(12) United States Patent
`Huth
`
`USOO6982O79B2
`(10) Patent No.:
`US 6,982,079 B2
`(45) Date of Patent:
`Jan. 3, 2006
`
`(54) COMPOSITIONS FOR TREATING
`HYPEREMIA
`
`(75) Inventor: Stanley W. Huth, Newport Beach, CA
`(US)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`(*) Notice:
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 446 days.
`
`(21) Appl. No.: 10/133,094
`(22) Filed:
`Apr. 26, 2002
`(65)
`Prior Publication Data
`
`US 2003/0203034 A1 Oct. 30, 2003
`(51) Int. Cl.
`A6 IK3I/74
`A6 IK 47/30
`
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ................................ 424/78.04; 514/772.3;
`514/781; 514/784; 514/785
`(58) Field of Classification Search .............. 424/78.04,
`424/427,400, 401, 466,422,514/7723.
`514/781, 784,785,772.4, 772.6, 249
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3.278.447 A 10/1966 McNicholas
`2. A 2. E. al
`5.188826 A 2/1993 Chandrasekaran
`et al. ....................... 424/78.04
`
`5,474,979 A 12/1995 Ding et al.
`5,607,698 A 3/1997 Martin et al.
`5,648,074 A 7/1997 Park et al.
`5,725,887 A
`3/1998 Martin et al.
`5,858,346 A 1/1999 Vehige et al.
`6,042.849 A 3/2000 Richardson et al.
`6,071,539 A 6/2000 Robinson et al.
`6,641,834 B2 * 11/2003 Olejnik et al. .............. 424/427
`FOREIGN PATENT DOCUMENTS
`WOO2O5822
`1/2002
`WOO2283.63
`4/2002
`OTHER PUBLICATIONS
`Abstract Submitted to ARVO for Conference held Nov.30,
`2001: The Effect of Different CMC Materials in Artificial
`Tears in the Tear Layer on Contrast Sensitivity.
`AQUALONGR CMC, Physical and Chemical Properties,
`Hercules Incorporated, 1999.
`* cited by examiner
`
`WO
`WO
`
`Primary Examiner-Carlos A. Azpuru
`(74) Attorney, Agent, or Firm-Stout, Uxa, Buyan &
`Mullins, LLP, Frank J. Uxa
`(57)
`ABSTRACT
`The present compositions advantageously treat hyperemia
`with substantially no added irritation to the eye. In one
`embodiment, the compositions include an ophthalmically
`acceptable carrier component, a vasoconstrictor component
`in an amount effective to treat hyperemia when the compo
`Sition is administered to an eye, and a polyanionic compo
`nent in an amount effective to provide lubrication to an eye
`when the compositions are administered to the eye.
`
`17 Claims, 2 Drawing Sheets
`
`'
`
`'
`
`.
`
`.
`
`.
`
`0.2B4 ra
`o282
`
`O.28
`o 278
`o 276
`i
`g 0.274
`0.272.
`
`t
`
`O.270
`
`0.268
`o,266 ,
`0.264
`
`0.252
`
`,
`
`F(28,1204)=2.60; pg.0000
`
`
`
`: V
`:
`
`: :
`
`v
`
`:
`
`5 : 5
`
`OROP. Vehicle
`
`

`

`U.S. Patent
`
`Jan. 3, 2006
`
`Sheet 1 of 2
`
`US 6,982,079 B2
`
`Figure 1
`pC,0000
`1204)
`2.60.
`F(28
`
`O.2B4
`
`0.22
`
`0.280
`
`O 278
`
`O 278
`
`0.274
`o,272.
