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WO2024134384A1 - Compositions pour dispositifs ophtalmologiques - Google Patents

Compositions pour dispositifs ophtalmologiques Download PDF

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Publication number
WO2024134384A1
WO2024134384A1 PCT/IB2023/062632 IB2023062632W WO2024134384A1 WO 2024134384 A1 WO2024134384 A1 WO 2024134384A1 IB 2023062632 W IB2023062632 W IB 2023062632W WO 2024134384 A1 WO2024134384 A1 WO 2024134384A1
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WIPO (PCT)
Prior art keywords
composition
microbial growth
compound
acid
microorganisms
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Ceased
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PCT/IB2023/062632
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English (en)
Inventor
Frank Neely
Donald E. Riederer
Justin Scott Jacobs
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Johnson and Johnson Vision Care Inc
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Johnson and Johnson Vision Care Inc
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Publication date
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Publication of WO2024134384A1 publication Critical patent/WO2024134384A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/10—Halogens or compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/12—Non-macromolecular oxygen-containing compounds, e.g. hydrogen peroxide or ozone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
    • A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
    • A61L12/12—Non-macromolecular oxygen-containing compounds, e.g. hydrogen peroxide or ozone
    • A61L12/124—Hydrogen peroxide; Peroxy compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/081—Gamma radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/10—Ultraviolet radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/10—Apparatus features
    • A61L2202/12—Apparatus for isolating biocidal substances from the environment
    • A61L2202/122—Chambers for sterilisation

Definitions

  • the present invention relates to a microbial growth inhibiting compound and buffer compound containing compositions, especially eye care compositions, achieving physiologically compatible pH and tonicity as well as good bacteriostatic properties. Methods of using the compositions of the present invention are also disclosed. BACKGROUND OF THE INVENTION Contact lenses are generally provided to consumers as individually packaged products.
  • the single unit containers which package such contact lenses typically use buffered saline as storage or packaging solutions.
  • Such packaging solutions should provide for, at least in some cases, a short-term period – e.g., between solution preparation and sterilization of the end-staged packaged product - an environment that does not facilitate the growth of harmful or undesirable microorganisms.
  • undesirable microorganisms include Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Bacillus subtilis and Aspergillus brasiliensis.
  • the packaging solutions should be gentle to the eye since at least some of the packaging solution will, most likely, remain on a contact lens once it is removed from the packaging solution and placed directly on (i.e., by direct application to) the eye.
  • the contact lens (or other ophthalmic device) packaging solution should also be compatible with the materials forming the contact lens (or other ophthalmic device) and the contact lens packaging. 1 Docket No. VTN6146WOPCT1 A challenge in preparing packaging solutions for ophthalmic devices is formulating solutions which do not negatively affect eye comfort or the solution’s compatibility with the material(s) forming the ophthalmic device.
  • ophthalmic compositions One important component of ophthalmic compositions, including packaging solutions, is the buffer incorporated, which helps to maintain the pH of the composition within an acceptable physiological range.
  • the present inventors have found that by appropriately combining microbial growth inhibiting compounds s and organic acid buffers, adequately buffered, bacteriostatic compositions (e.g., packaging solutions) can be achieved. More specifically, such buffered solutions can be achieved by combining microbial growth inhibiting compounds with organic acids at specific ratios of the microbial growth inhibiting compounds to organic acids buffers – as detailed below.
  • bacteriostatic compositions e.g., packaging solutions
  • buffered solutions can be achieved by combining microbial growth inhibiting compounds with organic acids at specific ratios of the microbial growth inhibiting compounds to organic acids buffers – as detailed below.
  • a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; iii. a reductant for neutralizing the microbial growth inhibiting compound, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv. an ophthalmically acceptable carrier comprising one or more tonicity agents at least one contact lens sealed in a container with the composition.
  • the present invention also relates to methods of inhibiting the growth of microorganisms in a composition for a period of time occurring from preparation of the composition to sterilization of the composition in sealed a container, comprising the steps of: 2 Docket No. VTN6146WOPCT1 a. mixing a composition comprising: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; and iii.
  • a reductant for neutralizing the microbial growth inhibiting compound after admixture to the composition provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; b. storing the composition for the period of time during which time there is inhibition of growth of microorganisms; c. placing the composition in a container; d. sealing the container of step c.; e. sterilizing the container of the d.
  • composition is free of or substantially free of one or more of boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • the present invention further relates to methods of packaging and sterilizing a composition in sealed a container, comprising the steps of: a. mixing a composition comprising: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; and iii.
  • a reductant for neutralizing the microbial growth inhibiting compound after admixture to the composition provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound 3 Docket No. VTN6146WOPCT1 remains effective to inhibit the growth of microorganisms in the composition for a period of time; b. placing the composition in a container; c. sealing the container of step b.; d. sterilizing the container of the c.
  • compositions are free of or substantially free of one or more of boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • the present invention further relates to sealed ophthalmic products, comprising: a) a composition for storing contact lenses as an admixture or mixture: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; iii.
  • a reductant for neutralizing the microbial growth inhibiting compound provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv. an ophthalmically acceptable carrier comprising one or more tonicity agents and b) a sealed package comprising at least one contact lens in the presence of the composition.
  • the present invention still further relates to sealed ophthalmic products comprising, a) a composition for storing contact lenses as an admixture or mixture: 4 Docket No. VTN6146WOPCT1 i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii.
  • a buffer compound iii. optionally, a reductant for neutralizing the microbial growth inhibiting compound, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv. an ophthalmically acceptable carrier comprising one or more tonicity agents at least one contact lens sealed in a container with the composition and b) a container comprising a sealed compartment comprising at least one contact lens in the presence of the composition.
  • the present invention also relates to methods of making and using the disclosed compositions.
  • FIGURES Figures 1-3 are graphs showing the inhibition of growth of the fungi Candida albicans and Aspergillus brasiliensis and the bacteria Bacillus subtilis – subspecies spizizenii, respectively, when each microorganism was spiked into the compositions of Table 3 comprising a microbial growth inhibiting compound at various concentrations.
  • DETAILED DESCRIPTION OF THE INVENTION As indicated above, the present invention relates to compositions comprising one or more microbial growth inhibiting compounds and one or more organic acid compound as an ophthalmically acceptable carrier.
  • the compositions may be useful for storing or as a packaging solution for ophthalmic devices.
  • the present invention provides ophthalmic solutions comprising a transient 5 Docket No. VTN6146WOPCT1 microbial growth inhibiting compound that is bacteriostatic from the formulation of the composition through heat sterilization, such as autoclaving, but substantially or entirely neutralized during sterilization providing a non-preserved ophthalmic solution after sterilization.
  • the present invention further provided hermetically sealed contact lens packages comprising a contact lens and an ophthalmic solution of the present invention.
  • the compositions may be useful for direct application to the eyes for an eye care benefit such as relieving eye discomfort.
  • compositions and methods of the present invention can comprise, consist of, or consist essentially of the steps, essential elements and limitations of the invention described herein, as well any of the additional or optional ingredients, components, or limitations described herein.
  • the term “comprising” (and its grammatical variations) as used herein is used in the inclusive sense of “having” or “including” and not in the exclusive sense of “consisting only of.”
  • the terms “a” and “the” as used herein are understood to encompass the plural as well as the singular. Unless otherwise indicated, all documents cited are incorporated herein by reference. Furthermore, all documents incorporated herein by reference are only incorporated herein to the extent that they are not inconsistent with this specification.
  • any document is not to be construed as an admission that it is prior art with response to the present invention.
  • the present invention as disclosed herein may be practiced in the absence of any compound or element (or group of compounds or elements) which is not specifically disclosed herein.
  • pharmaceutically acceptable means biologically tolerable, and otherwise biologically suitable for application or exposure to the eyes and surrounding tissues of the eyes without undue adverse effects such as toxicity, incompatibility, instability, irritation, allergic response and the like.
  • cationic preservatives as used herein, means net positively charged compounds having antimicrobial properties and include, without limitation thereto, one or more of 6 Docket No.
  • VTN6146WOPCT1 polymyxin B sulfate, quaternary ammonium compounds, poly(quaternary ammonium) compounds, benzalkonium chloride, cetylpridinium chloride, benzethonium chloride, cetyltrimethyl ammonium bromide, chlorhexidine, poly(hexamethylene biguanide), and mixtures thereof.
  • Poly(quaternary ammonium) compounds are compounds that are positively charged surface active agents (i.e., cationic surfactants ) which act to compromise the cell walls and membranes , and examples include BUSAN 77, ONAMERM, MIRAPOLA15, IONENES A, POLYQUATERNIUM 11, POLYQUATER NIUM 7, BRADOSOL, AND POLYQUAT D-17- 1742.
  • the term “lidstock”, as used herein means, a flexible film or sheet which is heat sealed to the concave side of the plastic blister packaging to form a sealed cavity. Lidstock is generally multilayered and comprises a support layer and a peelable seal layer. The lidstock may further comprise additional layers including print layers, lamination layers, foil layers and combinations thereof and the like.
  • ophthalmically acceptable and/or compatible means the composition or component(s) is pharmaceutically acceptable and is not or substantially is not, detrimental, negative, or harmful to any part of the eye (or surrounding tissues) or the other ingredients (including actives) in the composition itself.
  • water soluble means that the components, either alone or in combination with other components, do not form precipitates or gel particles visible to the human eye at the concentrations selected and across the temperatures and pH regimes common for manufacturing, sterilizing and storing the ophthalmic solution.
  • effective to inhibit means an amount which causes an inhibition in the growth of microorganisms.
  • the term “inhibition of growth of microorganisms” in the composition occurs where, and means that, there is a less than a 0.5 log, less than 0.3 log, or less than 0.2 log increase or no increase in the count of any microorganism present in the composition after 1 day, 2 days, 3 days, 5 days, 7 days, 8 days, 10 days, 13 days, 14 days, 15 days, 20 days, 21 days or 22 days from date of preparation of the compositions of the present invention. 7 Docket No. VTN6146WOPCT1 All percentages, parts and ratios are based upon the total weight of the composition of the present invention, unless otherwise specified.
  • compositions of the present invention at the time of mixing, comprise one or more microbial growth inhibiting compounds selected from peroxides (or sources of peroxide), chlorous acid compounds, salts thereof and/or mixtures thereof.
