
`EP 1 998 783 B1
`
`(11)
`
`EUROPEANPATENT SPECIFICATION
`
`(45) Date of publication and mention
`of the grant of the patent:
`07.05.2014 Bulletin 2014/19
`
`(21) Application number: 07752695.2
`
`(22) Dateoffiling: 09.03.2007
`
`(51) Int Cl.:
`AG1K 31/56 (2006.01)
`
`(86)
`
`International application number:
`PCT/US2007/006013
`
`(87) International publication number:
`WO 2007/106381 (20.09.2007 Gazette 2007/38)
`
`(54) OPHTHALMIC COMPOSITIONS COMPRISING POVIDONE-IODINE
`OPHTHALMISCHE ZUSAMMENSETZUNGEN MIT POVIDON-IOD
`
`COMPOSITIONS OPHTALMIQUES COMPRENANT DE LA POVIDONE IODEE
`
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FIFRGB GR
`HU IE IS IT LILTLU LV MC MT NL PL PT RO SE
`SISK TR
`
`(30) Priority: 14.03.2006 US 782629 P
`29.09.2006 US 848315 P
`
`07.12.2006 US 636293
`
`(43) Date of publication of application:
`10.12.2008 Bulletin 2008/50
`
`¢ CAPRIOTTI, Joseph, A.
`New York, NY 10003 (US)
`
`(74) Representative: Vossius & Partner
`Siebertstrasse 4
`
`81675 Munchen (DE)
`
`(56) Referencescited:
`US-A- 4 177 268
`
`¢ J. S. PELLETIER ET AL: “A combination
`
`(60) Divisional application:
`14162854.5
`
`povidone-iodine 0.4%/dexamethasone 0.1%
`ophthalmic suspension in the treatment of
`adenoviral conjunctivitis", ADVANCES IN
`THERAPY, vol. 26, no. 8, 1 August 2009
`(2009-08-01) , pages 776-783, XP55010388, ISSN:
`(73) Proprietor: CLS Pharmaceuticals, Inc.
`0741-238X, DOI: 10.1007/s12325-009-0062-1
`New York NY 10003 (US)
`¢ Couzos§Set al.: "Effectiveness of ototopical
`(72) Inventors:
`antibiotics for chronic suppurativeotitis media in
`¢ SAMSON, C., Michael
`Aboriginal children: a community-based,
`New York, NY 10016 (US)
`multicentre, double-blind randomised controlled
`¢ LIANG, Bo
`trial.", , 18 August 2003 (2003-08-18),
`East Brunswick, NJ 08816 (US)
`XP002662056, Retrieved from the Internet: URL:
`http ://www.ncbi.nim.nih.gov/pubmed/129
`14507 ?dopt=Abstract[retrieved on 2011-10-25]
`
`EP1998783B1
`
`
`
`Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
`Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
`Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`

`

`EP 1 998 783 B1
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`Description
`
`BACKGROUND OF THE INVENTION
`
`Infectious conjunctivitis is an ophthalmic disorder characterized by inflammation of the conjunctiva secondary
`[0001]
`to invasion of a microbe. Microbes capable of causing conjunctivitis in humans include bacteria (including Mycobacteria
`sp), viruses, fungi, or amoebae. Current treatment for bacterial conjunctivitis consists of antibiotic draps. Because anti-
`biotic drops are ineffective against viral conjunctivitis, treatment of such infections consists only of relieving symptoms.
`Treatments for fungi and amoeba conjunctivitis consist of a small selection of medications which lacks anti-bacterial or
`anti-viral activity and which, in addition, is toxic to the ocular surface.
`[0002] Diagnosis of the various causative agents such as bacteria, virus, or fungus, in infectious conjunctivitis is not
`economically feasible because accurate diagnosis requires sophisticated laboratory culture not easily integrated into
`the average healthcare practice. Because accurate diagnosis is impractical, most conjunctivitis is presumed to be bacterial
`without culturing and is treated with antibiotics. Antibiotic treatment is suboptimal becauseit is ineffective against viral
`or fungal conjunctivitis.