`
`O.270
`
`O.288
`
`0.288
`
`0.264
`
`O.282
`
`g
`
`e
`O)
`
`()
`DROP. Vehicle
`
`-|---z Kep
`
`N
`
`Visine
`droP
`
`

`

`U.S. Patent
`
`Jan. 3, 2006
`
`Sheet 2 of 2
`
`US 6,982,079 B2
`
`Figure 2a
`F(26.1118)e 1876, pco.OOO
`
`1.03
`
`1.04
`
`1.05
`
`
`
`3 min
`1 rin
`2. Air
`
`2ht
`45 min
`Smin
`25 in
`65 min
`TME
`
`4
`
`Sht
`
`day 7
`day 3
`day 8
`
`Figure 2b
`F(26,1118)=17.93, pco OOO
`
`1 Inn
`2nnar
`
`3 Tir
`
`45 min
`5 min
`4 run
`25 mr.
`65 in
`TIME
`
`2hr
`
`4t
`
`Shr
`
`day 7
`day 3
`day 8
`
`

`

`US 6,982,079 B2
`
`1
`COMPOSITIONS FOR TREATING
`HYPEREMIA
`
`2
`component, a chlorine dioxide precursor component in an
`amount effective in preserving the composition, and a vaso
`constrictor component in an amount effective to treat hype
`remia when the composition is administered to an eye.
`In a further broad aspect of the invention, compositions
`are provided comprising an ophthalmically acceptable,
`aqueous carrier component including at least one of a
`potassium component and an alkaline earth metal
`component, and a vasoconstrictor component in an amount
`effective to treat hyperemia when the composition is admin
`istered to an eye.
`In an additional broad aspect of the invention, composi
`tions are provided comprising an ophthalmically acceptable
`aqueous carrier component and a vasoconstrictor component
`in an amount effective to treat hyperemia when the compo
`Sition is administered to an eye, the component having a pH
`in a range of about 6.7 to about 7.2 or about 7.4 or about 8.0.
`Any Suitable vasoconstrictor component may be
`employed in the present invention provided it is effective to
`treat ocular hyperemia. Advantageously, the vasoconstrictor
`is compatible with the other components of the composition,
`for example, is stable in the presence of the other compo
`nents of the composition, for example for at least about 6
`months or at least about 12 months, during Storage. In one
`embodiment, the compositions are stable for about 36
`months.
`In a very useful embodiment, the vasoconstrictor compo
`nent comprises at least one alpha-1-adrenergic agonist. For
`example, the vasoconstrictor component may be Selected
`from the group consisting of tetrahydrozoline, ephedrine,
`naphazoline, phenylephrine, Salts thereof and mixtures
`thereof. More preferably, the vasoconstrictor component is
`Selected from tetrahydrozoline, Salts thereof and mixtures
`thereof. In one useful embodiment, the present composition
`comprises about 0.001% or about 0.005% to about 0.15% or
`about 0.5% (w/v), more preferably about 0.01% to about
`0.05% (w/v), of the vasoconstrictor component.
`Any Suitable demulcent may be employed in accordance
`with the invention, as long as it is compatible with other
`components in the composition. In one embodiment, the
`demulcent provides for lubrication to the eye. Non-limiting
`examples of demulcents include polyanionic components,
`hydroxyethylcellulose, hydroxypropylmethylcellulose,
`methylcellulose, dextran, gelatin, glycerin, polyethylene
`glycols, for example, polyethylene glycol 300, polyethylene
`glycol 400 and the like, polySorbate, propylene glycol,
`polyvinyl alcohol, polyvinyl pyrrollidone and the like and
`mixtures thereof. In one embodiment, the polyanionic com
`ponent is Selected from the group consisting of anionic
`cellulosic derivatives and mixtures thereof. In one
`embodiment, the polyanionic component is Selected from
`the group consisting of carboxy methyl celluloses and
`mixtures thereof. Preferably, the present compositions com
`prise about 0.05% or about 0.1% to about 5% (w/v), more
`preferably about 0.15% or about 0.3% to about 2%, of a
`polyanionic component.