  • the microbial growth inhibiting compounds and salts thereof are ophthalmically compatible with the eyes and surrounding tissue and are compatible with the ingredients in compositions of the present invention. Upon degradation during the course of sterilization and/or storage conditions, the microbial growth inhibiting compounds and salts degrade to ophthalmically compatible degradants.
  • chlorous acid compounds suitable for use in the compositions or methods of the present invention include (selected from or selected from the group consisting of), but are not limited to, chlorous acid; an alkali metal salt of chlorous acid including lithium chlorite, sodium chlorite, sodium chlorite trihydrate, or potassium chlorite and the like; an alkali earth metal salt of chlorous acid including magnesium chlorite, magnesium chlorite trihydrate, calcium chlorite, calcium chlorite trihydrate, barium chlorite, or barium chlorite dihydrate and the like; an earth metal salt of chlorous acid such as aluminum chlorite; a zinc-family salt of chlorous acid such as zinc chlorite dihydrate; a transitional metal salt of chlorous acid such as copper chlorite (II), copper chlorite (III), silver chlorite, nickel chlorite dihydrate or manganese chlorite
  • compositions of the present invention are sources of chlorous acid compounds such as stabilized oxychloro complex, (Purite, Bio-Cide International Inc., Ok, USA) and/or stabilized chlorite peroxide (SOC - Oxyd Tubilux.). Mixtures of any the above-mentioned chlorous acid compounds or sources of chlorous acid compounds may also be used.
  • sources of chlorous acid compounds such as stabilized oxychloro complex, (Purite, Bio-Cide International Inc., Ok, USA) and/or stabilized chlorite peroxide (SOC - Oxyd Tubilux.).
  • Salts of chlorous acid compounds which are particularly preferred for use herein are ophthalmically compatible salts including, but are not limited to, lithium chlorite, sodium chlorite, sodium chlorite trihydrate, or potassium chlorite and the like; an alkali earth metal salt of chlorous acid including magnesium chlorite, magnesium chlorite trihydrate, calcium chlorite, calcium chlorite trihydrate, aluminum chlorite, ammonium chlorite; a quaternary ammonium salt of chlorous acid such as tetramethylammonium chlorite; a quaternary phosphonium salt of chlorous acid such as (2,4-dinitrophenyl) triethylphosphonium chlorite; an amine salt of chlorous acid such as a methyl amine salt of chlorous acid, a tripropyl amine salt of chlorous acid, a pyridine salt of chlorous acid, a 4-methyl pyridine salt of chlorous acid, a 2,4-dimethyl pyridine salt of chlorous acid or a
  • Chlorite compounds suitable for use in the present invention include chlorite compounds and salts thereof, including (selected from or selected from the group consisting of), but not limited to, water soluble alkali metal chlorites, water soluble alkaline metal chlorites and mixtures thereof.
  • Specific examples of chlorite compounds include (selected from or selected from the group consisting of) potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite and mixtures thereof.
  • the chlorite compound may comprise sodium chlorite.
  • the chlorous acid compound may be an anhydride or a hydrate.
  • the salts of chlorous acid may be a mono or a double salt.
  • Suitable concentrations for the chlorous acid compound include concentrations from 0.0020% (or about 0.0020%) to 0.2000% (or about 0.2000%), or from 0.0020% (or about 0.0020%) to 0.1000% (or about 0.1000%), or from 0.0050% (or about 0.0050%) to 0.1000% (or 9 Docket No.
  • VTN6146WOPCT1 about 0.1000%), or from 0.0075% (or about 0.0075%) to 0.1000% (or about 0.1000%), or, from 0.0080% (or about 0.0080%) to 0.0500% (or about 0.0500%), or from 0.0090% (or about 0.0090%) to 0.0200%, (or about 0.0200%), or from 0.0095% (or about 0.0095%) to 0.0150% (or about 0.0150%), or 0.01% (or about 0.01%), based on the total weight of the composition upon formulation.
  • the chlorous acid compound preferably provides chlorite anion concentrations of from 0.0015% (or about 0.0015%) to 0.1500% (or about 0.1500%), or from 0.0015% (or about 0.0015%) to 0.0750% (or about 0.0750%), or from 0.0037% (or about 0.0037%) to 0.0750% (or about 0.0750%), or from 0.0056% (or about 0.0056%) to 0.0750% (or about 0.0750%), more or, from 0.0060% (or about 0.0060%) to 0.0370% (or about 0.0370%), or from 0.0067% (or about 0.0067%) to 0.0150%. (or about 0.0150%), or from 0.0071% (or about 0.0071%) to 0.0110%.
  • microbial growth inhibiting compound of the present invention are peroxides or sources of peroxide.
  • Sources of peroxide are compounds or materials that release (or can release peroxide or hydrogen peroxide) in aqueous solution.
  • Suitable peroxides or sources of peroxide useful herein include, but are not limited to, barium peroxide, sodium peroxide, zinc peroxide, magnesium peroxide, calcium peroxide, lithium peroxide, butanone peroxide, cyclohexanone peroxide, benzoyl peroxide, urea hydrogen peroxide (carbamide peroxide, carbamide perhydrate, or percarbamide), percarbonates such as calcium percarbonate or magnesium percarbonate, tert-butylhydroperoxide, perborate salts such as sodium perborate, peroxy acids such as methyl ethyl ketone peroxide, mixtures thereof and derivatives.
  • preferred peroxides are selected from benzoyl peroxide, hydrogen peroxide and mixtures thereof and most preferably hydrogen peroxide.
  • Suitable concentrations for the hydrogen peroxide (or source(s) of peroxide) include concentrations of from 0.0001% (or about 0.0001%) to 0.02% (or about 0.02%), from 0.0002% (or about 0.0002%) to 0.015% (or about 0.015%), or from 0.0003% (or about 0.0003%) to 0.013% (or about 0.013%), or from 0.0004 (or about 0.0004%) to 0.012% (or about 0.012%), or from 0.0005% (or about 0.0005%) to 0.011% (or about 0.011%), or from 0.0006% (or about 10 Docket No.
  • VTN6146WOPCT1 0.0006%) to 0.01% (or about 0.01%), or from 0.0007% (or about 0.0007%) to 0.005% (or about 0.005%), or from 0.0008 (or about 0.0008%) to 0.002% (or about 0.002%), or from 0.0009% (or about 0.0009%) to 0.001% (or about 0.001%), based on the total weight of the composition upon formulation.
  • Combinations of the above-described microbial growth inhibiting compound may also be used.
  • the microbial growth inhibiting compound is incorporated into the compositions of the present invention to provide bacteriostatic properties for inhibiting microbial growth in the compositions.
  • the bacteriostatic properties for inhibiting microbial growth may occur for and are in effect during a period of time which may be from the preparation or manufacture of the compositions of the present invention up to the time of performing at least one method sterilization on the composition, preferably sterilization of the composition in a sealed package with at least one contact lens as described below.
  • the microbial growth inhibiting compound concentration is substantially or entirely neutralized.
  • the concentration of the microbial growth inhibiting compound may be reduced by at by at least about 50%, about 70%, about 80%, about 90% or 100%. If the microbial growth inhibiting compound is not completely neutralized upon autoclaving it may be fully neutralized during storage of the lens after autoclaving and before use.
  • period of time as used in association with the bacteriostatic properties of the chlorous acid compound, it is meant up to or at least one day, two days, three days, four days, five days, six days, seven days, eight days, ten days, twelve days, fourteen days, fifteen days, 18 days, 20 days, 21 days or 22 days from date of preparation of the compositions of the present invention.
  • the period of time may be up two weeks, during which the solution is stored in a sealed container at ambient temperature.
  • the Buffer Compound comprise a buffer compound. Suitable buffer compounds include, but are not limited to, phosphate compounds, organic acid buffers and mixtures thereof.
  • phosphate or “phosphate compound” (used interchangeably herein) shall refer to phosphoric acid, salts of phosphoric acid and other pharmaceutically acceptable phosphates (e.g., inorganic or organic pharmaceutically acceptable salts), or combinations thereof.
  • examples of phosphate compounds useful in the compositions are those selected from pharmaceutically acceptable organic or inorganic phosphate salts of alkali and/or alkaline earth metals. Suitable phosphates may be incorporated as one or more monobasic phosphates, dibasic phosphates and the like.
  • the phosphate compound may include one or more of organic phosphates such as phytic acid (or salts thereof such as their potassium or sodium salts), or one or more inorganic phosphates such as sodium dibasic phosphate (Na 2 HPO 4 ), sodium monobasic phosphate (NaH2PO4), and potassium monobasic phosphate (KH2PO4) or mixtures of any above the above-mentioned phosphate compounds.
  • organic phosphates such as phytic acid (or salts thereof such as their potassium or sodium salts)
  • inorganic phosphates such as sodium dibasic phosphate (Na 2 HPO 4 ), sodium monobasic phosphate (NaH2PO4), and potassium monobasic phosphate (KH2PO4) or mixtures of any above the above-mentioned phosphate compounds.
  • the inorganic phosphate compound can be present in the compositions at concentrations of from 0.3% (or about 0.3%) w/v to 0.9% (or about 0.9%) w/v, or from 0.4% (or about 0.4%) w/v to 0.85% (or about 0.85%) w/v, or from 0.5% (or about 0.5%) w/v to 0.8% (or about 0.8%) w/v or from 0.6% (or about 0.6%) w/v to 0.75% (or about 0.75%) w/v of the total composition upon formulation.
  • the organic phosphate compound can be present in the compositions at concentrations of from 0.05% (or about 0.05%) w/v to 1.0% (or about 1.0%) w/v, or from 0.10% (or about 0.10%) w/v to 0.50% (or about 0.50%) w/v, or from 0.15% (or about 0.15%) w/v to 0.30% (or about 0.30%) w/v or from 0.17% (or about 0.17%) w/v to 0.25% (or about 0.25%) w/v of the total composition upon formulation. 12 Docket No.
  • the concentration of the phosphate compound may be at least 1.5 (or about 1.5), or at least 2.0 (or about 2.0), and or at least 2.5 (or about 2.5), but up to 4, or up to 3, times the amount of the borate compound on a weight basis upon formulation.