`[0003] The use of steroids is approached cautiously in the setting of ocular infection. While steroids can have the
`benefit of reducing the severity of the inflammation in an acute infection, they are also known to increase susceptibility
`to certain infections.
`
`[0004] Topical corticosteroids are routinely used to control ocular inflammation. Their mechanism of action involves
`the inhibition of the immune response and the subsequent tissue destruction that exuberant inflammation may cause.
`Corticosteroid has the undesirable side effect of limiting the body’sintrinsic ability to fight infection. In fact, inopportune
`steroids usage can worsen the course of an infection secondary to mycobacteria, virus, or fungus. Thus, the use of a
`combined antimicrobial-steroid medication in ocular infections is recommended only under careful observation of a
`trained ophthalmologist because of these significant risks.
`In fact, TobradexR (Alcon), the most commonly prescribed
`combination ophthalmic antimicrobial-steroid drug, specifically lists ’viral disease of the cornea and conjunctiva, myco-
`bacteria infection, and fungal infection’ as absolute contraindications to its use. Clearly, these combination drugs were
`not intended to be used in the face of infectious conjunctivitis in which bacterial infection cannot be confirmed.
`[0005]
`In summary,there is currently no ophthalmic antimicrobial drug with broad activity against all the causes of
`conjunctivitis or keratitis, and there is currently no approved antimicrobial/steroid, or antimicrobial/non steroidal anti-
`inflammatory combination drug that can be safely usedin infectious conjunctivitis or keratitis that can potentially be viral
`or fungal in origin.
`
`SUMMARYOF THE INVENTION
`
`[0006] The invention is an ophthalmic composition comprised of povidone-iodine 0.01% - 10% (weight/weight or
`weight/volume) combined with a steroid, or a combination of both an anti-inflammatory agent and a steroid. The steroid
`is selected from the group consisting of dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,
`and salts, esters, and combinations thereof. In a preferred embodiment, the povidone-iodine (PVP-]) is between 0.1%
`and 2.5%, between 0.5 and 2%, between 0.75 and 2%, between 0.8 and 2%, between 0.9 and 2%, between 1% and
`2% or between 1% and 1.5%.
`In another embodiment, the total weight of the PVP-!, anti-inflammatory and steroid is
`between 0.1% and 4.5%. This solution is useful in the treatment of infections of the conjunctiva and cornea. The broad
`spectrum of povidone-iodine would allow this combination to be used in cases of ocular conjunctival or corneal infection
`caused by mycobacteria, viruses, fungi, and amoeba; this is in distinction to currently available combination antimicrobial-
`steroid ophthalmic compositions, which are contraindicated in the aforementioned infections. Additionally the solution
`will be useful in the infectious prophylaxis and inflammatory control of patients recovering from recent ophthalmic surgery.
`There are no currently available antimicrobial/anti-inflammatory or antimicrobial/steroid combinations useful for viral,
`fungal, mycobacterial and amoebic infections in the post-operative period.
`[0007] One embodiment of the invention is directed to an ophthalmic composition suitable for topical administration
`to an eye, effective for treatment and/or prophylaxis of a microorganism infection or a disorder of at least one tissue of
`the eye. Prophylaxis may be, for example, prophylaxis from infection following surgery, prophylaxis from infection after
`birth for the newborn, or prophylaxis from accidental contact with contaminating material. Accidental contact with con-
`taminating material may occur, for example, during surgery or during food processing. The composition comprises
`povidone-iodine in a concentration between 0.01% to 10%, and a steroid or a combination of a steroid and an anti-
`inflammarory agent. The stercid is selected from the group consisting of dexamethasone, dexamethasone alcohol,
`dexamethasone sodium phosphate, andsalts, esters, and combinations thereof.
`[0008] The mammalian eye can be divided into two main segments: the anterior segment and the posterior segment.
