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`US 20060229219Al
`
`c19) United States
`c12) Patent Application Publication
`Yu et al.
`
`c10) Pub. No.: US 2006/0229219 Al
`Oct. 12, 2006
`(43) Pub. Date:
`
`(54) BORATE-POLYOL MIXTURES AS A
`BUFFERING SYSTEM
`
`(75)
`
`Inventors: Zhi-Jian Yu, Irvine, CA (US); Diane
`M. Croner, Tustin, CA (US)
`
`Correspondence Address:
`Advanced Medical Optics, Inc.
`Legal Department
`1700 E. St. Andrew Place
`Santa Ana, CA 92705 (US)
`
`(73) Assignee: ADVANCED MEDICAL
`INC.
`
`OPTICS,
`
`(21) Appl. No.:
`
`111104,233
`
`(22) Filed:
`
`Apr. 11, 2005
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`CllD 3100
`(2006.01)
`(52) U.S. Cl. .............................................................. 510/112
`
`(57)
`
`ABSTRACT
`
`A buffering system having a pKa which may be selected
`based on the environment in which the solution is designed
`to be used. Solutions containing the buffering system
`according to the present invention include borate-polyol
`complexes as the primary buffering agents, and may include
`one or more of the following: an aqueous liquid medium; an
`antimicrobial component; a surfactant component; a viscos(cid:173)
`ity-inducing component; and/or a tonicity component. The
`borate-polyol buffering system may be formulated to have a
`lower pKa than traditional systems.
`
`Exhibit 1095
`ARGENTUM
`IPR2017-01053
`
`000001
`
`

`

`Patent Application Publication Oct. 12, 2006 Sheet 1 of 2
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`US 2006/0229219 Al
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`000002
`
`

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`Patent Application Publication Oct. 12, 2006 Sheet 2 of 2
`
`US 2006/0229219 Al
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`000003
`
`

`

`US 2006/0229219 Al
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`Oct. 12, 2006
`
`1
`
`BORATE-POLYOL MIXTURES AS A BUFFERING
`SYSTEM
`
`BACKGROUND OF THE INVENTION
`
`[0001] 1. Field of the Invention
`
`[0002] The present invention relates to compositions and
`methods for formulating and using the same, and more
`particularly to compositions containing borate-polyol mix(cid:173)
`tures as the primary buffering agents.
`
`[0003] 2. Description of Related Art
`
`[0004] Contact lenses must be disinfected and cleaned to
`kill harmful microorganisms that may be present or grow on
`the lenses, and to remove any buildup that may have
`accumulated on the lenses. Some of the most popular
`products for disinfecting lenses are multi-purpose solutions
`that can be used to clean, disinfect and wet contact lenses,
`followed by direct insertion (placement on the eye) without
`rinsing.
`
`[0005] The ability to use a single solution for contact lens
`care is an advantage to many users. Such a solution must be
`strong enough to kill harmful microorganisms that may be
`present or grow on the lenses. It must also be particularly
`gentle to the eye, since at least some of the solution will be
`on the lens when inserted and will come into contact with the
`eye. Such a solution must also be compatible with all contact
`lens materials, particularly the silicone hydrogel materials,
`which represent the state-of-the-art contact lens materials.
`
`[0006] A significant challenge to improving the disinfect(cid:173)
`ing efficacy of a solution is to simultaneously improve or
`maintain its contact lens material compatibility and comfort.
`One important component of ophthalmic compositions is the
`buffer, which helps to maintain the pH of the composition
`within an acceptable physiological range.
`
`[0007] Conventional buffers which are typically used in
`ophthalmic compositions suffer either from the problems of
`the interaction with quaternary ammonium based antimicro(cid:173)
`bial, which reduces its antimicrobial efficacy (such as phos(cid:173)
`phate butter) or from the problem that their pKa values (the
`ability of an ionizable group to donate a proton in an
`aqueous media) typically fall outside of acceptable physi(cid:173)
`ological range. For example, borate buffers have a pKa of
`9.0. This is clearly outside the desired ophthalmic pH range
`of 7.0-7.8. While this may be overcome by increasing the
`concentration of said buffer, this increase in concentration
`may not be desirable to users from a physiological view(cid:173)
`point.