`Still further in accordance with the present invention, the
`compositions comprise a carrier component. In one
`embodiment, the carrier component comprises water and has
`a pH in a range of about 6.7 to about 8.0, more preferably
`about 6.8 to about 7.2. In one embodiment, the carrier
`component comprises an electrolyte component. In one
`embodiment, the carrier component includes an alkaline
`earth metal component, for example, calcium components,
`magnesium components and mixtures thereof. In one
`embodiment, the alkaline earth metal component is present
`
`15
`
`BACKGROUND OF THE INVENTION
`The present invention relates to compositions including
`vasoconstrictor components for treating ocular hyperemia,
`preferably without resulting in Significant eye irritation, and
`to methods for making and using Such compositions. In one
`embodiment, the present invention relates to compositions
`effective to provide dual treatments for eye conditions, for
`example a dual treatment of hyperemia and dry eye.
`Reddening or inflammation of the Superficial tissues of
`the eye is a relatively common affliction Since it usually
`accompanies various allergic reactions, Such as hay fever
`allergies and the like, foreign body irritation in the eye, or
`eye fatigue. Such Superficial conjunctival redness, often
`referred to as hyperemia or ocular hyperemia, can be the
`result of ciliary flush, dilation of the deep Straight vessels of
`the episclera, and/or dilation of the Superficial vessels of the
`conjunctiva.
`Various types of palliative treatments have been used to
`treat this condition. The most common treatment includes
`the administration of eye drops which contain emollients
`and other ingredients designed to ease the discomfort due to
`the inflammation and to eliminate the redness associated
`with the condition. These treatments have not been entirely
`Satisfactory, however.
`For example, many commercially available eye drops
`include preservatives, an ingredient which may be quite
`harmful to the eye. Furthermore, many of the commercially
`available eye drops include ethylenediaminetetraacetic acid
`and/or salts thereof (EDTA), which may produce substantial
`discomfort when the eye drops are administered to the eye.
`Also, these commercially available products often have
`pHS which are relatively acidic and can result in ocular
`irritation and/or discomfort.
`Thus, there is a continued need to have improved com
`40
`positions and methods for treating hyperemia.
`
`25
`
`35
`
`SUMMARY OF THE INVENTION
`New ophthalmic compositions useful for the treatment of
`hyperemia, and methods of making and using Such
`compositions, have been discovered. The present composi
`tions advantageously treat hyperemia with Substantially no
`added irritation to the eye. These compositions are relatively
`Straightforward, can be easily and cost effectively manufac
`tured and can be used much like conventional eye drops. In
`one embodiment, the present compositions are effective to
`provide dual treatments for eye conditions, for example a
`dual treatment of hyperemia and dry eye.
`In accordance with one broad aspect of the present
`invention, compositions are provided comprising an oph
`thalmically acceptable carrier component, preferably an
`aqueous carrier component, a vasoconstrictor component in
`an amount effective to treat hyperemia when the composi
`tion is administered to an eye, and a demulcent component,
`preferably a polyanionic component, in an amount effective
`to provide lubrication to an eye when the composition is
`administered to the eye. Advantageously, the present com
`positions are Solutions, more preferably, liquid Solutions, to
`facilitate convenient, consistent and effective use of the
`compositions.
`In another broad aspect of the invention, the present
`compositions comprise an ophthalmically acceptable carrier
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

`

`US 6,982,079 B2
`
`3
`in an amount in a range of about 0.001% to about 0.05%
`(w/v), preferably about 0.005% to about 0.2% (w/v). In one
`embodiment, the carrier component comprises an electrolyte
`component. In one embodiment, the present compositions
`are free of an ethylenediaminetetraacetic acid (EDTA)
`component, for example, EDTA, salts of EDTA, and the like
`and mixtures thereof.
`In one embodiment, the chlorine dioxide precursor com
`ponent is present in an amount in a range of about 10 ppm
`to about 200 ppm. Preferably, the chlorine dioxide precursor
`component is the Sole material effective as a preservative in
`the composition. In one embodiment, the chlorine dioxide
`precursor component includes at least one chlorite compo
`nent. In one embodiment, the chlorine dioxide precursor
`component includes Stabilized chlorine dioxide.