`The anterior segmentis the front third of the eye that includes the tissuesin front of the vitreous humor: the cornea, iris,
`ciliary body, and lens. Within the anterior segmentare twofluid-filled spaces: the anterior chamber and the posterior
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`EP 1 998 783 B1
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`chamber. The anterior chamber is located between the posterior surface of the cornea(i.e. the corneal endothelium)
`and the iris. The posterior chamber is located between the iris and the front face of the vitreous: The posterior segment
`is the back two-thirds of the eye that includes the anterior hyaloid membrane and all tissues behind it: the vitreous humor,
`retina, choroid, and optic nerve.
`In some animals, the retina contains a reflective layer (the tapetum lucidum) which
`increases the amount of light each photosensitive cell perceives, allowing the animal to see better under low light
`conditions.
`
`‘It was surprising to discover that the formulations of povidone-iodine combined with steroids, when presentin
`[0009]
`a suitable pH range, eliminated the undesiredirritating effect of PVP-| to the eye. The invention provides pH stable
`aqueous suspensions of water-insoluble drugs that remain in such a state even after extended periods of storage.
`[0010]
`Ina preferred embodiment, the ophthalmic composition contains povidone-iodine at a concentration between
`0.1% and 2.5% by weight, or more preferably, between 0.5% and 2% by weight. In another preferred embodiment, the
`ophthalmic composition hasa total weight of povidone-iodine, an anti-inflammatory, a steroid of between 0.1% to 2.5%
`(weight to volume, or weight to weight) or between 0.1 % to 4.5%.
`[0011] The steroid of the ophthalmic composition may be at a concentration of between 0.01 and 10%. In a preferred
`embodiment, the steroid is at a concentration of between 0.05 and 2%.
`[0012] The ophthalmic composition may further comprise (1) a topical anesthetic which relieves pain (2) a penetration
`enhancerwhich enhancesthe penetration of povidone-iodine into the tissues of the eye (this may be a topical anesthetic)
`(3) an antimicrobial preservative, which, for example, maybe at a concentration of about 0.001% to 1.0% by weight; (4)
`a co-solvent or a nonionic surface agent - surfactant, which, for example, may be about 0.01% to 2% by weight; (5)
`viscosity increasing agent, which, for example, may be about 0.01% to 2% by weight; and (6) asuitable ophthalmic vehicle.
`[0013] The ophthalmic composition may bein the form of a solution, a suspension, an emulsion, an ointment, a cream,
`a gel, or a controlled-release/sustain-release vehicle. For example, the composition maybein the form of a contact lens
`solution, eyewash, eyedrop, and thelike.
`[0014] The ophthalmic composition may be used for treatment and/or prophylaxis of a microorganism infection. The
`microorganism may be a bacterium, a virus, a fungus, or an amoeba, a parasite, or a combination thereof. The bacteria
`may be a mycobacterium. Further, the solution may be usedto treat or for prophylaxis of disorders such as conjunctivitis,
`corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis and herpesvirus-related keratitis.