`
`[0008] Similar problems are present with lens rewetting
`solutions and artificial tears.
`
`[0009]
`It is known in the art to use borate-polyol com(cid:173)
`plexes as antimicrobial agents. By way of example, this is
`taught by Chowhan et al., U.S. Pat. No. 6,849,253. However,
`this reference does not teach a buffering system having a
`pKa that may be selected for physiological compatibility
`based on the use for which the resulting solution will be
`used.
`
`[0010] Thus, it would be desirable to develop a buffering
`system which may be designed to have a pKa that is tailored
`for physiological capability. For example, in ophthalmic
`solutions it would be desirable to have a buffering system
`
`having a pKa that provides a pH buffering capacity within
`the normal physiological range of approximately 7.0 to 7.8.
`Such system may be used in any composition in which a
`buffer having a pH buffering capacity within that range may
`be employed including, but not limited to, for example,
`multi-purpose contact-lens solutions, rewetters and artificial
`tears.
`
`DETAILED DESCRIPTION
`
`[0011] A borate-polyol buffering system which may be
`designed to have a pKa that is significantly lower than that
`of boric/borate. Associated compositions and methods
`employing this buffering system according to the present
`invention provide improved, physiologically acceptable
`solutions and treatments, and for ease in formulating the
`same solutions and treatments.
`
`[0012] The pKa of the buffering system according to the
`present invention may be selected based on the environment
`in which the solution is designed to be used. As a general
`statement, the larger the molar ratio of the polyol to boric
`acid, the higher the complexation. Since the buffering capac(cid:173)
`ity is provided by the boric-polyol complex, the amount of
`the complex in solution affects the overall pKa value. That
`is, the larger the amount of complexes, the lower the pKa
`value. Similarly, the smaller the amount of the complex, the
`higher pKa value. Therefore the pKa value can be adjusted
`by changing the amount and the ratio of the boric acid and
`polyol. Therefore the buffer according to the present inven(cid:173)
`tion is unique in that it can provide a wide range of buffering
`capacities around physiological pH from 6-9.
`
`[0013] As used herein, a polyol is an organic compound
`having two or more hydroxyl (-OH) group adjacent to each
`other.
`
`[0014] As used herein, the term 'boric acid' is used to
`mean boric acid (H3B03 ), metal salts of boric acid
`(MH2B03 ), and borate (M2 B40 7 ), all of which will complex
`with polyols. Sodium salt of boric acid is one example of a
`metal salt of boric acid. Sodium borate is one example of
`borate. When the boric acid is complexed with the polyol, it
`is a borate-polyol complex. The concentration of borate(cid:173)
`polyol complex in solutions according to the present inven(cid:173)
`tion ranges from about 0.005 to about 2% w/w, preferably
`from about 0.01 % to about 0.5% w/w, and most preferably
`from about 0.04% to about 0.4% w/w.
`
`[0015] The buffer component is present in an amount
`effective to maintain the pH of the composition or solution
`in the desired range, for example, in a physiologically
`acceptable range of about 4 or about 5 or about 6 to about
`8 or about 9 or about 10. In particular, the solution preferably
`has a pH in the range of about 6 to about 8.
`
`[0016] The present compositions preferably further com(cid:173)
`prise effective amounts of one or more additional compo(cid:173)
`nents, such as one or more antimicrobial agent(s); detergent
`or surfactant component; a viscosity inducing or thickening
`component; a surfactant; a chelating or sequestering com(cid:173)
`ponent; a tonicity component; and the like and mixtures
`thereof. Compositions according to the present invention
`may also include beneficial. amino acids. The additional
`component or components may be selected from materials
`which are known to be useful in contact lens care compo(cid:173)
`sitions and are included in amounts effective to provide the
`
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`US 2006/0229219 Al
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`Oct. 12, 2006
`
`2
`
`desired effect or benefit. When an additional component is
`included, it is preferably compatible under typical use and
`storage conditions with the other components of the com(cid:173)
`position. For instance, the aforesaid additional component or
`components preferably are substantially stable in the pres(cid:173)
`ence of the antimicrobial and buffer components described
`herein.