`Any feature or combination of features described herein
`are included within the Scope of the present invention
`provided that the features included in any Such combination
`are not mutually inconsistent as will be apparent from the
`context, this Specification, and the knowledge of one of
`ordinary skill in the art.
`Additional advantages and aspects of the present inven
`tion are apparent in the following detailed description and
`claims.
`
`15
`
`25
`
`4
`1-adrenergic agonists include tetrahydrozoline, ephedrine,
`naphazoline, phenylephrine, Salts thereof and mixtures
`thereof. Preferably, the vasoconstrictor component is stable
`in the composition. For example, it is preferred that the
`vasoconstrictor component is not degraded, is Soluble in the
`compositions and/or is therapeutically effective when the
`compositions are administered to the eye. Also, it is prefer
`able that the vasoconstrictor component is Stable in the
`compositions for more than about 10 months, preferably
`about 18 months, more preferably about 36 months or more,
`at Storage conditions. In a preferred embodiment, the vaso
`constrictor component comprises a tetrahydrozoline and/or a
`Salt thereof.
`The compositions comprise an amount of vasoconstrictor
`component effective to treat hyperemia when the composi
`tions are administered to the eye. In one embodiment, the
`compositions comprise about 0.005% to about 0.15% (w/v)
`of the vasoconstrictor component. In one embodiment, the
`compositions comprise about 0.01% to about 0.10%, pref
`erably 0.01% to about 0.05% of the vasoconstrictor com
`ponent.
`In one embodiment, the present compositions comprise a
`demulcent component. Without wishing to limit the inven
`tion to any theory or mechanism of operation, it is believed
`that the demulcent component is believed to be effective in
`lubricating an eye, for example, an eye which has, or has a
`propensity for having, dry eye syndrome. Non-limiting
`examples of demulcent components include polyanionic
`component S,
`hydroxyethylcellulose,
`hydroxypropylmethylcellulose, methylcellulose, dextran,
`gelatin, glycerin, polyethylene glycols, for example, poly
`ethylene glycol 300, polyethylene glycol 400 and the like,
`polySorbates, propylene glycol, polyvinyl alcohol, polyvinyl
`pyrrolidone and the like and mixtures thereof. See U.S. Pat.
`Nos. 4,421,748 and 5,474,979, the disclosure of each of
`which is incorporated in its entirety herein by reference. The
`demulcent component preferably is present, if at all, in a
`range of about 0.1% to about 5 (w/v).
`AS used herein, the term “polyanionic component” refers
`to a chemical entity, for example, an ionically charged
`Species, Such as an ionically charged polymeric material,
`which includes more than one discrete anionic charge, that
`is multiple discrete anionic charges. Preferably, the polya
`nionic component is Selected from the group consisting of
`polymeric materials having multiple anionic charges and
`mixtures thereof.
`Any Suitable polyanionic component may be employed in
`accordance with the present invention provided that it func
`tions as described herein and has no Substantial detrimental
`effect on the compositions as a whole or on the eye to which
`the compositions are administered. The polyanionic com
`ponent is preferably ophthalmically acceptable at the con
`centrations used. The polyanionic component preferably
`includes three (3) or more anionic (or negative) charges. In
`the event that the polyanionic component is a polymeric
`material, it is preferred that each of the repeating units of the
`polymeric material include a discrete anionic charge. Par
`ticularly useful anionic components are those which are
`water Soluble, for example, Soluble at the concentrations
`used in the present compositions at ambient (room) tem
`perature.
`Examples of Suitable polyanionic components useful in
`the present compositions include, without limitation, anionic
`cellulose derivatives, anionic acrylic acid-containing
`polymers, anionic methacrylic acid-containing polymers,
`anionic amino acid-containing polymers and mixtures
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 shows a presentation of eye redness data from a
`comparative Study of a composition, in accordance with the
`present invention and Visine(E) eye drops.
`FIG.2a shows another presentation of these redness data.
`FIG. 2b shows a further presentation of these redness
`data.