`[0015]
`For example, the ophthalmic composition may comprise the following: 0.5 to 2% (w/w) polyvinylpyrrolidinone-
`iodine complex; 0.05 to 2% (w/w)steroid; 0.005% to 0.02% (w/w) EDTA(ethylenediaminetetraacetic acid); 0.01 to 0.5%
`(w/w) sodium chloride; 0.02 to 0.1% (w/w) tyloxapol; 0.5% to 2% (w/w) sodium sulfate; and 0.1 to 0.5% (w/w) hydrox-
`yethylcellulose; at pH range from 5 to 7. More specifically, the ophthalmic composition may comprisethe following: 1.0%
`(w/w) polyvinylpyrrolidinone-iodine complex; 0.1% (w/w) steroid; 0.01% (w/w) EDTA dehydrate; 0.3% (w/w) sodium
`chloride salt; 0.05% (w/w) tyloxapol; 1.2% (w/w) sodium sulfate; and 0.25% (w/w) hydroxyethylcellulose; at pH range
`from 5.5 to 6.5. In one embodiment, the composition consists essentially of 0.5 to 2% (w/w) polyvinylpyrrolidinone-iodine
`complex; 0.05 to 2% (w/w) steroid; 0.005% to 0.02% (w/w) EDTA (ethylenediaminetetraacetic acid); 0.01 to 0.5% (w/w)
`sodium chloride; 0.02 to 0.1% (w/w)tyloxapol; 0.5% to 2% (w/w) sodium sulfate; and 0.1 to 0.5% (w/w) hydroxyethyl
`cellulose; at pH range from 5 to 7. In another embodiment, the composition consists essentially of 1.0% (w/w) polyvi-
`nylpyrrolidinone-iodine complex; 0.1% (w/w) steroid; 0.01% (w/w) EDTA disodium salt; 0.3% (w/w) sodium chloride salt;
`0.05% (w/w) tyloxapol; 1.2% (w/w) sodium sulfate; and 0.25% (w/w) hycroxyethylcellulose; at pH range from 5.5 to 6.5.
`[0016]
`It is known, of course, that EDTA can be in many forms such as a free acid, disodium, or tetrasodium salts.
`The steroid may be dexamethasone. This steroid may bein the sodium phosphate form (e.g., dexamethasone sodium
`phosphate) or acetate form (e.g., dexamethasone acetate).
`[0017]
`Ina preferred embodiment, the ophthalmic composition retains at least 90% of its PVP-| and at least 90% of
`its steroid after 1 month, 2 months, 3 months, 6 months or 1 year after it is manufactured. This can be accomplished,
`at least, by producing the ophthalmic composition according to the formula listed above (e.g. previous two paragraphs).
`This stability is maintained even when the composition is stored at room temperature in a lighted indoor environment of
`100 lux to 1000 lux. In one preferred embodiment, the composition is an aqueous solution.
`[0018]
`In another embodiment, the invention is directed to an ophthalmic composition as described abovefor use in
`the treatment and/or prophylaxis of an eye disorder or a microorganism infection of at least one tissue of the eye
`comprising the step of administering one of more dosesof an ophthalmic composition, discussed above, to the eye. The
`eye disorder may be, for example, a microorganism infection of at least one tissue of the eye, conjunctivitis, corneal
`abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis and herpesvirus-related keratitis. The micro-
`organism maybe a bacteria (e.g., mycobacteria), virus, fungi, or amoebae.
`[0019] The treatment may comprise administering a solution of the invention where the sum of the povidone-iodine,
`the anti-inflammatory, and the steroid is between 0.001 mg to 5 mg per dose. Further, the dose volume may be between
`10 microliters to 200 microliters or between 50 microliters to 80 microliters; about one drop per eye. Administration may
`be between 1 to 24 times a day, between 2 to 4 times a day or between 2 to 24 times a day.
`[0020] Herein described is also a step of storing the solution for at least one month, at least two months, at least three
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`months, at least six months, or at least one year before it is administered. The storage may be in a clear mottle (a
`container that does not substantially block light) in a lighted environment. A lighted environment may be, for example,
`an indoorlighted environment with about 100 lux to 1000 lux oflight.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Ina preferred embodiment, the compositions of the present invention are administered topically. The dosage
`[0021]
`range is 0.001 to 5.0 mg/per eye; wherein the cited mass figures represent the sum of the three components: anti-
`inflammatory, povidone-iodine and topical anesthetic. Dosage for one eye is understood to be about one drop ofsolution.
`One drop of solution may be between 10 yu! to 200 wl, between 20 wl and 120 wl, or between about 50 pl (microliters)
`to about 80 yl of solution or any values in between. For example, dispensers such aspipettors can dispense fluid drops
`from at least | wl to 300 wl and any value in between.