  • organic acid buffer means a non-phosphate containing organic acid having two or more carboxylic acid groups.
  • the organic acid also has a buffer capacity over the range of pH values consistent with ophthalmic compositions (e.g., eye drops and eye washes) and packaging solutions for eye care devices (e.g., contact lens) and may buffer the compositions of the present invention to a pH of from about 6.0 to a pH of about 8.0, or a pH of from about 6.5 to a pH of about 8.0, or a pH of from about 6.5 to a pH of about 7.5, or a pH of about 7.0 to a pH of about 7.5, or a pH of greater than 7.2 (or about 7.2) to a pH of 7.5 (or about 7.5).
  • ophthalmic compositions e.g., eye drops and eye washes
  • packaging solutions for eye care devices e.g., contact lens
  • Preferred organic acid buffers for use in the compositions of the present invention have a pK value in the range of 6 (or about 6) to 8 (or about 8), or 6 (or about 6) to 7 (or about 7).
  • Also useful herein is phytic acid (or salts thereof such as their potassium or sodium salts).
  • the organic acid buffer may be selected from mellitic acid, maleic acid and salts thereof (such the sodium or potassium salts of the organic acids) and mixtures thereof. In certain embodiments, the organic acid buffer may be selected from maleic acid, its sodium or potassium salts and mixtures thereof. In some embodiments, the organic acid buffer may be selected from mellitic acid, its sodium or potassium salts and mixtures thereof. 13 Docket No. VTN6146WOPCT1 The organic acid buffer content of the present compositions is in the range of about 0.10% to about 0.4%, or about 0.18% to about 0.30%, or about 0.20% to about 0.28%, by weight the total weight of the composition upon formulation.
  • the organic acid buffer is preferably a combination of salts of the dibasic organic acid anion (e.g., dibasic sodium maleate monohydrate) and salts of the monobasic organic acid anion (monobasic sodium maleate) where the concentration, prior to sterilization of the composition, of the dibasic organic acid anion is from about 0.1% to about 0.3% and the concentration, prior to sterilization of the composition, of the monobasic organic acid anion is from 0.005% to about 0.002%, by weight of the composition, when present as the metal (e.g., sodium) monohydrate in the case of the dibasic organic acid.
  • the concentration, prior to sterilization of the composition of the dibasic organic acid anion is from about 0.1% to about 0.3%
  • the concentration, prior to sterilization of the composition, of the monobasic organic acid anion is from 0.005% to about 0.002%, by weight of the composition, when present as the metal (e.g., sodium) monohydrate in the case of the dibasic organic acid.
  • compositions of the present invention optionally, comprise a reductant for quenching (or reducing) the microbial growth inhibiting compound so as to neutralize it from the composition.
  • Suitable reductants include, but are not limited to, the following salts (or metal ions thereof: iron (II), bisulfite such as sodium metabisulfite, tin metal, formate, phosphite, hypophosphite, sulfur, thiosulfate (such as sodium thiosulfate), zinc metal, dithionite, manganese metal, aluminum metal, magnesium metal, dithiothreitol, NADH 2 , ascorbate, ferricyanide, hydroquinone, tyrosine, , tyrosine copolymers, aldehydes (such as cinnamic aldehyde), N- acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, ethylenedi
  • the reductant may 14 Docket No. VTN6146WOPCT1 comprise from 15:85 or 10:90 polymethyl acryloyltyrosinate co N,N-dimethylacrylamide, L- glucose, 4-nitrophenol, vanillin, hydroquinone, ethylenediaminetetraacetic acid (EDTA), Cellobiose, PVP and mixtures thereof.
  • the reductant may comprise 15:85 or 10:90 polymethyl acryloyltyrosinate co N,N-dimethylacrylamide, L-glucose, ethylenediaminetetraacetic acid (EDTA), Cellobiose, PVP and mixtures thereof.
  • the reductant may comprise EDTA.
  • the EDTA may be used in a molar excess compared to the chlorous acid compound.
  • the EDTA may be used in concentrations of about 0.01 to about 0.075 wt% EDTA, or about 0.05 to about 0.075 wt% EDTA.
  • the reductant and the microbial growth inhibiting compound are present such that the ratio, in molar equivalents of the microbial growth inhibiting compound to the reductant is from 1:1 to 1:20, or 1:1 to 1:15, or 1:1 to 1:10, or 1:1 to 1:5, or greater than 1:1 to 1:1.5.
  • the reductant is EDTA
  • the molar equivalents of chlorous acid compound to EDTA may be 1:2 to 1:5, or 1:3 to 1:5 or 1:4.
  • the molar equivalents of chlorite to EDTA may be greater than 1:1 to 1:5, 1:2 to 1:5, or 1:3 to 1:5 or 1:4.
  • the microbial growth inhibiting compound is a peroxide the molar equivalents of peroxide to EDTA may be greater than 1.1 to 1.5, 1:2 to 1:5, or 1:3 to 1:5 or 1:4.
  • the composition comprising the chlorous acid compound and reductant remains colorless or lightly colored, even after autoclaving, which can be determined visually or measured via known methods such as APHA color technique.
  • the solution after autoclaving may have a APHA color value of less than about 180, or less than about 40.
  • compositions of the present invention comprise an ophthalmically acceptable carrier.
  • the ophthalmically acceptable carrier may be water or an aqueous excipient solution.
  • aqueous typically denotes a formulation wherein the excipient is at least about 50%, or at least about 75% or at least about 90% and up to about 95% or about 99%, by weight, water.
  • the compositions of the present invention are free of or substantially free of oils or oily substances (e.g., medium-chain triglycerides, castor oil, flaxseed oil and the like or mixtures thereof).
  • oils or oily substances e.g., medium-chain triglycerides, castor oil, flaxseed oil and the like or mixtures thereof.
  • substantially free as used with respect to the oil 15 Docket No.
  • VTN6146WOPCT1 or lipid compounds means the present compositions contain less than 0.05%, or less than 0.025%, or less than 0.01%, or less than 0.005%, of such oils or oily components, by weight, based on the total composition.
  • the compositions are not multiphasic compositions such as oil in water emulsions.
  • the water is preferably distilled water.
  • the carrier is preferably free of C1-4 alcohols such as methanol, ethanol, propanol, isopropanol, butanol, and the like which can sting, irritate, or otherwise cause discomfort to the eye.
  • the water may be present in the ophthalmically acceptable carrier at concentrations of from about 96% to about 99.9%, or from about 98% to about 99.5%, or from about 99.0% to about 99.5%, by weight of the total composition.
  • the ophthalmically acceptable carrier may be present at concentrations of from about 96% to about 99.5%, or from about 98% to about 99.5%, or from about 98.5% to about 99.2%, by weight of the total composition.
  • the compositions may be sterile, namely such that the absence of microbial contaminants in the product prior to release or use are statistically demonstrated to the degree necessary for such products.
  • the compositions may be selected to have no or substantially no detrimental, negative, harmful effect on the contact lens being therein or on the eye (or on the region around the eye).
  • compositions according to the present invention are physiologically compatible with the eye and ophthalmic devices.
  • the composition should be “ophthalmically safe” for use with an ophthalmic device such as a contact lens, meaning that a contact lens treated with the solution is generally suitable and safe for direct placement on or direct application to the eye without rinsing, that is, the solution is safe and comfortable for ophthalmic devices, of any frequency of application, wetted with the solution, including contact lenses of any wear frequency.
  • An ophthalmically safe composition has a tonicity and pH that is compatible with the eye and includes materials, and amounts thereof, that are ophthalmically compatible and non- cytotoxic according to ISO standards and U.S. Food & Drug Administration (FDA) regulations.
  • FDA Food & Drug Administration
  • compositions of the present invention may be adjusted with tonicity agents, to approximate the osmotic pressure of normal lacrimal fluids, which is equivalent to a 0.9 percent 16 Docket No. VTN6146WOPCT1 solution of sodium chloride.
  • the compositions may be made substantially isotonic with physiological saline used alone or in combination with other tonicity agents such as dextrose, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the ophthalmic devices such as contact lenses may lose their desirable optical parameters.
  • excess saline may result in the formation of a hypertonic composition, which will cause stinging, and eye irritation.
  • the osmolality of the composition may be at least about 200 mOsm/kg to less than 500 mOsm/kg, or from about 200 to about 450 mOsm/kg, orfrom about 205 to about 380 mOsm/kg, or from about 210 to about 360 milliosmoles per kilogram (mOsm/kg), or from about 250 to about 350 mOsm/kg, or from about 270 to about 330 mOsm/kg, as measured using osmolality measurement method USP ⁇ 785> (current as of November, 2022).
  • the ophthalmic compositions will generally be formulated as sterile aqueous compositions or as non-sterile compositions which are subsequently sterilized.
  • suitable tonicity adjusting agents include (selected from or selected from the group consisting of), but are not limited to, sodium, potassium, calcium, zinc and magnesium chloride, alkali metal halides, dextrose, and the like and mixtures thereof. These agents may be used individually in amounts ranging from about 0.01 to about 2.5% w/v or from about 0.2 to about 1.5% w/v, based on the total composition.
  • the tonicity adjusting agent may be sodium chloride which can be incorporated at concentrations of from about 0.4 to about 0.9, or from about 0.4 to about 0.7, or from about 0.5% to about 0.6%, by weight of the total composition.
  • the ophthalmically acceptable carrier can contain one or more of the above-mentioned tonicity agents.
  • compositions of the present invention may have a pH of from about 6.0 to a pH of about 8.0, or a pH of from about 6.5 to a pH of about 8.0, or a pH of from about 6.5 to a pH of about 7.5, or a pH of about 7.0 to a pH of about 7.5 or a pH of about 7.2 to a pH of about 7.4.
  • Compositions may have a pH matching the physiological pH of the human tissue to which the composition will contact or be directly applied.
  • the pH of the ophthalmic composition may be adjusted using acids and bases, such as mineral acids, such as, but not limited to hydrochloric acid and bases such as sodium hydroxide. 17 Docket No.
  • compositions of the present invention are also useful as packaging solutions for packaging of ophthalmic devices and for storing such ophthalmic devices.
  • the packaging solutions of the present invention may have a viscosity of less than about 5.2 cP at 25oC.