`
`35
`
`45
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention involves ophthalmic compositions,
`which are advantageously ophthalmically acceptable, com
`prising an ophthalmically acceptable carrier component, a
`40
`vasoconstrictor component and, optionally, a demulcent
`component, for example a polyanionic component.
`A composition, carrier component or other material is
`“ophthalmically acceptable” when it is compatible with
`ocular tissue, that is, it does not cause Significant or undue
`detrimental effects when brought into contact with ocular
`tissue. Preferably, the ophthalmically acceptable material is
`also compatible with other components of the present com
`positions.
`The present compositions treat hyperemia advantageously
`with substantially no added irritation to the eye. In one
`embodiment, the present compositions treat hyperemia and
`dry eye Syndrome advantageously with Substantially no
`added irritation to the eye.
`The present compositions preferably are Solutions,
`although other forms, Such as ointments, gels, and the like,
`may be employed.
`Preferably, the present compositions meet, and pass, the
`EP-B antimicrobial preservative effectiveness criteria.
`60
`The present compositions include a vasoconstrictor com
`ponent. In one embodiment, the vasoconstrictor component
`comprises an agent, for example a compound, which is
`effective in constricting a blood vessel of an eye, preferably
`a blood vessel on or near the ocular Surface of the eye. In one
`embodiment, the vasoconstrictor component comprises an
`alpha-1-adrenergic agonist. Non-limiting examples of alpha
`
`50
`
`55
`
`65
`
`

`

`S
`thereof. Anionic cellulose derivatives are very useful in the
`present invention.
`A particularly useful class of polyanionic components is
`one or more polymeric materials having multiple anionic
`charges. Examples include, but are not limited to:
`metal carboxy methylcelluloses
`metal carboxy methylhydroxyethylcelluloses
`metal carboxy methylstarchs
`metal carboxy methylhydroxyethylstarchs
`hydrolyzed polyacrylamides and polyacrylonitriles
`heparin
`glucoaminoglycans
`hyaluronic acid
`chondroitin Sulfate
`dermatan Sulfate
`peptides and polypeptides
`alginic acid
`metal alginates
`homopolymers and copolymers of one or more of
`acrylic and methacrylic acids
`metal acrylates and methacrylates
`vinylsulfonic acid
`metal vinylsulfonate
`amino acids, Such as aspartic acid,
`glutamic acid and the like
`metal Salts of amino acids
`p-styreneSulfonic acid
`metal p-styreneSulfonate
`2-methacryloyloxyethylsulfonic acids
`metal 2-methacryloyloxyethylsulfonates
`3-methacryloyloxy-2-hydroxypropylsulfonic acids
`metal 3-methacryloyloxy-2-hydroxypropylsulfonates
`2-acrylamido-2-methylpropanesulfonic acids
`metal 2-acrylamido-2-methylpropanesulfonates
`allylsulfonic acid
`metal allylsulfonate and the like.
`Excellent results are achieved using polyanionic compo
`nents Selected from carboxy methylcelluloses and mixtures
`thereof, for example, alkali metal and/or alkaline earth metal
`carboxy methylcelluloses.
`In one embodiment, carboxymethylcellulose is a cellulose
`ether, produced by reacting alkali cellulose with Sodium
`monochloroacetate. Cellulose is a polymer composed of
`repeating cellobiose units. These, in turn, are composed of
`two anhydroglucose units (beta-glucopyranose residues).
`The number of anhydroglucose units, which are joined
`through 14 glucosidic linkages, represent the degree of
`polymerization. Each anhydroglucose unit contains three
`hydroxyl groups. By Substituting carboxymethyl groups for
`Some of these hydroxyls, Sodium carboxymethylcellulose is
`obtained. The degree of substitution in the carboxymethyl
`cellulose raw material used in this product formula may be
`0.7, or an average of 7 carboxymethyl groups per 10
`anhydroglucose units. A derivative of a carboxymethylcel
`lulose may include a Sucrose unit in the polymer.