`
`[0017] The compos1t10ns and methods of the present
`invention may be used to achieve stand-alone disinfection
`standards against four of the five FDA contact lens disin(cid:173)
`fection panel organisms (P. aeruginosa, S. aureus, S. marce(cid:173)
`scens and F. solani) and regimen disinfection against the
`fifth organism, C. albicans.
`
`[0018] Antimicrobial components which may be used in
`association with the buffering system according to the
`present invention include chemicals which derive their anti(cid:173)
`microbial activity from chemical or physiochemical inter(cid:173)
`action with microbes or microorganisms such as those
`contaminating a contact lens. Suitable additional antimicro(cid:173)
`bial components include, but are not limited to, those
`generally employed in ophthalmic applications such as
`quaternary ammonium salts such as poly [dimethylimino-
`2-butene-1,4-diyl] chloride, alpha-[ 4-tris(2-hydroxyethyl)
`ammonium]-dichloride (chemical registry number 75345-
`27-6, available under, the trademark Polyquatemium 1 ®
`from Onyx Corporation), benzalkonium halides, and bigu(cid:173)
`anides, such as salts of alexidine, alexidine-free base, salts
`of chlorhexidine, hexamethylene biguanides and their poly(cid:173)
`mers, and salts thereof, antimicrobial polypeptides, chlorine
`dioxide precursors, and the like and mixtures thereof. Gen(cid:173)
`erally, the hexamethylene biguanide polymers (PHMB), also
`referred to as polyaminopropyl biguanide (PAPB), have
`molecular weights of up to about 100,000. Such compounds
`are known and are disclosed in Ogunbiyi et al, U.S. Pat. No.
`4,759,595, the disclosure of which is hereby incorporated in
`its entirety by reference herein.
`
`[0019] Generally, the antimicrobial component is present
`in the liquid aqueous medium at an ophthalmically accept(cid:173)
`able or safe concentration such that the user may remove the
`disinfected lens from the liquid aqueous medium and there(cid:173)
`after directly place the lens in the eye for safe and comfort(cid:173)
`able wear. Alternatively, the antimicrobial component is
`present in the liquid aqueous medium at an ophthalmically
`acceptable or safe concentration and sufficient for maintain(cid:173)
`ing preservative effectiveness. The additional antimicrobial
`components useful in the present invention preferably are
`present in the liquid aqueous medium in concentrations in
`the range of about 0.00001 % to about 0.01 % (w/w), and
`more preferably in concentrations in the range of about
`0.00005% to about 0.001 % (w/w) and most preferably in
`concentrations in the range of about 0.00005% to about
`0.0005% (w/w).
`
`[0020] Antimicrobial components suitable for inclusion in
`the present invention include chlorine dioxide precursors.
`Specific examples of chlorine dioxide precursors include
`stabilized chlorine dioxide (SCD), metal chlorites, such as
`alkali metal and alkaline earth metal chlorites, and the like
`and mixtures thereof. Technical grade sodium chlorite is a
`very useful chlorine dioxide precursor. Chlorine dioxide
`containing complexes such as complexes of chlorine dioxide
`with carbonate, chlorine dioxide with bicarbonate and mix(cid:173)
`tures thereof are also included as chlorine dioxide precur-
`
`sors. The exact chemical compos1t10n of many chlorine
`dioxide precursors, for example, SCD and the chlorine
`dioxide complexes, is not completely understood. The
`manufacture or production of certain chlorine dioxide pre(cid:173)
`cursors is described in McNicholas, U.S. Pat. No. 3,278,447,
`which is incorporated in its entirety herein by reference.
`Specific examples of useful SCD products include that sold
`under the trademark Dura Klar® by Rio Linda Chemical
`Company, Inc., and that sold under the trademark Anthium
`Dioxide® by International Dioxide, Inc.