  • ophthalmic device refers to an object that resides in or on the eye. These devices can provide optical correction, cosmetic enhancement, light blocking (including UV, HEV, visible light and combinations thereof) glare reduction, therapeutic effect, including preventing the progression of myopia, wound healing, delivery of drugs or neutraceuticals, diagnostic evaluation or monitoring, or any combination thereof.
  • Ophthalmic devices include (selected from or selected from the group consisting of), but are not limited to, soft contact lenses, intraocular lenses, overlay lenses, ocular inserts, punctual plugs, and optical inserts.
  • the ophthalmic device may be a contact lens.
  • Contact lenses (or “contacts”) are placed directly on the surface of the eyes (e.g., placed on the film of tears that covers the surface of the eyes).
  • Contact lenses include soft contact lens (e.g., conventional or silicone hydrogel), rigid contact lenses or hybrid contact lenses (e.g., with soft skirt or shell).
  • Soft contact lenses may be formed from hydrogels. Contact lenses useful with the compositions can be manufactured employing various conventional techniques, to yield a shaped article having the desired posterior and anterior lens surfaces.
  • Contact lens polymer materials useful for manufacturing suitable contact lenses include (selected from or selected from the group consisting of), but are not limited to, acofilcon A, alofilcon A, alphafilcon A, amifilcon A, aquafilcon A, astifilcon A, atalafilcon A, balafilcon A, bisfilcon A, bufilcon A, comfilcon, crofilcon A, cyclofilcon A,balilcon A, deltafilcon A, delefilcon, deltafilcon B, dimefilcon A, drooxifilcon A, epsifilcon A, esterifilcon A, etafilcon A, fanfilcon A, focofilcon A, galyfilcon A, genfilcon A, govafilcon A, hefilcon A, hefilcon B, hefilcon D, hilafilcon A, hilafilcon B, hioxifilcon B, hioxifilcon C, hixoifilcon A, hydrofilcon A, lene
  • VTN6146WOPCT1 riofilcon A, samfilcon A, senofilcon A, senofilcon C, silafilcon A, siloxyfilcon A, somofilcon A, stenfilcon A, tefilcon A, tetrafilcon A, trifilcon A, vasurfilcon, vifilcon, and xylofilcon A.
  • the contact lenses may be manufactured using polymer materials selected from (or selected from the group consisting of) comfilcon, etafilcon A, galyfilcon A, senofilcon A, senofilcon C, nelfilcon A, hilafilcon, samfilcon, serafilcon, tetrafilcon A, vasurfilcon, vifilcon, and polymacon.
  • Conventional hydrogel contact lenses do not contain silicone containing components, and generally have higher water content, lower oxygen permeability and moduli than silicone hydrogels.
  • hydrogels are prepared from monomeric mixtures predominantly containing hydrophilic monomers, such as 2-hydroxyethyl methacrylate (“HEMA”), N-vinyl pyrrolidone (“NVP”) or polyvinyl alcohols.
  • hydrophilic monomers such as 2-hydroxyethyl methacrylate (“HEMA”), N-vinyl pyrrolidone (“NVP”) or polyvinyl alcohols.
  • HEMA 2-hydroxyethyl methacrylate
  • NDP N-vinyl pyrrolidone
  • United States Patents Nos.4,495,313, 4,889,664, 5,006,622, 5,039,459, 5,236,969, 5,270,418, 5,298,533, 5,824,719, 6,420,453, 6,423,761, 6,767,979, 7,934,830, 8,138,290, and 8,389,597 disclose the formation of conventional hydrogels.
  • Conventional hydrogels may be ionic or non-ionic and include (selected from or selected from the group consisting of) polymacon, etafilcon, genfilcon, hilafilcon, nesofilcon, nelfilcon, ocufilcon, omafilcon, lenefilcon and the like.
  • the oxygen permeability of these conventional hydrogel materials is typically below 20-30 barrers.
  • Silicon hydrogel formulations may include aquafilcon, balafilcon samfilcon, lotrafilcon A and B, delfilcon, galyfilcon, senofilcon A, B and C, narafilcon, comfilcon, formofilcon, riofilcon, fanfilcon, serafilcon, stenfilcon, somofilcon, kalifilcon, verofilcon and the like.
  • “Silicone hydrogels” refer to polymeric networks made from at least one hydrophilic component and at least one silicone-containing component.
  • hydrophilic components examples include (meth)acrylates, styrenes, vinyl ethers, (meth)acrylamides, N-vinyl lactams, N-vinyl amides, N-vinyl imides, N- vinyl ureas, O-vinyl carbamates, O-vinyl carbonates, other hydrophilic vinyl compounds, and mixtures thereof.
  • Non-limiting examples of hydrophilic components include N,N-dimethyl acrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), N-vinyl pyrrolidone (NVP), N-vinyl acetamide (NVA), N-vinyl-N-methylacetamide (VMA), and mixtures thereof.
  • DMA N,N-dimethyl acrylamide
  • HEMA 2-hydroxyethyl methacrylate
  • NVP N-vinyl pyrrolidone
  • NPA N-vinyl acetamide
  • VMA N-vinyl-N-methylacetamide
  • silicone-containing component may comprise at least one polymerizable group (e.g., a (meth)acrylate, a styryl, a vinyl ether, a (meth)acrylamide, an N- 19 Docket No.
  • the silicone- containing components may, for instance, contain from 1 to 220, from 3 to 100, from 3 to 40, or from 3 to 20 siloxane repeat units.
  • the silicone-containing component may also contain at least one fluorine atom.
  • the ophthalmic devices may also include a polymeric wetting agent, which may be incorporated into the ophthalmic device in a number of ways including, but not limited to, as a non-reactive polymer and become entrapped in the hydrogel upon polymerization forming a semi-interpenetrating network, may be polymerized (with or without crosslinking) in a preformed contact lens to form a fully or semi-interpenetrating network respectively or may be added to the packaging solution of the present invention and uptaken into the contact lens during sterilization Examples of these are disclosed in 6,367,929, US10,935,695, US8,053,539, US10,371,865, US10,370,476, US6,822,016, US7,431,152, US7,841,716 and US7,262,232.
  • the polymeric wetting agent may be polymerizable, for example as polyamide macromers or prepolymers, and in this case, are covalently incorporated into the silicone hydrogels. Mixtures of polymerizable and non-polymerizable polyamides may also be used.
  • suitable wetting agents include cyclic and linear polyamides, and specific examples include polyvinylpyrrolidone (PVP), polyvinylmethyacetamide (PVMA), polydimethylacrylamide (PDMA), polyvinylacetamide (PNVA), poly(hydroxyethyl(meth)acrylamide), polyacrylamide, and copolymers and mixtures thereof.
  • the polymeric wetting agent may be PVP, a mixture of PVP (e.g., PVP K90) and PVMA (e.g., having a Mw of about 570 KDa).
  • PVP polyvinyl
  • PVMA polyvinyl acrylate copolymer
  • the polyamides may have a weight average molecular weight of at least 100,000 daltons; greater than about 150,000; between about 150,000 to about 2,000,000 daltons; between about 300,000 to about 1,800,000 daltons. Higher molecular weight polyamides may be used if they are compatible with the reactive monomer mixture. 20 Docket No.
  • the hydrogel or silicone hydrogel formulations may also contain additional components such as, but not limited to, diluents, initiators, UV absorbers, visible light absorbers, photochromic compounds, pharmaceuticals, nutraceuticals, antimicrobial substances, tints, pigments, copolymerizable dyes, nonpolymerizable dyes, release agents, and combinations thereof.
  • additional components such as, but not limited to, diluents, initiators, UV absorbers, visible light absorbers, photochromic compounds, pharmaceuticals, nutraceuticals, antimicrobial substances, tints, pigments, copolymerizable dyes, nonpolymerizable dyes, release agents, and combinations thereof.
  • photochromic compounds tints or dyes are preferably stable in the presence of the microbial growth inhibiting compound at the selected microbial growth inhibiting compound concentrations.
  • An example of a UV absorber which is stable in the presence of chlorous acid compound is Norbloc.
  • Silicone hydrogel lenses may contain a coating, and the coating may be the same or different material from the substrate. Silicone hydrogels may have moduli in the range of 60-200, 60-150 or 80 -130 psi, water contents in the range of 20 to 60% and contact angles less than about 100 ⁇ , less than about 80 ⁇ , and less than about 60 ⁇ .
  • silicone hydrogels examples include acquafilcon, asmofilcon, balafilcon, comfilcon, delefilcon, enfilcon, fanfilcon, formofilcon, galyfilcon, lotrafilcon, kalifilcon, narafilcon, riofilcon, samfilcon, senofilcon, serafilcon, somofilcon, stenfilcon, unifilcon and verofilcon, including all of their variants, as well as silicone hydrogels as prepared in US Patent Nos.4,659,782, 4,659,783, 5,244,981, 5,314,960, 5,331,067, 5,371,147, 5,998,498, 6,087,415, 5,760,100, 5,776,999, 5,789,461, 5,849,811, 5,965,631, 6,367,929, 6,822,016, 6,867,245, 6,943,203, 7,247,692, 7,249,848, 7,553,880, 7,666,
  • VTN6146WOPCT1 9156,934, 9,170,349, 9,244,196, 9,244,197, 9,260,544, 9,297,928, 9,297,929 as well as WO03/22321, WO2008/061992, US2010/0048847, US2023/0037781, US2021/0109255, US10,935,695, US8,053,539, US10,371,865, and US10,370,476.
  • the contact lens polymer material may be a silicone hydrogel polymer.
  • the silicone hydrogel may be selected from (or selected from the group consisting of) acquafilcon, asmofilcon, balafilcon A, comfilcon, delefilcon, enfilcon, fanfilcon, galyfilcon, lehfilcon, lotrafilcon, kalifilcon, riofilcon, senofilcon, samfilcon, serafilcon, somofilcon, stenfilcon, unifilcon and verofilcon.
  • the compositions may also be useful for direct application to eye as a wetting or rewetting eye drop for providing relief to eye discomfort (e.g., burning sensations relating to the eye or general eye irritation).
  • compositions of the present invention are not further mixed with another or separate composition(s) prior to direct application to the eye or for storing of (or as packaging solution for) ophthalmic devices (e.g., contacts) – namely the compositions of the present invention (or products thereof) are not in the form of 2- or multi- compositions or products.