`In one embodiment, the compositions comprise about
`0.05% to about 5.0% of the demulcent component, prefer
`ably polyanionic component. For example, compositions of
`the present invention may comprise about 0.05% to about
`5%, preferably about 0.1% to about 3%, more preferably
`about 0.2% to about 2.5%, of a carboxymethylcellulose.
`Preservatives which are commonly used in pharmaceuti
`cal compositions are often less effective when used in the
`presence of polyanionic components, for example carboxy
`
`5
`
`15
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`US 6,982,079 B2
`
`6
`methyl celluloses. In certain instances, this reduced preser
`Vative efficacy can be compensated for by using increased
`amounts of the preservative. However, where Sensitive or
`delicate body tissue is involved, this approach may not be
`available Since the preservative itself may cause Some
`adverse reaction or Sensitivity in the human or animal, to
`whom the compositions are administered.
`In one embodiment, chlorine dioxide precursor compo
`nents are effective as preservatives in the present composi
`tions. Furthermore, chlorine dioxide precursor components
`have reduced toxicity and preferably Substantially no tox
`icity to the eye when it is administered along with the
`present compositions.
`Preferably, the present preservative components or com
`ponents effective in aiding to preserve the compositions are
`effective in concentrations of less than about 500 ppm, for
`example, in the range of about 10 ppm or less to about 200
`ppm. Preservative components or components effective in
`aiding to preserve the compositions in accordance with the
`present invention preferably include, but are not limited to,
`those which form complexes with the polyanionic compo
`nent to a lesser extent than does benzalkonium chloride.
`Examples of the components effective in aiding to pre
`Serve the compositions include, but are not limited to,
`oxidative preservative components, for example chlorine
`dioxide precursor components, peroxides, perSalts, peracids,
`and the like, and mixtures thereof. Specific examples of
`chlorine dioxide precursor components useful as preserva
`tives in accordance with the present invention include
`hypochlorite components, for example hypochlorites, chlo
`rate components, for example chlorates, perchlorate
`components, for example perchlorates; and chlorite compo
`nents. Examples of chlorite components include Stabilized
`chlorine dioxide (SCD), metal chlorites, such as alkali metal
`and alkaline earth metal chlorites, and the like and mixtures
`therefor. Technical grade (or USP grade) sodium chlorite is
`a very useful preservative component. The exact chemical
`compositions of many chlorite components, for example,
`SCD, is not completely understood. The manufacture or
`production of certain chlorite components is described in
`McNicholas U.S. Pat. No. 3,278.447, the disclosure of
`which is incorporated in its entirety herein by reference.
`Specific examples of useful SCD products include that sold
`under the trademark Dura Klor by Rio Linda Chemical
`Company, Inc., and that Sold under the trademark Anthium
`Dioxide by International Dioxide, Inc. An especially useful
`SCD is a product sold under the trademark Purite(R) by
`Allergan, Inc. Other examples of oxidative preservative
`components include peroxy components. For example, trace
`amounts of peroxy components Stabilized with a hydrogen
`peroxide Stabilizer, Such as diethylene triamine penta
`(methylene phosphonic acid) or 1-hydroxyethylidene-1,1-
`diphosphonic acid, may be utilized as a preservative for use
`in components designed to be used in the ocular environ
`ment. Also, Virtually any peroxy component may be used So
`long as it is hydrolyzed in water to produce hydrogen
`peroxide. Examples of Such Sources of hydrogen peroxide,
`which provide an effective resultant amount of hydrogen
`peroxide, include Sodium perborate decahydrate, Sodium
`peroxide and urea peroxide. It has been found that peracetic
`acid, an organic peroxy compound, may not be Stabilized
`utilizing the present System. See, for example, Martin et al
`U.S. Pat. No. 5,725,887, the disclosure of which is incor
`porated in its entirety herein by reference.