`[0021] The polyquaternium-1 that may be used in the
`present invention may come in the form of a pure liquid, a
`liquid concentrate, a salt, or a salt in aqueous solution. One
`particularly useful form of polyquaternium-1 is polyquater(cid:173)
`nium-1 chloride in aqueous solution. Likewise, the PHMB
`that may be used in the present invention may come in the
`form of a pure liquid, a liquid concentrate, a salt, or a salt in
`aqueous solution. One particularly useful form of PHMB is
`a hydrochloride salt in aqueous solution at between 1 and 20
`w/w %.
`
`[0022]
`If a chlorine dioxide precursor in included in the
`present compositions, it generally is present in an effective
`preservative or contact lens disinfecting amount. Such effec(cid:173)
`tive preservative or disinfecting concentrations usually are
`in the range of about 0.002 to about 0.06% (w/w) of the
`present compositions. The chlorine dioxide precursors may
`be used in combination with other antimicrobial compo(cid:173)
`nents, such as biguanides, biguanide polymers, salts thereof
`and mixtures thereof.
`[0023]
`In the event that chlorine dioxide precursors are
`employed as antimicrobial components, the compositions
`usually have an osmolality of at least about 200 mOsmol/kg
`and are buffered to maintain the pH within an acceptable
`physiological range, for example, a range of about 6 to about
`10.
`
`[0024]
`In one embodiment, the additional antimicrobial
`component is non-oxidative. It has been found that reduced
`amounts of non-oxidative antimicrobial components, for
`example, in a range of about 0.1 ppm to about 3 ppm or less
`than 5 ppm (w/w), in the present compositions are effective
`in disinfecting contact lenses and reduce the risk of such
`antimicrobial components causing ocular discomfort and/or
`irritation. Such reduced concentration of antimicrobial com(cid:173)
`ponent is very useful when the antimicrobial component
`employed is selected from biguanides, biguanide polymers,
`salts thereof and mixtures thereof.
`[0025] Cetylpyridinium chloride (CPC) is an example of
`an antimicrobial agent that may be used in conjunction with
`the buffer system according to the present invention. One of
`the present inventors previously discovered that cetylpyri(cid:173)
`dinium chloride (CPC) at low concentrations, in combina(cid:173)
`tion with a non-ionic poly(oxypropylene)-poly(oxyethyl(cid:173)
`ene) block copolymer surfactant, can be efficacious as a
`contact lens disinfection agent. Such efficacy may be seen in
`concentrations ranging from as low as 0.1 ppm or 0.3 ppm
`to about 8 ppm, 9 ppm or 10 ppm. The benefits which may
`be achieved through the use of CPC are disclosed in U.S.
`patent application Ser. No. 10/820,486, to Zhi-Jian Yu et al.,
`entitled "Cetylpyridinium Chloride as an Antimicrobial
`Agent" which is incorporated herein by reference.
`[0026] The viscosity-inducing components which may be
`employed in the present solutions preferably are effective at
`
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`US 2006/0229219 Al
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`Oct. 12, 2006
`
`3
`
`low or reduced concentrations, are compatible with the other
`components of the present solutions and are nonionic. Such
`viscosity inducing components are effective to enhance
`and/or prolong the cleaning and wetting activity of the
`surfactant component and/or condition a contact lens surface
`rendering it more hydrophilic (less lipophilic) and/or to act
`as a demulcent on the eye. Increasing the solution viscosity
`provides a film on the lens which may facilitate comfortable
`wearing of the treated contact lens. When the present
`buffering system is incorporated in a rewetter or multi(cid:173)
`purpose solution, the viscosity-inducing component may
`also act to cushion the impact on the eye surface during
`insertion of the lens and serves also to alleviate eye irrita(cid:173)
`tion.