  • the compositions described herein may, at the time of mixing, be free of or substantially free of boric acid, borates, certain non-chlorous acid or non-peroxide preservatives (especially cationic preservatives), persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and/or derivatives thereof.
  • borate shall refer to salts of boric acid and other pharmaceutically acceptable borates, or combinations thereof.
  • Suitable borates include, but are not limited to, boric acid; pharmaceutically acceptable salts, such as alkaline metal salts such as sodium borate, potassium borate; alkaline earth metal salts such as calcium borate, magnesium borate; transition metal salts such as manganese borate; and mixtures thereof.
  • alkaline metal salts such as sodium borate, potassium borate
  • alkaline earth metal salts such as calcium borate, magnesium borate
  • transition metal salts such as manganese borate
  • non-chlorous acid or non-peroxide preservative or “non-chlorous acid/non- peroxide preservative” means compounds, which are not chlorous acid compounds or the specific peroxides (or the sources peroxide) mentioned above, but have antimicrobial properties.
  • preservatives include, but are not limited to, 4-chlorocresol, 4- chloroxylenol, benzalkonium, benzalkonium chloride (BAK), benzoic acid, benzyl alcohol, chlorhexidine, chlorobutanol, imidurea, m-cresol, methylparaben, phenols 0.5%, phenoxyethanol, sorbate, propionic acid, propylparaben, sodium benzoate, sorbic acid, thimerosol, polyquaternium compounds (such as polyquarternium-42 and polyquarternium-1), biguanide compounds (e.g., polyhexamethylene biguanide or polyaminopropyl biguanide).
  • BAK 4-chlorocresol, 4- chloroxylenol, benzalkonium, benzalkonium chloride
  • benzoic acid benzyl alcohol, chlorhexidine, chlorobutanol, imidurea, m-cresol, methylparaben, phenol
  • Non- chlorous acid or non-peroxide preservatives can be harsh, irritating to eye and/or cause allergic reactions, undesirably affecting consumers’ use of the eye care compositions or contact lens which contain (on its surface) such non-chlorous acid/non- peroxide preservative due to the storage of the contact lens with such compounds.
  • ⁇ ⁇ Baudouin See C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly.
  • persulfates means persulfate anions or salts of such persulfates and other pharmaceutically acceptable persulfates, or combinations thereof. Suitable persulfates include, but are not limited to, sodium peroxomonosulfate, potassium peroxymonosulfate, sodium persulfate , ammonium persulfate potassium persulfate and mixtures thereof.
  • Persulfates can be harsh and irritating to eye and can undesirably affect consumers’ use of contact lens which contain (on its surface) the persulfates due to the storage of the contact lens with such compounds.
  • Humectants and/or demulcents such as carboxy vinyl polymers (e.g., carbomers), natural gums (e.g., guar gum, gum tragacanth), glycerin, polyoxyethylene-castor oil and/or derivatives thereof are well known thickening agents which, when present on surface of contact lenses, can undesirably affect consumers’ vision through contact lens, causing blurring or otherwise reducing vision clarity by either interacting with the surface of the contact lens or slowly diffusing from the tear fluid trapped between the eye-facing side of the contact lens and the corneal surface.
  • substantially free as related to compounds selected from boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers (e.g., carbomers), natural gums (e.g., guar gum, gum tragacanth), glycerin, polyoxyethylene-castor oil and/or derivatives means that such compounds are present in the compositions of the present invention at a concentration of less than 2% (or about 2%), or less than 1.5% (or about 1.5%), or less than 1% (or about 1%), or less than 0.5% (or about 0.5%), or less than 0.1% (or about 0.1%), or less than 0.05% (or about 0.05%), or less than 0.01% (or about 0.01%), or less than 0.005% (or about 0.005%), by weight of
  • compositions of the present invention may be free of such compounds.
  • contact lenses can be immersed in a composition of the present invention and stored in a suitable packaging container, in certain embodiments, a packaging container for single contact lens unit.
  • a packaging container for the storage of a contact lens includes at least a sealing layer sealing the container containing an unused contact 24 Docket No. VTN6146WOPCT1 lens immersed in the composition of the present invention.
  • the sealed container may be hermetically sealed packaging container and may have any form that creates a sealed space to contain the composition and contact lens.
  • the hermetically sealed packaging container may have any suitable form include sealed packets formed from two sheets of plastic, metal or multilayer structures or a blister pack in which a base with a concave well containing a contact lens is covered by a metal, plastic or laminate sheet adapted for peeling in order to open the blister-pack.
  • the sealed container may be formed from any suitable, generally inert packaging material providing a reasonable degree of protection to the lens.
  • the packaging material may be formed of plastic material such as polypropylene, polysulfone (PSU), polyethersulfone (PESU), polycarbonate (PC), polyetherimide (PEI), polyamides, including nylons, polyolefins including polypropylene, polymethylpentene, (PMP), and olefin co-polymers, including COPs (Cyclic Olefin Polymer) and COCs,(Cyclic Olefin Co-polymers), acrylics, rubbers, urethanes, fluorocarbons, polyoxymethylene, polyvinylchloride (PVC), polyphenylsulfide (PPS), polycarbonate copolymers, polyvinylidene fluoride (PVDF), and the like and copolymers and blends of the foregoing.
  • plastic material such as polypropylene, polysulfone (PSU), polyethersulfone (PESU), polycarbonate (PC), polyetherimide (PE
  • Blends include polybutylene terephthalate polyester blends, including PBT and PC blends, PC/polyester blends, and polypropylene blended with COPs or COCs.
  • the plastic material may be selected from polypropylene, COPs (Cyclic Olefin Polymer) and COCs, (Cyclic Olefin Co-polymers) and blends thereof.
  • any water soluble, demulcent (or demulcent like – e.g., having demulcent properties such as viscosity increasing capabilities) polymer may also be employed in the composition of this invention provided that it has no (or no substantial) detrimental effect on the contact lens being stored or on the wearer of the contact lens (e.g., blurring or otherwise reducing vision clarity) at the concentrations used in the composition of the present invention or on the eye (or on the region around the eye).
  • Particularly useful components are those, which are water soluble, for example, soluble at the concentrations used in the presently useful liquid aqueous media.
  • Suitable water soluble demulcent polymers include, but are not limited to, demulcent polymers, such as block copolymer surfactants (e.g., block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO)); polyvinyl alcohol, polyvinyl pyrrolidone; polyacrylic acid; polyethers such as polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400) and polyethylene oxides; hyaluronic acid, and hyaluronic acid derivatives; chitosan; polysorbates such as polysorbate 80, polysorbate 60 and 25 Docket No.
  • block copolymer surfactants e.g., block copolymers of polyethyleneoxide (PEO) and polypropyleneoxide (PPO)
  • PEO polyethyleneoxide
  • PPO polypropyleneoxide
  • polyvinyl alcohol polyvinyl pyrrolidone
  • polyacrylic acid polyethers such
  • VTN6146WOPCT1 polysorbate 40 dextrans such as dextran 70; cellulosic derivatives such as carboxy methyl cellulose methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and methyl ethyl cellulose; acyclic polyamides such as those having a weight average molecular weight of 2,500 to 1,800,000 Daltons as disclosed in US7,786,185 herein incorporated by reference in its entirety; salts of any of the above and mixtures of any of the above.
  • the block copolymers of PEO and PPO include poloxamers and poloxamines, including those disclosed in U.S.6,440,366, herein incorporated by reference in its entirety.
  • the water-soluble demulcent polymer is selected from polyvinyl pyrrolidone, methyl ethyl cellulose, polyvinyl alcohol, polymethacrylic acid, carboxymethyl cellulose, propylene glycol, 1,3-propanediol, polyethylene glycols, and mixtures thereof.
  • Water-soluble demulcent polymers may have molecular weights in excess of 100,000. When propylene glycol and/or 1,3-propanediol are used as water-soluble demulcent polymer, they may have molecular weights lower than 100,000.
  • any water-soluble polymer when used in the packing solutions of the present invention, it may be included and present in amounts up to about 0.5, 1 or 2 weight %preferably between about 0.001 and about 2%, between about 0.005 and about 1%, between about 0.01 and about 0.5 weight %, or between about 100 ppm and about 0.5 weight %, all based upon the weight of total composition.
  • any water soluble polymer when used in the direct application eye care formulation, such as an eye drop of the present invention, it may be included and present in amounts up to about 2, 5 or 10 weight %, preferably between about 0.001 and about 10%, between about 0.005 and about 2% , between about 0.01 and about 0.5 weight %, or between about 100 ppm and about 2 weight%, all based upon the weight of total composition.
  • the water-soluble demulcent polymer aids in preventing the ophthalmic device from sticking to the packaging container and may enhance the initial (and/or extended) comfort of the contact lens, packaged in the composition, when placed on the eye after removal from the packaging container.
  • the water-soluble demulcent polymer may be a cellulosic derivative.
  • the cellulosic derivative may be present at concentrations of from about 0.002 to about 0.01, or preferably, from about 0.004 to about 0.006 by weight of the total composition of the present invention.
  • Various other materials may be included with the compositions described herein. In the case of compositions of the present invention for direct application to the eye, surfactants may be included.
  • Surfactants suitable for such use include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20, poloxamers such as Pluronic® F68, and block copolymers such as poly(oxyethylene)-poly(oxybutylene) compounds set forth in U.S. Patent Application Publication No.2008/0138310 (which publication is herein incorporated by reference).
  • the poly(oxyethylene)-poly(oxybutylene) block copolymer may have the formula (EO)m(BO)n, wherein EO is oxyethylene and BO is oxybutylene, and wherein m is an integer having an average value of 10 to 1000 and n is an integer having an average value of 5 to 1000, as disclosed in US8,318,144; m may also be 10 and n may be 5. It should be appreciated that some of the components may perform more than one function, for example, some demulcents may also function as surfactants (e.g., PEO-PPO and PEO-PBO block copolymers).
  • surfactants e.g., PEO-PPO and PEO-PBO block copolymers.