`[0022]
`Ina preferred embodiment, the solution may be administered as an eye drop using any of the manytypes of
`eye drop dispensers on the market. Although not required, the container for the compositions of the invention may be
`clear, translucent, and opaque and maycontain other properties or combination of properties such as being glasslined,
`tamper proof, packagedin single or few dose aliquots, and a combination thereof.
`[0023]
`Povidone-iodine has the following chemical structure:
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`Suitable anti-inflammatories for the compositions of the invention include, at least, the following: ketotifen
`[0024]
`fumarate, diclofenac sodium, flurbiprofen sodium, ketorlac tromethamine, suprofen, celecoxib, naproxen, rofecoxib, or
`a derivative or combination thereof. Ketorolac (also called ketorlac, or ketorolac tromethamine) is a non-steroidal anti-
`inflammatory drug (NSAID) in the family of prapionic acids.
`[0025]
`Suitable steroids for the compositions of the invention include at least: dexamethasone, dexamethasone alcohol,
`dexamethasone sodium phosphate, and salts, esters, and derivatives and combinations thereof. Steroids which addi-
`tionally can be addedinclude fluromethalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, pred-
`nisolone, prednisone, prednisolone acetate, prednisolone sodium phosphate, rimexolone, hydrocortisone, hydrocorti-
`sone acetate, lodoxamide tromethamine, or a derivative or combination thereof.It is understood, for any of the chemicals
`of this disclosure, that the chemicals may be in various modified forms such as acetate forms, and sodium phosphate
`forms, sodium salts, and the like.
`[0026] Dexamethasone hasthe following chemical structure:
`
` 3
`
`It is known that any of the reagents mentioned anywherein this disclosure may be in chemically equivalent
`[0027]
`forms such assalts, hydrides, esters and other modifications of the basic chemical. For example, dexamethasone in
`any of the compositions of the invention may be replaced with any of its derivatives, including esters and salts thereof.
`Examples of such derivatives include, at least, Dexamethasone-17-acetate (CAS RN: 1177-87-3), Dexamethasone
`Disodium Phosphate (CAS RN: 2392-39-4), Dexamethasone Valerate (CAS RN: 14899-36-6), Dexamethasone-21-
`isonicotinate (CAS RN: 2265-64-7), Dexamethasone Palmitate (CAS RN: 33755-46-3), Dexamethasone Propionate
`(CAS RN: 55541-30-5), Dexamethasone Acefurate (CAS RN: 83880-70-0), Dexamethasone-21-galactoside (CAS RN:
`
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`EP 1 998 783 B1
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`92901-23-0), dexamethasone 21-thiopivalate, dexamethasone 21-thiopentanoate, dexamethasone 21-thiol-2-methyl-
`butanoate, dexamethasone 21-thiol-3-methyl-butanoate, dexamethasone 21-thiohexanoate, dexamethasone 21-thiol-
`4-methyl-pentanoate, dexamethasone 21-thiol-3,3-dimethyl-butanoate, dexamethasone 21-thiol-2-ethyl-butanoate,
`dexamethasone 21-thiooctanoate, dexamethasone 21-thiol-2-ethylhexanoate, dexamethasone 21-thiononanoate, dex-
`amethasone 21-thiodecanoate, dexamethasone 21-p-fluorothiobenzoate or a combination thereof. Dexamethasone de-
`rivatives are also described in US patent 4,177,268.
`[0028]
`Suitable topical anesthetics for the compositions of the invention include, at least, proparacaine, lidocaine,
`tetracaine or a derivative or combination thereof.
`
`[0029] The compositions of the present invention can be administered as solutions, suspensions, emulsions (disper-
`sions), gels, creams, or ointments in a suitable ophthalmic vehicle.