`In one embodiment of the invention, additional preserva
`tives other than oxidative preservative components may be
`included in the compositions. These preservatives include
`
`

`

`US 6,982,079 B2
`
`15
`
`25
`
`7
`quaternary ammonium compounds, in particular the mixture
`of alkylbenzyl dimethyl ammonium compounds and the like
`known generically as “benzalkonium chloride.” Other pre
`servatives which may be used include alkyl esters of
`p-hydroxybenzoic acid and the like and mixtures thereof,
`Such as the mixture of methyl, ethyl, propyl and butyl esters
`which is sold under the trade name “Nipastat.” In one
`embodiment, the present compositions are Substantially free
`of benzalkonium chloride.
`The carrier component is ophthalmically acceptable and
`may include one or more components which are effective in
`providing Such ophthalmic acceptability and/or otherwise
`benefitting the composition and/or the eye to which the
`composition is administered and/or the patient whose eye is
`being treated. Advantageously, the carrier component is
`aqueous-based, for example, comprising a major amount
`that is at least about 50% by weight, of water. Other
`components which may be included in the carrier compo
`nents include, without limitation, buffer components, tonic
`ity components, preservative-components, pH adjustors,
`components commonly found in artificial tears, one or more
`alkali metal components, electrolyte component, alkaline
`metal earth components, and the like and mixtures thereof.
`In one embodiment, the carrier component is free of a
`chelating agent. In one advantageous embodiment, the car
`rier component is free of EDTA components. The compo
`Sitions of the present invention may be Substantially free or
`completely free of EDTA.
`The present compositions preferably include an effective
`amount of an electrolyte component, that is one or more
`electrolytes, for example, Such as is found in natural tears
`and artificial tear formulations. Examples of particularly
`useful Such electrolytes for inclusion in the present compo
`Sitions include, without limitation, alkaline earth metal Salts,
`Such as alkaline earth metal inorganic Salts, and mixtures
`thereof, e.g., calcium Salts, magnesium Salts and mixtures
`thereof. Very good results are obtained using an electrolyte
`component Selected from calcium chloride, magnesium
`chloride and mixtures thereof.
`The amount or concentration of Such electrolyte compo
`nent in the present compositions can vary widely and
`depends on various factors, for example, the Specific elec
`trolyte component being employed, the Specific composition
`in which the electrolyte is to be included and the like factors.
`In one useful embodiment, the amount of the electrolyte
`component is chosen to at least partially resemble, or even
`Substantially resemble, the electrolyte concentration in natu
`ral human tears. Preferably, the concentration of the elec
`trolyte component is in the range of about 0.01% to about
`0.5% or about 1% (w/v) of the present composition.
`50
`In a useful embodiment, the electrolyte component com
`prises an alkaline earth metal component and/or an alkali
`metal component. The compositions of the invention may
`advantageously comprise about 0.001% to about 0.05%,
`preferably 0.001% to about 0.02% (w/v), of an alkaline earth
`metal component. In one embodiment, the compositions
`comprise about 0.05% to about 0.5% (w/v) of an alkali metal
`component.
`The alkaline metal earth component preferably comprises
`calcium components and/or magnesium components. The
`calcium component and the magnesium component
`comprise, for example, a calcium Salt and a magnesium Salt,
`respectively. Non-limiting examples of anionic counter ions
`for the calcium and magnesium Salt include halide ions
`(Such as chloride ions) and hydroxide ions. In one
`embodiment, the alkaline earth metal component comprises
`a calcium chloride and/or a magnesium chloride.
`
`8
`The alkali metal component preferably comprises Sodium
`components and/or potassium components. The Sodium
`component and the potassium component comprise, for
`example, a Sodium Salt and potassium Salt, respectively.
`Non-limiting examples of anionic counter ions for the
`Sodium and potassium Salt include halide ions (such as
`chloride ions) and hydroxide ions. In one embodiment, the
`alkali metal component comprises a Sodium chloride and/or
`a potassium chloride.