  • Surfactants may be present at concentrations of from about 0.01 to about 3%, preferably from about 0.01 to about 1%, preferably, from about 0.02 to about 0.5%, or preferably, from about 0.02 to about 0.1% by weight of the total composition of the present invention. It should be appreciated that some of the components may perform more than one function, for example, some demulcents may also function as surfactants (e.g., PEO-PPO and PEO-PBO block copolymers). If desired, one or more additional components may be, optionally, included in the composition. Such optional component(s) are chosen to impart or provide at least one beneficial or desired property to the composition.
  • Such additional, but optional, components may be selected from components that are conventionally used in ophthalmic device care compositions
  • optional components include (or, are selected from or selected from the group consisting of) cleaning agents (for example in direct application eye drops or cleaning [or eye care solution]), wetting agents, nutrient agents, therapeutic agent, sequestering agents, viscosity builders, contact lens conditioning agents, antioxidants, and the like and mixtures thereof.
  • cleaning agents for example in direct application eye drops or cleaning [or eye care solution]
  • wetting agents for example in direct application eye drops or cleaning [or eye care solution]
  • nutrient agents for example in direct application eye drops or cleaning [or eye care solution]
  • wetting agents for example in direct application eye drops or cleaning [or eye care solution]
  • nutrient agents for example in direct application eye drops or cleaning [or eye care solution]
  • wetting agents for example in direct application eye drops or cleaning [or eye care solution]
  • nutrient agents for example in direct application eye drops or cleaning [or eye care solution]
  • wetting agents for example
  • the ophthalmic solution as formulated comprises about 0.0007 to about 0.005 wt% (7-50 ppm) or 0.0008 to 0.0020wt% (8-20 ppm) hydrogen peroxide, buffer selected from a phosphate buffer, and organic acid buffer or a mixture thereof, about 0.05 to about 0.075 wt% (500-750 ppm) EDTA, about 0.005 to about 0.01 wt% methyl ethyl cellulose, and optionally a reductant, all based on the ophthalmic solution as formulated, prior to autoclaving.
  • the ranges may be combined in any permutation.
  • the ophthalmic solution may be used as a packaging solution with contact lenses, including silicone hydrogel contact lenses, comprising PVP.
  • One or more therapeutic agent may also be incorporated into the ophthalmic solution.
  • a wide variety of therapeutic agents may be used, so long as the selected active agent is inert in the presence of the microbial growth inhibiting compound (e.g., chlorites or peroxides) or oxidating agents generally.
  • Suitable therapeutic agents include those that treat or target any part of the ocular environment, including the anterior and posterior sections of the eye and include pharmaceutical agents, vitamins, nutraceuticals combinations thereof and the like.
  • Suitable classes of active agents include antihistamines, antibiotics, glaucoma medication, carbonic anhydrase inhibitors, anti-viral agents, anti-inflammatory agents, non-steroid anti-inflammatory drugs, antifungal drugs, anesthetic agents, miotics, mydriatics, immunosuppressive agents, antiparasitic drugs, anti-protozoal drugs, combinations thereof and the like.
  • active agents When active agents are included, they are included in an amount sufficient to produce the desired therapeutic result (a “therapeutically effective amount”).
  • Useful optional sequestering agents include, but are not limited to, citric acid, sodium citrate and the like and mixtures thereof. 28 Docket No.
  • the method of packaging and storing a contact lens comprises immersing the device in the compositions described above in a suitable container.
  • the method may include immersing the device in the composition prior to delivery to the customer/wearer, directly following manufacture of the contact lens.
  • the incorporation and storing of the device in the compositions may occur at an intermediate point before delivery to the ultimate customer (wearer) but following manufacture and transportation of the device in a dry state, wherein the dry device is hydrated by immersing the device in the compositions.
  • a package for delivery to a customer may comprise a hermetically sealed container containing one or more unused devices (e.g., contact lenses) immersed in the compositions.
  • the steps for packaging the ophthalmic device in the composition of the present invention may include: (1) molding an ophthalmic device (e.g., contact lens) in a mold comprising at least a first and second mold portion, (2) removing the device from the mold portions and removal of unreacted monomer and processing agents (3) introducing the composition and the device into the packaging (or container), and (4) sealing the packaging.
  • the method may also include the step of sterilizing the contents of the packaging.
  • Sterilization may take place prior to, or most conveniently after, sealing of the container and may be performed by any suitable method known in the art, e.g., by autoclaving of the sealed container at temperatures of about 120° C. or higher (autoclave [or steam] sterilization method), or by using ultraviolet (UV) sterilization or gamma electron beam sterilization methods.
  • the compositions of the present invention are sterilized by autoclave sterilization.
  • the packaging may be a plastic blister packaging (or package), including a recess for receiving an ophthalmic device and the composition, where the recess is hermetically sealed with lidstock prior to sterilization of the package contents. 29 Docket No.
  • VTN6146WOPCT1 The following examples are provided to enable one skilled in the art to practice the compositions and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims. 30 Docket No. VTN6146WOPCT1 EXAMPLES The compositions of the present invention as described in following examples illustrate specific embodiments of compositions of the present invention but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. Materials used in the following Examples are provided as listed below: Material Supplier Sodium chloride J. T.
  • Table 1 shows a formulation for a chlorous acid compound containing composition of the present invention incorporating an organic maleate buffer and useful as a solution for storing (or as packaging) solution for ophthalmic devices (e.g., contact lenses) or direct application eye drop solution, which was prepared using conventional mixing technology.
  • EDTA Disodium ethylene diamine tetraacetic acid
  • Table 1 shows a formulation for a chlorous acid compound containing composition of the present invention incorporating an organic maleate buffer and useful as a solution for storing (or as packaging) solution for ophthalmic devices (e.g., contact lenses) or direct application eye drop solution, which was prepared using conventional mixing technology.
  • Nominal chlorite content in the composition of Table 1 was about 71 ⁇ g/mL Pot Life analysis was performed on the composition of Table 1 to determine the useful life of the composition for inhibiting microbial growth for a period of time - as a function of decreasing chlorite concentration in the composition over time.
  • the chlorite containing composition of Table 6 was sufficient to inhibit microbial growth of the panel organisms for a period of at least 5 days.
  • the Pot Life sample was prepared as follows 1. About 10 mL of the composition of Table 1 was placed into several 20 mL glass screw cap scintillations vials. 2.
  • step 1 The vials of step 1 were sealed with gray butylene caps and stored at room temperature in a light blocking container and placed in refrigerator at as function of time (typically 1 vial every day for 5 days) 3. Samples were analyzed via ion chromatography with conductivity detection for chlorite concentration at the time periods shown in Table 2, below. The separation was performed using a Dionex AS9-HC column, 4 mm diameter X 250 mm length with a matching guard column. The mobile phase was 9 mmol.L sodium bicarbonate and the suppressor eluent was 500 mL sulfuric acid. The injection volume and flow rate parameters were generally set at 20 ⁇ L and 1 mL/min, respectively.
  • Standardization was performed using certified chlorite reference standards diluted to the applicable concentration regime, typically 0.1 – 20 ⁇ g/mL.
  • the chlorite peak area of standard solutions were fitted to a least-squares fit with the corresponding chlorite concentrations.
  • the equation of the least- squares regression was used to calculate the chlorite concentration of test solutions.
  • the results of the Pot Life are summarized in Table 2.
  • 32 Docket No. VTN6146WOPCT1 Table 2 Age (days) Chlorite, ⁇ g/ml % of Initial Chlorite Concentration 0 52.9 100.0 1 51.7 97.7 2 53.0 100.2 3 50.7 95.9 4 50.7 95.9 5 DNT 95.0 a a Estimated result based on linear extrapolation.
  • the Pot Life study shows that at least 95% of the initial chlorite concentration remained viable in the composition of Table 1 in the presence of the EDTA and PVP reductants for at least 5 days. Such viability for such period time can be useful in situations where the packaging/storage composition may require shelving for a period of time prior to sterilized (e.g., by autoclave). At least 95% remnant amount of the initial concentration of an active is considered commercially/consumer acceptable.
  • Table 3 shows the formulations for compositions having a range of chlorite concentrations useful as a solution for storing (or as packaging) solution for ophthalmic devices (e.g., contact lenses) or direct application eye drop solution, which composition was prepared using conventional mixing technology.
  • samples of each of the compositions of Examples 2-6 were poured from the original specimen cup containers and filter sterilized through a 0.22 ⁇ m membrane using a 150-mL Analytical Filter Unit. The filtered individual compositions were then aseptically transferred into new individual sterile specimen cups for storage and testing.
  • microorganisms were used to assess microbial activity: ⁇ ⁇ (AB) Aspergillus brasiliensis ((Quanti-CultTM)) - ATCC 16404 (Remel Inc.) ⁇ ⁇ (BS) Bacillus subtilis – subspecies spizizenii (Epower TM) - ATCC 6633 (Microbiologics®) ⁇ ⁇ (CA) Candida albicans (Epower TM) - ATCC 10231 (Microbiologics ® ) 34 Docket No.
  • VTN6146WOPCT1 The test microorganisms were resuspended following manufacturers’ instructions and approximately 0.5mL aliquots were spread plated onto two separate tryptic soy agar (TSA) media and Sabouraud dextrose agar (SDA) plates. The TSA and SDA plates were incubated at 30-35oC and 20-25oC respectively, for 2-7 days. Sterile filtered deionized (DI) water and inoculating loops were used to resuspend the designated test microorganisms from the plate surfaces and the suspensions were aseptically transferred with a sterile pipette into individual 50mL centrifuge tubes.
  • DI Sterile filtered deionized
  • test microorganism suspensions were diluted until their population counts could be estimated using a hemocytometer. A population count of approximately 1.0 x 107 cells/mL was targeted for each final test microorganism suspension. Depending on the test microorganism targeted suspension count, an aliquot ranging from 2.5 ⁇ L to 100 ⁇ L) was inoculated into 20mL of each of the samples of the test compositions of Table 3 to obtain an average starting microorganism population count of approximately 7000 CFU/mL.
  • Each inoculated sample of the compositions of Table 3 containing the designated test microorganism was stored at room temperature and at Day 0, Day 1, Day 2, and Day 3 samples were pour-plated in duplicate (Day 0 only) or triplicate with either molten TSA or SDA containing chloramphenicol as required. The aliquot volumes were bracketed to increase the chances of the pour plate count results to be within the 25 CFU – 300 CFU countable range. All pour plate sample volumes were adjusted to 1mL using sterile water for injection (WFI) (i.e., 50 ⁇ L + 950 ⁇ L WFI) to allow for sufficient sample dispersion. AB was pour-plated with both TSA and SDA + chloramphenicol. When pour plated in parallel, the counts of A.