`[0030]
`In any of the compositions of this disclosure for topical administration, such as topical administration to the eye,
`the mixtures are preferably formulated as 0.01 to 2.0 percent by weight solutions in water at a pH of 5.0 to 8.0 (figures
`relate to combined presence of povidone-iodine and dexamethasone). This pH range may be achieved by the addition
`of buffers to the solution. We have found that, surprisingly, the formulation of the present invention is stable in buffered
`solutions. Thatis, there is no adverse interaction between the buffer and the iodine or other component that would cause
`the composition to be unstable. While the precise regimen is left to the discretion of the clinician, it is recommended that
`the resulting solution be topically applied by placing one drop in each eye 1 to 24 times daily. For example, the solution
`may be applied 1, 2, 4, 6, 8, 12, 18 or 24 times a day.
`
`Antimicrobial Preservative
`
`[0031] As an optional ingredient, suitable antimicrobial preservatives may be addedto prevent multi-dose package
`contamination. Such agents may include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl
`paraben, phenylethyl alcohol, EDTA, sorbic acid, Onamer M, other agents known to thoseskilled in the art, or a com-
`bination thereof. Typically such preservatives are employed at a level of from 0.001% to 1.0% by weight.
`
`Co-Solvents/Surfactants
`
`[0032] The compositions of the invention may contain an optional co-solvent. The solubility of the components of the
`present compositions may be enhancedby a surfactant or other appropriate co-solvent in the composition. Such co-
`solvents/surfactants include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g. Pluronic
`F-68, F-84 and P-103), cyclodextrin, tyloxapol, other agents knownto those skilled in the art, or a combination thereof.
`Typically such co-solvents are employedat a level of from 0.01% to 2% by weight.
`
`Viscosity Agents
`
`[0033] The compositions of the invention may contain an optional viscosity agent - that is, an agent that can increase
`viscosity. Viscosity increased abovethat of simple aqueous solutions may be desirable to increase ocular absorption of
`the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components
`of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity
`builder agents include as examplespolyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl’ methylcel-
`lulose, hydroxyethyl! cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, other agents known to those skilled
`in the art, or a combination thereof. Such agents are typically employed at a level of fram 0.01% to 2% by weight.
`
`The Formulation
`
`[0034] The following two reactions must be considered for the chemistry of PVP-I in aqueous solutions:
`
`a.
`
`b.
`
`PVP-l5 = PVP + Io
`
`PVP-Hl3 = PVP + H® + 159
`
`[0035] The affinity of free iodine (lz) for reaction with -OH, -SH and -NH functional groups is well described in the
`literature and forms the basis for the anti-microbial activity of iodine-containing solutions (Rackur H. J. Hosp. Infect.,
`1985; 6: 13-23, and references therein). Dexamethasone (9-Fluoro-11, 17, 21-trinydroxy-16a-methylpregna-1, 4-diene-
`3, 20-dione) contains three such moieties (-OH) at the 11, 17 and 21 positions. A person in the field would conclude that
`these hydroxyl groups would be prone to covalent substitution reactions by the free iodine generated in the solution
`equilibrium reaction described above for PVP-l».
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`In deriving the present formulations, experiments of combinations of various anti-inflammatories and PVP-I, or
`[0036]
`steroids and PVP-I, were performed. It was observed that most formulations were unsuccessful because of the rapid
`reaction between PVP-I and the added reagent (anti-inflammatory or steroid). Some of these unsuccessful formulations
`are described elsewhere in this disclosure. Particularly, the limiting factor for lower concentrations of PVP-| solutions is
`stability and efficacy as a microbicidal.
`[0037]
`It is thus the object of the present invention to discover novel formulation of combinations of PVP-I and an anti-
`inflammatory to solve three problems ofstability, efficacy and non-irritating to the eye. We have found, unexpectedly,
`that a 1% PVP-I solution is effective for treatment of infection or prophylaxis of infections when.combined with dexam-
`ethasone. The literature has previously indicated that while 1% PVP-|is desirable, the side effects of ocular administration
`precluded its use. The undesirable side effects include pain and irritation.
`[0038]
`It was surprising to discover that the solution of PVP-l and dexamethasone remains stable for many months.