`[0027] Suitable viscosity-inducing components include,
`but are not limited to, water soluble natural gums, gelatin,
`polyols (by way of example, and not of limitation, including
`glycerin, and propylene glycol) cellulose-derived polymers
`and the like. Useful natural gums include guar gum, gum
`tragacanth and the like. Useful cellulose-derived viscosity
`inducing components include cellulose-derived polymers,
`such as hydroxypropyl cellulose, hydroxypropylmethyl cel(cid:173)
`lulose, methyl cellulose, hydroxyethyl cellulose, hyalur(cid:173)
`onate (HA) and the like. Polyethylene glycol 300, polyeth(cid:173)
`ylene glycol 400, and polysorbate 80 are also useful. More
`preferably, the viscosity-inducing agent is selected from
`cellulose derivatives (polymers) and mixtures thereof. A
`very useful viscosity inducing component is hydroxypropy(cid:173)
`lmethyl cellulose (HPMC).
`[0028] Additional demulcents include, but are not limited
`to, the approved ophthalmic demulcents described in the
`United States Ophthalmic Demulcents Monograph. See 21
`CFR 349.12 (2003).
`[0029] The present invention may also include hyaluronic
`acid (e.g., sodium hyaluronate) as the primary active demul(cid:173)
`cent ingredient. As one of ordinary skill in the art will know,
`a demulcent is an agent (usually a water soluble polymer)
`which is applied topically to the eye to protect and lubricate
`mucous membrane surfaces and relieve dryness and irrita(cid:173)
`tion. In this embodiment of the present invention, the
`hyaluronic acid preferably has a molecular weight of about
`200,000 to about 4,000,000 daltons. Preferably, the range is
`from about 750,000 to about 2,000,000 daltons. More pref(cid:173)
`erably, the range is from about 800,000 to about 1,750,000
`daltons or from about 900,000 to about 1,500,000 daltons. In
`one embodiment, the concentration of hyaluronic acid is
`from about 0.005% to about 0.5% (w/w). Preferably, the
`hyaluronic acid concentration ranges from about 0.01 to
`about 0.3% w/w. In a more preferred embodiment, the
`hyaluronic acid concentration ranges from about 0.02 to
`about 0.2% w/w. In another preferred embodiment the
`concentration of hyaluronic acid is from about 0.05% to
`about 2% w/w, and more preferably from about 0.1 to about
`0.5% w/w.
`[0030] The viscosity-inducing component is used in an
`amount effective to increase the viscosity of the solution,
`preferably to a viscosity in the range of about 1.5 to about
`30, or even as high as about 75 cps at 25° C., preferably as
`determined by USP test method No. 911 (USP 23, 1995). To
`achieve this range of viscosity increase, an amount of
`viscosity-inducing component of about 0.01 % to about 5%
`(w/w) preferably is employed, with amounts of about 0.05%
`to about 0.5% or 0.2 to about 2.5 being more preferred.
`
`[0031] A stabilized oxy-chloro complex may be used as a
`preservative. Preferably the stabilized oxy-chloro complex
`concentration ranges from about 0.0015 to about 0.05%
`w/w. More preferably the stabilized oxy-chloro complex
`concentration ranges from about 0.0025 to about 0.03%
`w/w. Another preferred stabilized oxy-chloro complex con(cid:173)
`centration ranges from about 0.003 to about 0.02% w/w. In
`a further preferred embodiment, the stabilized oxy-chloro
`concentration ranges from about 0.0035 to about 0.01 %
`w/w. More preferably, the stabilized oxy-chloro complex
`concentration ranges from about 0.004 to about 0.009%
`w/w.
`
`[0032] As used herein, the term "stabilized oxy-chloro
`complex" is a broad term used in its ordinary sense. The
`term includes, without limitation, a stable solution compris(cid:173)
`ing a chlorine dioxide precursor or a chlorine dioxide
`precursor with chlorine dioxide in equilibrium. Chlorine
`dioxide precursors include, but are not limited to, chlorite
`components such as metal chlorites, for example alkali
`metal and alkaline earth metal chlorites. One particularly
`preferred metal chlorite is sodium chlorite. Stabilized oxy(cid:173)
`chloro complex as stabilized chlorine dioxide is available
`commercially as OCUPURE™ from Advanced Medical
`Optics, Inc., PURITE® from Allergan, Inc., and PURO(cid:173)
`GENE from Biocide, Inc.