  • WFI sterile water for injection
  • brasiliensis were similar for the TSA and SDA+chloramphenicol. Consequently, TSA enabled the enumeration of A. brasiliensis on plates without interference due to sporulation.
  • Figure 1-3 respectively show the results for Candida albicans, Aspergillus brasiliensis and the bacteria Bacillus subtilis – subspecies spizizenii. Log counts for Candida albicans are shown in Table 4, below. 35 Docket No. VTN6146WOPCT1 Table 4 C.
  • Candida albicans and the bacteria Bacillus subtilis – subspecies spizizenii decreased over the test period for all chlorite concentrations evaluated, when each microorganism was spiked into the composition of Table 3 containing at least 0.84 ⁇ g/ml of chlorite.
  • the fungus Aspergillus brasiliensis count remained the same (within test limits) at the lowest chlorite concentrations (0.84 and 1.7 ⁇ g/ml) and decreased over the test period at the higher concentrations (about 0.2 to about 0.5 log reduction at 3.7 and 7.6 ⁇ g/ml and 2.5 log reduction at 15 ⁇ g/ml.
  • Examples 2-6 show that a range of chlorite concentration provide effective inhibition of the growth of microorganisms across at least 22 days.
  • Example 7 Table 5 shows a formulation for a peroxide or source of peroxide containing composition of the present invention incorporating an organic maleate buffer and useful as a solution for storing (or as packaging) solution for ophthalmic devices (e.g., contact lenses) or direct application eye drop solution, which composition can be prepared using conventional mixing technology.
  • VTN6146WOPCT1 Table 5 Component Weight % (the balance is water) Sodium Chloride 0.7903% Monobasic sodium maleate 0.0098% Dibasic sodium maleate m onohydrate 0.2342% Hydrogen Peroxide 0.0101% pH 7.3 Osmolality 281 mOsm/Kg
  • Table 6 shows the formulation for another chlorous acid compound containing composition of the present invention incorporating an organic maleate buffer and useful as a solution for storing (or as packaging) solution for ophthalmic devices (e.g., contact lenses) or direct application eye drop solution, which composition can be prepared using conventional mixing technology.
  • Peroxide was determined by UV-vis spectroscopy using titanium sulfate as a color forming reagent.
  • the stock titanium sulfate solution was prepared by transferring approximately 83 mL concentrated sulfuric acid to a 500 mL Erlenmeyer flask. Approximately 38 Docket No. VTN6146WOPCT1 3.3 g titanium oxysulfate was added and the solution warmed slightly and stirred using a magnetic stir bar. Upon dissolution, the solution was allowed to cool.
  • the working reagent solution was prepared by adding approximately 300 mL deionized water to a 500 mL volumetric flask.
  • the flask was cooled in an ice bath as the stock titanium sulfate solution was slowed added to the volumetric flask.
  • the solution was mixed and diluted to the mark with deionized water after allowing the solution to return to room temperature.
  • Working standards of hydrogen peroxide were prepared by diluting a stock solution of hydrogen peroxide with deionized water to produce a series of solutions ranging from 15 to 300 ⁇ g/mL in concentration. When not in use, these solutions were stored in a refrigerator in amber glass vials to retard decomposition. To perform the analysis, 1 mL aliquots consisting of sample and standard solutions were diluted with 9 mL of DI water and 1 mL titanium sulfate reagent solution.
  • VTN6146WOPCT1 Table 10 Summary of Hydrogen Peroxide Reduction During Autoclave, Maleate Buffer. Ex# [EDTA] [MEC] [additive] [Hydrogen Peroxide], ppm % I nitial 1 2 3 Reduced cycle cycles 16 0.100% N/A N/A 109.4 30.6 6.5 1.0 72 17 0.050% N/A N/A 109.8 54.0 30.7 10.2 51 18 0.020% N/A N/A 110.6 77.4 66.3 47.7 30 19 0.010% N/A N/A 123.7 85.0 75.8 63.0 31 20 0.000% N/A N/A 89.1 44.5 16.8 10.1 50 21 0.010% 0.005% N/A 140.0 99.8 DNT DNT 29 22 0.010% 0.005% N/A 46.5 20.5 DNT DNT 56 Examples 9-22 show that increasing concentrations of EDTA increase the amount of hydrogen peroxide reduced at each autoclaving cycle, with more hydrogen peroxide being reduced
  • Example 23 Accelerated aging experiments were performed using commercial ACUVUE OASYS® 1-Day brand contact lenses and the solutions of Examples 15, 21 and a solution similar to Example 15, but without any PVP (Example 23). Individual lenses were removed from their blister packages, dipped briefly in DI water to remove the commercial packing solution and blotted with a lint free wipe to remove adherent water. The lenses were then individually placed into 7 mL glass, crimp-top vials containing 3 mL of the respective packing solution.
  • the vials were sealed with gray butyl septa and subjected to a single autoclave cycle.
  • the accelerated aging was conducted in a stability chamber held at a temperature of 55 o C with a relative humidity of 35%.
  • desired incubation 40 Docket No. VTN6146WOPCT1 period the appropriate number of vials were removed and submitted for testing directly, i.e. without transferred to standard packing solution prior to submission for testing. Peroxide content was measured as described in Examples 9-12.
  • Advancing dynamic contact angle was determined using a modified Wilhelmy plate method using a calibrated Kruss K100 tensiometer at room temperature (23 ⁇ 4° C.) using the following borate buffer solution: Component Weight % Deionized water 98.06% Sodium chloride 0.83% Boric acid 0.89% Sodium borate decahydrate 0.21% EDTA 0.01% 10% PVP solution N/A Methyl ether cellulose (MEC) 0.005% All equipment was clean and dry; vibrations were minimized around the instrument during testing. The tensiometer was equipped with a humidity generator and a temperature and humidity gauge was placed in the tensiometer chamber. The relative humidity was maintained at 70 ⁇ 5%.
  • the experiment was performed by dipping the contact lens test strip into the borate buffer while measuring the force, in each case, exerted on the contact lens sample due to wetting by the probe solution using a sensitive balance (i.e., as in the case of the Kruss K100).
  • the advancing dynamic contact angle of the contact lens sample was determined from the force data collected during sample dipping.
  • the receding contact angle is determined from force data while withdrawing the contact lens sample (in the form of a test strip) from the test liquid.
  • Each strip was approximately 5 mm in width and 14 mm in length, attached to a metallic clip using plastic tweezers, pierced with a metallic wire hook, and equilibrated in packing solution for at least 3 hours. Then, each sample was cycled four times, and the results were averaged to obtain the advancing and receding contact angles of the lens. Typical measuring speeds were 12 mm/min. The contact lens test samples were kept completely immersed in the packing solution during the data acquisition and analysis without touching the metal clip. Values from five individual contact lens test samples were averaged to obtain the reported advancing (and receding) dynamic contact angles of the sample lenses. The results are summarized In Tables 11 through 14, below.
  • An ophthalmic composition comprising: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; iii. a reductant for neutralizing the microbial growth inhibiting compound, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv.
  • an ophthalmically acceptable carrier comprising one or more tonicity agents at least one contact lens sealed in a container with the composition.
  • the microbial growth inhibiting compound is selected from peroxides, sources of peroxide, chlorous acid compounds, salts thereof and/or mixtures thereof.
  • the microbial growth inhibiting compound is a chlorous acid compound.
  • the chlorous acid compound is a chlorite selected from water soluble alkali metal chlorites, water soluble alkaline metal chlorites and mixtures thereof.
  • the chlorite is selected from potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite and mixtures thereof. 6.
  • composition of embodiment 2 wherein the microbial growth inhibiting compound is a peroxide or source of peroxide.
  • the peroxide or source of peroxide is benzoyl peroxide, hydrogen peroxide and mixtures thereof.
  • the buffer compound is selected from phosphate compound, organic acid buffers, salts thereof or mixtures thereof.
  • the composition of embodiment 11 wherein the buffer compound is a phosphate compound.
  • the phosphate compound is a combination of salts of the dibasic phosphate anion (HPO 4 ) 2 - and salts of the monobasic phosphate anion (H 2 PO 4 )-.
  • the phosphate compound is sodium dibasic phosphate (Na2HPO4), sodium monobasic phosphate (NaH2PO4) or a mixture thereof.
  • the composition of embodiment 11 wherein the organic acid buffer is a non-phosphate containing organic acid having two or more carboxylic acid groups. 16.
  • the composition of embodiment 11 wherein the buffer compound is an organic acid buffer. 17.
  • composition of embodiment 16 wherein the one organic acid buffer is selected from phytic acid, mellitic acid, maleic acid and ophthalmically compatible salts thereof. Docket No. VTN6146WOPCT1 18.
  • the composition of embodiment 16 wherein the organic acid buffer is selected from maleic acid, its sodium or potassium salts and mixtures thereof. 19.
  • the composition of embodiment 16 wherein the organic acid buffer is selected from mellitic acid, its sodium or potassium salts and mixtures thereof.
  • the organic acid buffer comprises salts of dibasic organic acid anion (e.g., dibasic sodium maleate monohydrate) and salts of monobasic organic acid anion (monobasic sodium maleate). 21.
  • 23. The composition of any of the preceding embodiments and any succeeding embodiments, wherein the composition has a pH of from about 7.0 to about 7.5, or about 7.2 to about 7.4.
  • 24. The composition of embodiment 1, further comprising a reductant. 25.
  • composition of embodiment 13, wherein the reductant is selected from iron (II), bisulfite, tin metal, formate, phosphite, hypophosphite, sulfur, thiosulfate, zinc metal, dithionite, manganese metal, aluminum metal, magnesium metal, dithionite, manganese metal, aluminum metal, magnesium metal, dithiothreitol, NADH2, ascorbate, ferricyanide, hydroquinone, tyrosine, aldehydes, N-acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid (EDTA), diethylenetriamine pentaacetic acid (DTPA) and ophthalmically compatible salts thereof, Cellobiose, glucose (L and D isomers), phenols, polymeric aldehydes, poly methyl acryloyltyrosinate co N,N-dimethylacrylamide, poly Norbloc
  • VTN6146WOPCT1 benzo[d][1,2,3]triazol-2-yl)-4-(2-hydroxyethyl)phenol) co N,N-dimethylacrylamide, polymeric phenols or mixtures thereof.