`Based on the stability data disclosed, we conjecture that the compositions of the invention may be stable for years -
`although experimentsare still ongoing at this point. It is a further unexpected result that the reaction of dexamathasone
`and PVP-I does not proceed to any appreciable extent at room temperature, in light or dark, over time. Unexpectedly
`the reaction between the free iodine in solution and the hydroxyl groups present on the dexamethasone molecule as
`compoundedin our formulation does not proceed.
`[0039] Due to the high propensity of oxidative potential of PVP-I, the resulted stable combination of PVP-i and dex-
`amethasone is unexpected for the average worker/scientist/physician in this field. |twas observed when the concentration
`of PVP-I is larger than 0.5%, a stable combination formulation can be achieved. Surprisingly,
`it was found that 0.3%
`PVP-I combination with dexamethasone was much less stable. This is once again unexpected because the lower
`concentrations of iodine are expected to be less reactive and hence, less destructive to either parts. After 8 weeks, the
`available iodine in the combination (0.3% PVP-I initially) decreased by 20%. Though 0.1% diluted PVP-! has the strongest
`antimicrobial activity (Gottardi W. J. Hosp. Infect., 1985; 6(Suppl): 1-11) our data showed we need atleast 0.5% PVP-
`|
`in combination with dexamethasone to show the best antimicrobial activity. We have observed PVP-| reacted with
`Ketorolac (a non-steroidal anti-inflammatory) rapidly and the Ketorolac was completely consumed and the available
`iodine in the PVP-I complex was reducedsignificantly depending on the ratio between Ketorolac and PVP-I. The com-
`bination of PVP-l and dexamethasone sodium phosphate also proved to be less successful but also useful. We observed
`some dissociation of PVP-Il complex to an unknown polymeric complex in the UV spectra and the iodine reduction is
`around 5% after 12 weeks. It was further observed that PVP-| reacts immediately with proparacaine and releases free
`iodine rapidly.
`[0040]
`Surprisingly, the combination formulation has contributed to the stability of diluted PVP-! solution. The available
`iodine of a 0.625% povidone-iodine solution was 91% at 25 °C and 98% at 4 °C after 5 weeks storage, respectively.
`(Iryo Yakugaku 2003, 29(1), 62-65). Our data showed that our formulation stabilized the diluted PVP-I solution. After 8
`weeks at room temperature, the available iodine in solutions with 0.5% and 1% PVP-I were over 99%.
`[0041] The use of topical steroids alone is contraindicated in suspected viral and fungal infections of the human eye.
`Furthermore the use of combination anti-bacterial/steroid solutions is contraindicated in the setting of suspected viral
`infection. There are no steroid-containing solutions described that are safe for use in the human eyein the setting of
`presumedviral or fungal infection. It is therefore unexpected to the authors and othersin the field that a steroid-containing
`solution would be of use in the treatment of an acute viral or fungal ocular infection.
`[0042] Apotent anti-inflammatory steroid allows the temperance of the potentially devastating ocular immune response
`in the setting of an active infection. However, due to the antiseptic (antibacterial, antiviral, and antifungal, antiprotozoal)
`power of PVP-I, the compound is useable in the setting of active infection without the risk of worsening the infection.
`This unique property (poly-antimicrobicide and potentanti-inflammatory)is a significant improvementover all other ocular
`antibiotics and anti-inflammatory.