`
`[0033] As used herein, concentrations of stabilized oxy(cid:173)
`chloro complex are measured in terms of potential chlorine
`dioxide. Potential chlorine dioxide is a broad term, used in
`its ordinary sense. As such, one sense of the term refers to
`the amount of chlorine dioxide potentially provided if all
`chlorine dioxide precursor, such as sodium chlorite, were
`converted to chlorine dioxide. One way to convert sodium
`chlorite to chlorine dioxide is to dissolve the sodium chlorite
`and acidify the resulting solution. One of ordinary skill in
`the art will know of other means to convert sodium chlorite
`to chlorine dioxide including, but not limited to, exposure to
`transition metals.
`
`[0034] The liquid aqueous medium preferably includes an
`effective amount of a tonicity component to provide the
`liquid medium with the desired tonicity. Among the suitable
`tonicity adjusting components that may be employed are
`those conventionally used in contact lens care products, such
`as various inorganic salts and non-ionic polyols (as one of
`ordinary skill in the art will realize, in the event that a
`non-ionic polyol is used, the concentrations of the buffering
`system will have to be adjusted). Sodium chloride and/or
`potassium chloride and the like are very useful tonicity
`components, as are propylene glycol, glycerin, sorbitol,
`mannitol and the like. The amount of tonicity component
`included is effective to provide the desired degree oftonicity
`to the solution. Such amount may, for example, be in the
`range of about 0.4% to about 1.5% (w/w). If a combination
`of sodium chloride and potassium chloride is employed, it is
`preferred that the weight ratio of sodium chloride to potas(cid:173)
`sium chloride be in the range of about 3 to about 6 or about
`8.
`
`[0035]
`In another embodiment of the invention, the solu(cid:173)
`tion may comprise balanced salts. The balanced salts pref(cid:173)
`erably include NaCl, KC!, CaCl2 , and MgCl2 in a ratio that
`provides an osmolality range of about 140 to about 400,
`preferably about 240 to about 330 mOsm/kg, and even more
`preferably about 260 to about 300 mOsm/kg, with the most
`
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`4
`
`preferred osmolality of approximately 270 mOsm/kg. In one
`embodiment, NaCl ranges from about 0.1 to about 1 % w/w,
`preferably from about 0.2 to about 0.8% w/w, and even more
`preferably about 0.39% w/w, KC! ranges from about 0.02 to
`about 0.5% w/w, preferably about 0.05 to about 0.3% w/w,
`more preferably about 0.14% w/r, CaCl2 ranges from about
`0.0005 to about 0.1 % w/w, preferably about 0.005 to about
`0.08% w/w, more preferably about 0.06% w/w, and MgCl 2
`ranges from about 0.0005 to about 0.1% w/w, preferably
`about 0.005 to about 0.08% w/w, more preferably about
`0.06% w/w.
`
`[0036] A chelating or sequestering component preferably
`is included in an amount effective to enhance the effective(cid:173)
`ness of the antimicrobial component and/or to complex with
`metal ions to provide more effective cleaning of the contact
`lens.
`
`[0037] A wide range of organic acids, amines or com(cid:173)
`pounds which include an acid group and an amine function
`are capable of acing as chelating components in the present
`compositions. For example, nitrilotriacetic acid, diethylen(cid:173)
`etriaminepentacetic acid, hydroxyethylethylene-diaminetri(cid:173)
`acetic acid, 1,2-diaminocyclohexane
`tetraacetic acid,
`hydroxyethylaminodiacetic acid, ethylenediamine-tetraace(cid:173)
`tic acid and its salts, polyphosphates, citric acid and its salts,
`tartaric acid and its salts, and the like and mixtures thereof,
`are useful as chelating components. Ethylenediaminetet(cid:173)
`raacetic acid (EDTA) and its alkali metal salts, are preferred,
`with disodium salt of EDTA, also known as disodium
`edetate, being particularly preferred.