  • the reductant is selected from ethylenediaminetetraacetic acid (EDTA), Cellobiose, glucose (L and D isomers), phenols, or mixtures thereof or comprises EDTA.
  • the composition of any of the preceding embodiments and any succeeding embodiments, wherein the composition further comprises a demulcent polymer.
  • the composition of embodiment 29, wherein the demulcent polymer is selected from block copolymer surfactants; polyvinyl alcohol, polyvinyl pyrrolidone; polyacrylic acid; polyethers; hyaluronic acid and hyaluronic acid derivatives; chitosan; polysorbates; dextrans; cellulosic derivatives; acyclic polyamides and mixtures thereof.
  • the demulcent polymer is selected from polyvinyl pyrrolidone, methyl ethyl cellulose, polyvinyl alcohol, polymethacrylic acid, carboxymethyl cellulose, propylene glycol, 1,3-propanediol, polyethylene glycols, and mixtures thereof.
  • composition of embodiment 29, wherein the demulcent polymer is methyl ethyl cellulose. Docket No. VTN6146WOPCT1 33.
  • the demulcent polymer is a water-soluble polymer present in amounts up to about 0.5, about 1 or about 2 weight %, or between about 0.001 and about 2%, between about 0.005 and about 1 weight %, between about 0.01 and about 0.5 weight %, or between about 100 ppm by weight and about 0.5 weight %, all based upon the weight of total composition.
  • the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for at least one day.
  • composition of any of the preceding embodiments and any succeeding embodiments wherein the osmolality is from 200 mOsm/kg to less than about 500 mOsm/kg, from about 200 to about 450 mOsm/kg, from about 205 to about 380 mOsm/kg, from about 210 to about 360 (mOsm/kg), from about 250 to about 350 mOsm/kg, from about 270 to about 330 mOsm/kg, or about 205 mOsm/kg to about 350 mOsm/kg. 40.
  • the composition of any of the preceding embodiments and any succeeding embodiments wherein the composition is free of or substantially free of one or more of boric acid, Docket No.
  • VTN6146WOPCT1 borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • 41. The composition of any of the preceding embodiments and any succeeding embodiments, wherein the composition is free of boric acid, borates, non-chlorous acid /non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof. 42.
  • composition of any of the preceding embodiments and any succeeding embodiments wherein the composition is manufactured under sterile conditions or sterilized during and/or after the period of time.
  • the composition of any of the preceding embodiments and any succeeding embodiments wherein the composition is sterilized after the period of time by a sterilization process selected from autoclave sterilization, UV sterilization and gamma electron beam sterilization.
  • a method of inhibiting the growth of microorganisms in a composition for a period of time occurring from preparation of the composition to sterilization of the composition in sealed a container comprising the steps of: a. mixing a composition comprising: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii.
  • a buffer compound iii. a reductant for neutralizing the microbial growth inhibiting compound after admixture to the composition, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time ;
  • the composition is free of or substantially free of one or more of boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • the sterilization is selected from autoclave sterilization, UV sterilization and gamma electron beam sterilization.
  • the sterilization is by autoclave sterilization.
  • the period of time is at least 1 day.
  • 48. The method of embodiment 31, wherein the period of time is at least 3 days.
  • a method of packaging and sterilizing a composition in sealed a container comprising the steps of: a. mixing a composition comprising: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; and iii. a reductant for neutralizing the microbial growth inhibiting compound after admixture to the composition, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; b. placing the composition in a container; c. sealing the container of step b.; Docket No. VTN6146WOPCT1 d.
  • the composition is free of or substantially free of one or more of boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • the composition is stored for a period of time during which time there is an inhibition of growth of microorganisms.
  • the composition is manufactured under sterile conditions or sterilized during and/or after the period of time. 53.
  • a sealed ophthalmic product or kit comprising, a) a composition for storing contact lenses as an admixture or mixture: i. a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; iii.
  • a reductant for neutralizing the microbial growth inhibiting compound provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv. an ophthalmically acceptable carrier comprising one or more tonicity agents and b) a container comprising a sealed compartment comprising at least one contact lens in the presence of the composition.
  • a sealed ophthalmic product or kit comprising, a) a composition for storing contact lenses as an admixture or mixture: i.
  • a microbial growth inhibiting compound in an amount effective to inhibit the growth of microorganisms in the composition; ii. a buffer compound; iii. optionally, a reductant for neutralizing the microbial growth inhibiting compound, provided that, after the reductant’s admixture to the composition, the microbial growth inhibiting compound remains effective to inhibit the growth of microorganisms in the composition for a period of time; and iv. an ophthalmically acceptable carrier comprising one or more tonicity agents at least one contact lens sealed in a container with the composition; and b) a container comprising a sealed compartment comprising at least one contact lens in the presence of the composition.
  • a sterilization process selected from autoclave sterilization, UV sterilization and gamma electron beam sterilization.
  • the microbial growth inhibiting compound is selected from peroxides, sources of peroxide, chlorous acid compounds, salts thereof and/or mixtures thereof.
  • the chlorite is selected from potassium chlorite, sodium chlorite, calcium chlorite, magnesium chlorite and mixtures thereof.
  • the method, product or kit of embodiment 58, wherein the chlorite comprises sodium chlorite. 63.
  • 64. The method, product or kit of embodiment 57, wherein the microbial growth inhibiting compound is a peroxide or source of peroxide. 65.
  • the method, product or kit of embodiment 63 wherein the peroxide or source of peroxide is benzoyl peroxide, hydrogen peroxide and mixtures thereof.
  • the buffer compound is selected from phosphate compound, organic acid buffers, salts thereof or mixtures thereof. Docket No. VTN6146WOPCT1 68.
  • the phosphate compound is a combination of salts of the dibasic phosphate anion (HPO4) 2- and salts of the monobasic phosphate anion (H2PO4)-. 70.
  • the organic acid buffer is a non-phosphate containing organic acid having two or more carboxylic acid groups.
  • the buffer compound is an organic acid buffer.
  • the one organic acid buffer is selected from phytic acid, mellitic acid, maleic acid and ophthalmically compatible salts thereof. 74.
  • the method, product or kit of embodiment 70 wherein the organic acid buffer is selected from maleic acid, its sodium or potassium salts and mixtures thereof.
  • the method, product or kit of embodiment 70 wherein the organic acid buffer is selected from mellitic acid, its sodium or potassium salts and mixtures thereof.
  • the composition of embodiment 70 wherein the organic acid buffer comprises salts of dibasic organic acid anion (e.g., dibasic sodium maleate monohydrate) and salts of monobasic organic acid anion (monobasic sodium maleate). 77.
  • Docket No. VTN6146WOPCT1 78 The method, product or kit of any of the preceding embodiments and any succeeding embodiments, wherein the composition is free of boric acid and borates. 79.
  • the reductant is selected from iron (II), bisulfite, tin metal, formate, phosphite, hypophosphite, sulfur, thiosulfate, zinc metal, dithionite, manganese metal, aluminum metal, magnesium metal, dithionite, manganese metal, aluminum metal, magnesium metal, dithiothreitol, NADH2, ascorbate, ferricyanide, hydroquinone, tyrosine, aldehydes, N-acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediaminetetraacetic acid (EDTA), Cellobiose, glucose (L and D isomers), phenols, polymeric aldehydes, poly methyl acryloyltyrosinate co N,N-dimethylacrylamide, poly Norbloc (2-(2H- benzo[d][1,2,3]triazol
  • the demulcent polymer is selected from block copolymer surfactants; polyvinyl alcohol, polyvinyl pyrrolidone; polyacrylic Docket No. VTN6146WOPCT1 acid; polyethers; hyaluronic acid and hyaluronic acid derivatives; chitosan; polysorbates; dextrans; cellulosic derivatives; acyclic polyamides and mixtures thereof.
  • the method, product or kit of embodiment 83 wherein the demulcent polymer is selected from polyvinyl pyrrolidone, methyl ethyl cellulose, polyvinyl alcohol, polymethacrylic acid, carboxymethyl cellulose, propylene glycol, 1,3-propanediol, polyethylene glycols, and mixtures thereof.
  • the demulcent polymer is methyl ethyl cellulose.
  • VTN6146WOPCT1 The method, product or kit of any of the preceding embodiments and any succeeding embodiments wherein the osmolality is from 200 mOsm/kg to less than about 500 mOsm/kg, from about 200 to about 450 mOsm/kg, from about 205 to about 380 mOsm/kg, from about 210 to about 360 (mOsm/kg), from about 250 to about 350 mOsm/kg, from about 270 to about 330 mOsm/kg, or about 205 mOsm/kg to about 350 mOsm/kg.
  • composition is free of or substantially free of one or more of boric acid, borates, non-chlorous acid/non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • composition is free of boric acid, borates, non-chlorous acid /non-peroxide preservatives, persulfates, carboxy vinyl polymers, natural gums, glycerin, polyoxyethylene-castor oil and derivatives thereof.
  • the antimicrobial inhibiting compound concentration is reduced after autoclaving by at least about 50%, about 70%, about 80% or about 90%.
  • the microbial growth inhibiting compound is a peroxide the molar equivalents of peroxide to EDTA may be greater than 1.1 to 1.5, 1:2 to 1:5, or 1:3 to 1:5 or 1:4.
  • hydrogel contact lens is silicone hydrogel contact lens.
  • contact lens is a hybrid contact lens.

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Abstract

La présente invention concerne un composé inhibant la croissance microbienne et un composé tampon contenant des compositions, en particulier des compositions de soins oculaires, permettant d'obtenir un pH et une tonicité physiologiquement compatibles ainsi que de bonnes propriétés bactériostatiques. Des procédés d'utilisation des compositions de la présente invention sont également divulgués.
PCT/IB2023/062632 2022-12-21 2023-12-13 Compositions pour dispositifs ophtalmologiques Ceased WO2024134384A1 (fr)

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