`[0043] Although a topical steroid is of tremendous benefit in the treatment of ocular inflammation, its use is fraught
`with risks. Topical steroids applied to the eye act by a variety of well described genomic and non-genomic mechanisms
`to reduce the production of constituent proteins of the inflammatory cascade, decrease vascular permeability, decrease
`the production of pro-inflammatory cytokines, decrease the potencyof soluble inflammatory factors, inhibit the production
`of acute phase proteins, decrease leukocyte migration and increasethe stability of cell membranes. Through all of these
`mechanisms, topically applied steroids can reduce the local concentrations of activated products toxic to the eye including
`the gelatinase, collaginase and matrixmetalloproteinase families of proteins. With this reduction in potentially toxic sub-
`stances comesthe increased risk of prolonged infection and potential infection. Ifthe topical steroid is given in combination
`with an appropriate antimicrobial (i.e. and antibacterial for bacterial infection, an antiviral for viral infection, an antifungal
`for fungal infection) its risk can be reduced and/or eliminated. The usual practicing ophthalmologist cannotreliably
`distinguish the causative agent in most cases of acute external eye infection in a time frame relevant to the prescription
`of treatment. Thus the beneficial effects one may gain from the promptuse oftopical steroids are delayed or eliminated
`entirely as the clinician either waits for culture results or more likely delays treatment indefinitely, The novel combination
`of a polymicrobicidal effective against bacteria, viruses and fungi and a topical steroid eliminatesthis risk and allows the
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`EP 1 998 783 B1
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`immediate control of inflammation and eradication of pathogen. In our view, this is the most preferred embodiment of
`the present invention.
`[0044] Wealso noted that the other components in our preferred composition appear to further stabilize the formulation.
`That is, the EDTA, sodium chloride, tyloxapol, sodium sulfate and hydroxyethylcellulose appear to have additional
`beneficial effects of further stabilizing the composition.
`[0045] Embodiments of the present invention are summarized in the following items:
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`1. An ophthalmic composition suitable for topical administration to an eye, effective for treatment and/or prophylaxis
`of a microorganism infection or a disorder of at least one tissue of the eye, comprising
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`a) povidone-iodine in a concentration between 0.01% and 10%, and
`b) a steroid selected from the group consisting of dexamethasone, dexamethasone alcohol, dexamethasone
`sodium phosphate, and salts, esters and combinations thereof.
`
`2. The ophthalmic composition of item 1 wherein said povidone-iodine is between 0.1% and 2.5% by weight.
`3. The ophthalmic composition of item 1 wherein said povidone-iodine is between 0.5% and 2% by weight.
`4. The ophthalmic composition of item 1 wherein a total weight of said povidone-iodine, an optional anti-inflammatory,
`and said steraid is between 0.1% and 4.5% in said solution:
`
`5. The ophthalmic composition of item 1 further comprising an anti-inflammatory agent selected from the group
`consisting of ketotifen fumarate, diclofenac sodium, flurbiprofen sodium, ketorlac ttomethamine, suprofen, celecoxib,
`naproxen, rofecoxib, and a combination thereof.
`6. The ophthalmic composition of item 1 wherein said steroid is at a concentration of between 0.01 and 10%.
`7. The ophthalmic composition of item 1 wherein said steroid is at a concentration of between 0.05 and 2%.
`8. The ophthalmic composition of item 1, further comprising a steroid selected from the group consisting of flurome-
`thalone acetate, fluromethalone alcohol, lotoprendol etabonate, medrysone, prednisolone, prednisone, prednisolone
`acetate, prednisolone sodium phosphate, rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide trometh-
`amine and salts, esters, and derivatives and combinations thereof.
`9. The ophthalmic composition of item 1 wherein said composition further comprises a topical anesthetic which
`relieves pain.
`10. The ophthalmic compositian of item 9 wherein said topical anesthetic is selected from the group consisting of
`proparacaine, lidocaine, tetracaine and a combination thereof.
`11. The ophthalmic composition of item 1 wherein said composition further comprises a penetration enhancer which
`enhances the penetration of povidone-iodine into the tissues of the eye.
`12. The ophthalmic composition of item 11 wherein said penetration enhancer is a topical anesthetic.
`13. The ophthalmic composition of item 1 wherein said composition further comprises an antimicrobial preservative.
`14. The ophthalmic composition of item 13 wherein said antimicrobial preservative is selected from the group
`consisting of benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,
`EDTA, sorbic acid, Onamer M and a combination thereof.
`15. The ophthalmic composition of item 13 wherein said antimicrobial preservative is at a concentration of about
`0.001% to 1.0% by weight