`
`[0038] The chelating component preferably is present in
`an effective amount, for example, in a range of about 0.01 %
`and about 1 % (w/w) of the solution.
`
`[0039]
`In a very useful embodiment, particularly when the
`chelating component is EDTA, salts thereof and mixtures
`thereof, a reduced amount is employed, for example, in the
`range of less than about 0.05% (w/w) or even about 0.02%
`(w/w) or less. Such reduced amounts of chelating compo(cid:173)
`nent have been found to be effective in the present compo(cid:173)
`sitions while, at the same time, providing for reduced
`discomfort and/or ocular irritation.
`
`[0040] Beneficial amino acids may also be included in the
`present compositions. By way of example, and not of
`limitation, taurine, glycine and serine may be included.
`Taurine, which has been shown to serve a membrane pro(cid:173)
`tective function for ocular tissues, may be included in those
`embodiments of the present invention that will be used
`within the eye. The amount of amino acids which may be
`added to compositions according to the present invention is
`generally from about 0.0001 w/w % to about 0.1 w/w %.
`
`[0041] The benefits of including taurine are disclosed in
`U.S. patent application Ser. No. 10/328,641, to S. Huth,
`entitled "Contact Lens Care Compositions, Methods of Use,
`and Preparation which Protect Ocular Tissue," which is
`incorporated herein by reference. The amount of taurine
`useful in the present invention to maintain ocular tissue cell
`membrane integrity, particularly during contact lens wear,
`may be determined by objective clinical measures such as
`tear LDH release from corneal epithelial cells or fluorescein
`barrier permeability measurements or another means to
`evaluate ocular cell membrane integrity such as fluorescein
`or rose bengal staining. Yet another means to evaluate ocular
`
`cell membrane integrity is the use of confocal microscopy to
`measure epithelial cell area. In lieu of using tear LDH as a
`response factor, another inflammatory mediator may be
`measured in tears to indicate a beneficial effect from taurine.
`Useful amounts of taurine can also be determined by sub(cid:173)
`jective clinical measures such as itching, lacrimation (tear(cid:173)
`ing) and comfort. The amount of taurine useful in the present
`invention is generally from about 0.01 to about 2.0 w/w %,
`and may be from about 0.05 to about 1.00 w/w %.
`
`[0042] A surfactant component preferably is present in an
`amount effective in cleaning, that is to at least facilitate
`removing, and preferably effective to remove, debris or
`deposit material from, a contact lens contacted with the
`surfactant containing solution.
`
`[0043] The surfactant component preferably is nonionic,
`and more preferably is selected from poly (oxyethylene)(cid:173)
`poly(oxypxopylene) block copolymers and mixtures
`thereof. Such surfactant components can be obtained com(cid:173)
`mercially from the BASF Corporation under the trademarks
`Pluronic® or Tetronic®. Pluronic® block copolymers can
`be generally described as polyoxyethylene/polyoxypropy(cid:173)
`lene condensation polymers terminated in primary hydroxyl
`groups. They may be synthesized by first creating a hydro(cid:173)
`phobe of desired molecular weight by the controlled addi(cid:173)
`tion of propylene oxide to the two hydroxyl groups of
`propylene glycol or glycerin. In the second step of the
`synthesis, ethylene oxide is added to sandwich this hydro(cid:173)
`phobe betweenhydrophile groups. Tetronic® surfactants are
`also known as poloxamines and are symmetrical block
`copolymers of ethylene diamine with polyoxyethylene and
`polyoxypropylene.