`The present compositions preferably have Viscosities in
`excess of the Viscosity of water. In one embodiment, the
`Viscosity of the present compositions is about 1 to about 10
`cps (centipoise), more preferably in a range of about 2 to
`about 5 cps. In one embodiment, the viscosity of the
`compositions is about 10 cps to about 500 cps or about 1,000
`cpS. Advantageously, the Viscosity of the present composi
`tions is in a range of about 15 cps or about 30 cps or about
`70 to about 150 cps or about 200 cps or about 300 cps or
`about 500 cps. The viscosity of the present compositions
`may be measured in any Suitable, for example, conventional
`manner. A conventional Brookfield Viscometer measuring
`Such Viscosities may be employed.
`In one very useful embodiment the carrier component
`includes at least one of the following: an effective amount of
`a buffer component, an effective amount of a tonicity
`component; an effective amount of a preservative compo
`nent; and water.
`These additional components preferably are ophthalmi
`cally acceptable and can be chosen from materials which are
`conventionally employed in ophthalmic compositions, for
`example, compositions used to treat eyes afflicted with dry
`eye syndrome, artificial tear formulations and the like.
`Acceptable effective concentrations for these additional
`components in the compositions of the invention are readily
`apparent to the skilled practitioner.
`The carrier component preferably includes an effective
`amount of a tonicity adjusting component to provide the
`compositions with the desired tonicity. The carrier compo
`nent preferably includes a buffer component which is
`present in an amount effective to maintain the pH of the
`compositions in the desired range.
`In one embodiment, the pH of the compositions is about
`6 to about 8, preferably about 6.7 to about 7.5, more
`preferably about 6.7 to about 7.2, even more preferably,
`about 6.9 or about 7.0 to about 7.2.
`Among the Suitable tonicity adjusting components that
`may be employed are those conventionally used in oph
`thalmic compositions, Such as one or more various inorganic
`Salts and the like. Sodium borate, boric acid, Sodium
`chloride, potassium chloride, mannitol, dextrose, glycerin,
`propylene glycol and the like and mixtures thereof are very
`useful tonicity adjusting components. Among the Suitable
`buffer components or buffering agents that may be employed
`are those conventionally used in ophthalmic compositions.
`The buffer salts include alkali metal, alkaline earth metal
`and/or ammonium Salts. Conventional organic buffers, Such
`as Goode’s buffer and the like, may also be employed.
`The present compositions may be prepared using conven
`tional procedures and techniques. For example, the present
`compositions can be prepared by blending the components
`together, Such as in one bulk.
`In one particularly useful embodiment, a Solution of the
`polyanionic component and purified water is obtained.
`Separately, the other components to be included in the final
`composition are solubilized in purified water. The two
`Solutions are combined into a single Solution. This latter
`Solution is Sterile filtered, for example, through a 0.2 micron
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`

`

`US 6,982,079 B2
`
`10
`
`TABLE 1.
`
`sterilizing pre-filter, such as that sold by Millipore under the
`tradename Milliguard. The final solution is sterile filtered
`once again, to provide a clear, Smooth Solution which is then
`aseptically filled into containers.
`In one embodiment, compositions are featured compris
`ing an ophthalmically acceptable carrier component, a vaso
`constrictor component in an amount effective to treat hype
`remia when the composition is administered to an eye, and
`a polyanionic component in an amount effective to provide
`lubrication to an eye when the compositions are adminis
`tered to the eye. Preferably, the compositions are in a
`Solution form, for example not gel form. In one embodiment,
`the present compositions are free of a chelating agent, for
`example EGTA and/or EDTA. In a preferred embodiment,
`the present compositions are effective to treat hyperemia in
`Subjects, for example human Subjects, effectively without
`inducing Substantial irritation. Also in a preferred
`embodiment, the present compositions are able to treat
`hyperemia and dry eye conditions in Subjects, for example
`human Subjects, effectively without inducing Substantial
`irritation.
`In one embodiment, compositions are featured compris
`ing an ophthalmically acceptable carrier component, a chlo
`rine dioxide precursor component in an amount effective in
`preserving the composit