`
`[0044] Examples of some non-ionic surfactants for use in
`the present invention are disclosed in, for example, Kirk(cid:173)
`Othmer, Encyclopedia of Chemical Technology, 3rd Edition,
`Vol. 22 (John Wiley E Sons, 1983), Sislet & Wood, Ency(cid:173)
`clopedia of Surface Active Agents (Chemical Publishing
`Co., Inc. 1964), McCutcheon's Emulsifiers & Detergents,
`North American and International Edition (McCutcheon
`Division, The MC Publishing Co., 1991), Ash, The Con(cid:173)
`densed Encyclopedia of Surfactants (Chemical Publishing
`Co., Inc., 1989), Ash, What Every Chemical Technologist
`Wants to Know About ... Emulsifiers and Wetting Agents,
`Vol. 1 (Chemical Publishing Co., Inc., 1988), Tadros, Sur(cid:173)
`factants (Academic Press, 1984), Napper, Polymeric Stabi(cid:173)
`lization of Colloidal Dispersion (Academic Press, 1983) and
`Rosen, Surfactants & Interfacial Phenomena, 2nd Edition
`(John Wiley & Sons, 1989), all of which are incorporated
`herein by reference.
`
`[0045]
`In accordance with a more preferred embodiment
`of the invention, such block copolymers having molecular
`weights in the range of about 2500 to 13,000 daltons are
`suitable, with a molecular weight range of about 6000 to
`about 12,000 daltons being still more preferred. Specific
`examples of surfactants which are satisfactory include:
`polbxamer 108, poloxamer 188, poloxamer 237, poloxamer
`238, poloxamer 288 poloxamer 407, Tetronic® 1107,
`Tetronic®1304 (mwt 10,500), and Tetronic® 1307. Particu(cid:173)
`larly good results are obtained with with poloxamer 237 and
`Tetronic® 1304. Poloxamer 237 is also known as Pluronic
`F87.
`
`[0046] Alternative exemplary surfactant components
`include, but are not limited to, nonionic surfactants, for
`
`000007
`
`

`

`US 2006/0229219 Al
`
`Oct. 12, 2006
`
`5
`
`example, polysorbates (such as polysorbate 20-Trademark
`tocopherol polyethylene glycol succinate
`Tween 20),
`("TPGS"), polyethylene glycol (PEG)-400, 4-(1,1,3,3-tet(cid:173)
`ramethylbutyl) phenol/poly(oxyethylene) polymers (such as
`the polymer sold under the trademark Tyloxapol), poly( oxy(cid:173)
`ethylene )-poly( oxypropylene) block copolymers, and the
`like, and mixtures thereof.
`
`[0047] The amount of surfactant component, if any,
`present varies over a wide range depending on a number of
`factors, for example, the specific surfactant or surfactants
`being used, the other components in the composition and the
`like. Often, the amount of surfactant is in the range of about
`0.005% or about 0.01 % to about 0.1 % or about 0.5% or
`about 1.0% (w/w). The preferred surfactant concentration is
`between about 0.05% and 0.20% (w/w).
`
`[0048] When the present buffering system is used as an
`ophthalmic solution such as a multi-purpose solution, rewet(cid:173)
`ter or tear, the liquid aqueous medium used is selected to
`have no substantial deleterious effect on the lens being
`treated, or on the wearer of the treated lens. The liquid
`medium is constituted to permit, and even facilitate, the lens
`treatment or treatments by the present compositions. The
`liquid aqueous medium advantageously has an osmolality in
`the range of at least about 200-mOsmol/kg to about 300 or
`about 350 mOsmol/kg. The liquid aqueous medium more
`is substantially isotonic or hypotonic (for
`preferably
`example, slightly hypotonic) and/or is ophthalmically
`acceptable.
`
`[0049]
`In one embodiment, the present compositions com(cid:173)
`prise: a liquid aqueous medium, a borate-polyol buffer in an
`amount effective in maintaining the pH of the composition
`within a physiologically acceptable range, an antimicrobial
`agent in an amount effective to, in association with the
`remainder of the solution, disinfect a contact lens contacted
`with the composition; a non-ionic surfactant component in
`an amount effective in cleaning a contact lens contacted with
`the composition; an effective amount of a viscosity inducing
`component; and an effective amount of a tonicity compo(cid:173)
`nent. The present compositions may also include an effective
`amount of a chelating or sequestering component, more
`preferably in a range of less than 0.05% (w/w). Each of the
`components, in the concentration employed, included in the
`solutions and the formulated solutions of the present inven(cid:173)
`tion generally are ophthalmically acceptab