WO2020219707A1 - Compositions and methods for treatment of ocular conditions - Google Patents

Compositions and methods for treatment of ocular conditions Download PDF

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Publication number
WO2020219707A1
WO2020219707A1 PCT/US2020/029566 US2020029566W WO2020219707A1 WO 2020219707 A1 WO2020219707 A1 WO 2020219707A1 US 2020029566 W US2020029566 W US 2020029566W WO 2020219707 A1 WO2020219707 A1 WO 2020219707A1
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WIPO (PCT)
Prior art keywords
topical ophthalmic
concentration
ophthalmic compositions
ophthalmic composition
compositions comprise
Prior art date
Application number
PCT/US2020/029566
Other languages
French (fr)
Inventor
Michael R. Robinson
Jaya GIYANANI
Anuradha Gore
Original Assignee
Allergan, Inc.
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Publication of WO2020219707A1 publication Critical patent/WO2020219707A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof

Definitions

  • the invention generally relates to topical ophthalmic compositions comprising one or more active components, a buffer, wherein the topical ophthalmic compositions have a pH of about 3.0 to 7.4 and generally do not contain a viscosity-enhancing component.
  • compositions should be maximized as much as possible, although sometimes formulation considerations (e.g ., drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • formulation considerations e.g ., drug stability
  • the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
  • Currently available commercial ophthalmic formulations are typically formulated with viscosity enhancing polymers (Ritch et al, The Glaucomas, Mosby (St. Louis), p. 517, 1989). Unfortunately, the viscosity due to added polymers in such ophthalmic formulations result in adverse effects such as vision blur that limit their use (Hall et ah, Optom. Vis. Sci., 88, pp. 872-880,
  • the invention relates to topical ophthalmic compositions comprising one or more active components.
  • the active components in the topical ophthalmic compositions include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I (as defined below), and pharmaceutically acceptable salts thereof.
  • the topical ophthalmic compositions include a buffer, have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity enhancing component.
  • the invention further provides topical ophthalmic compositions comprising one or more active components.
  • the active components in the topical ophthalmic composition include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof.
  • topical ophthalmic compositions include a buffer, have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps.
  • a buffer have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps.
  • the invention further provides topical ophthalmic compositions comprising one or more active components.
  • the active components in the topical ophthalmic composition include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof.
  • topical ophthalmic compositions include a buffer, have a pH of about about 3.0 to 7.4, or about 3.0 to about 6.0, or 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps without the need for including a viscosity-enhancing agent.
  • a buffer have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps without the need for including a viscosity-enhancing agent.
  • the invention also provides methods of treating an ocular condition in a subject in need of treatment thereof, comprising administering one or more topical ophthalmic compositions of the invention.
  • the invention further provides methods of treating myopia in a subject in need thereof.
  • the method comprises administering to at least one eye of the subject topical ophthalmic compositions comprising atropine and have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity-enhancing component.
  • the invention additionally provides methods of improving at least one vision parameter in a subject in need thereof.
  • the methods comprise administering to at least one eye of the subject a topical ophthalmic composition comprising atropine and have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity-enhancing component.
  • the vision parameter includes, but is not limited to, intermediate vision acuity, distance vision acuity and night vision.
  • the invention also provides topical ophthalmic compositions for use in treating, or for preparing a medicament for treating, ocular conditions in a subject in need of treatment thereof, including myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery, presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil or other causes of parasympathetic denervation, complications arising after refractive surgery, decentered ablations following LASIK or PRK, LASIK undercorrections, LASIK overcorrections, corneal scars, hazing, and refractive errors.
  • the invention provides topical ophthalmic compositions comprising one or more active components.
  • topical refers to a composition intended for direct application to the corneal surface of an eye of a subject in need thereof.
  • topical does not include injections to the eye of a subject ( e.g ., anterior chamber injections).
  • ophthalmic composition or“ophthalmic compositions of the invention” as used herein refers to compositions suitable for application to an eye of a subject, which are in such form as to permit the biological activity of the one or more active components (e.g., atropine) to be effective, and which contain no additional components that are unacceptably toxic to the subject to which the composition would be administered.
  • active components e.g., atropine
  • Such ophthalmic compositions will generally be sterile.
  • the ophthalmic compositions of the present invention will generally be formulated as sterile aqueous compositions (e.g., suspensions, solutions, emulsions or the like) and typically include at least 70 w/w %, more typically 80 w/w % and even more typically at least 90 or 95 w/w % purified water.
  • sterile aqueous compositions e.g., suspensions, solutions, emulsions or the like
  • Such ophthalmic compositions may be in the form of liquid preparations, e.g., eye drops.
  • the ophthalmic compositions may be suitable for single-dose or multiple-dose topical application.
  • ophthalmic compositions suitable for multi-dose topical application are often disposed in a dispenser (e.g., an eye dropper), which can dispense the ophthalmic composition (e.g., as individual drops) to the corneal surface of the eye.
  • a dispenser e.g., an eye dropper
  • the term“active component” refers to a component of the topical ophthalmic compositions of the invention which is responsible for the therapeutic effect of the composition, whereas the other components of the composition (e.g., excipients, carriers, and diluents) are not responsible for the therapeutic effect of the composition, even if they have other functions in the composition which are necessary or desired as part of the formulation (such as lubrication, pH control, emulsification, stabilization, preservation, and other functions).
  • the active components have therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the active components in the topical ophthalmic compositions of the invention include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, pilocarpine, physostigmine, phospholine iodide, aceclidine, and the compound of Formula I.
  • the topical ophthalmic compositions do not include pilocarpine.
  • the topical ophthalmic compositions do not include physostigmine. In further embodiments, the topical ophthalmic compositions do not include both pilocarpine and physostigmine.
  • the active component or components in the topical ophthalmic compositions of the invention include a compound of Formula I:
  • At least one of the one or more active components in the compositions of the present invention is/are present at a concentration of at least about 0.01% w/w. In other embodiments, at least one of the one or more active components is present at a concentration of less than about 0.01% w/w. In additional embodiments, the one or more active components are each present at a concentration of at least about 0.01% w/w. In certain aspects, at least one of the one or more active components is present at a concentration from about 0.001% w/w to about 20% w/w. In other aspects, the one or more active components are each present at a concentration from about 0.001% w/w to about 20% w/w.
  • At least one of the one or more active components is present at a concentration from about 0.01% w/w to about 20% w/w. In other aspects, the one or more active components are each present at a concentration from about 0.01% w/w to about 20% w/w. In some embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 10% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to about 10% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 2% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 2% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about
  • the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.75 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.75% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 1.5 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.5% w/w. In certain
  • At least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.25 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.25% w/w. In additional embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 1% w/w. In further embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1% w/w. In certain embodiments, at least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.50% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.50% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.30% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.30% w/w. In certain
  • At least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.10% w/w to at least about 0.10% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.09% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.09% w/w. In certain
  • At least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.07% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.07% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.05% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.05% w/w. In certain
  • At least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.04% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.03 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.03% w/w. In certain embodiments, at least one of the one or more active components is present at a
  • the one or more active components are each present at a concentration from about 0.001% w/w to at least about 0.03% w/w. In other embodiments, at least one of the one or more active components is present at a concentration of at least about 0.001% w/w, 0.01% w/w, 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.1% w/w, 0.3% w/w, 0.5% w/w, 0.7% w/w, 0.9% w/w, 1.0% w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w and 2% w/w, as well as between any of these concentrations.
  • the one or more active components is present at a concentration of at least about 0.001% w/w, 0.01% w/w, 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.1% w/w, 0.3% w/w, 0.5% w/w, 0.7% w/w, 0.9% w/w, 1.0% w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w and 2% w/w, as well as between any of these concentrations.
  • At least one of the one or more active components is present at a concentration from about 1% w/w to about 5% w/w. In other embodiments, the one or more active components are each present at a concentration from about 1% w/w to about 5% w/w.
  • the topical ophthalmic compositions may also include pharmaceutically acceptable salts of the active components.
  • pharmaceutically acceptable salts refers to salts of the one or more active agents of the topical ophthalmic compositions of the invention that are substantially non-toxic to living organisms, e.g., subjects in need of the topical ophthalmic compositions.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the one or more active components of the invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the one or more active components of the invention.
  • Inorganic acids which may be used to prepare pharmaceutically acceptable salts of the active components include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like.
  • Organic acids which may be used to prepare pharmaceutically acceptable salts include, without limitation, aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl-heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like.
  • Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include, but are not limited to, hydrochloride,
  • Suitable pharmaceutically acceptable salts may also be formed by reacting the active components with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like.
  • Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups that may be found on some of the active components and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium. All of these salts may be prepared by conventional means from the active components of the invention by reacting, for example, the appropriate acid or base with the active components of the invention.
  • the topical ophthalmic compositions of the invention comprise atropine as an active component.
  • atropine is the sole active component present in the topical ophthalmic compositions of the invention.
  • atropine is present as a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of atropine includes, without limitation, atropine sulfate, atropine hydrochloride, atropine nitrate, atropine hydrobromide, atropine pyrosulfate, atropine bisulfate, atropine sulfite, atropine bisulfite, atropine hydroiodide, atropine hydrofluoride, atropine acetate, atropine formate, atropine oxalate, atropine citrate, atropine lactate, atropine toluenesulfonate, atropine methanesulfonate, atropine maleate, atropine monohydrogenphosphate, atropine dihydrogenphosphate, atropine metaphosphate, atropine pyrophosphate, and atropine phosphate.
  • atropine sulfate atropine hydrochloride, atropine nitrate, atropine hydrobromide, atropine pyrosulfate, at
  • Atropine is present as atropine sulfate.
  • the compound when atropine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the ocular condition is myopia.
  • topical ophthalmic compositions of the invention comprise at least about 0.01% w/w atropine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w atropine. In some embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 2% w/w.
  • the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.0 % w/w.
  • the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.09 % w/w.
  • the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise atropine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise oxymetazoline as an active component.
  • oxymetazoline is the sole active component present in the topical ophthalmic compositions of the invention.
  • oxymetazoline is present as a pharmaceutically acceptable salt.
  • the compound when oxymetazoline is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions of the invention comprise at least about 0.01% w/w
  • the topical ophthalmic compositions comprise less than about 0.01% w/w oxymetazoline. In some embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 2% w/w.
  • the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.0 % w/w.
  • the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.09 % w/w.
  • the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise oxymetazoline at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise brimonidine as an active component.
  • brimonidine is the sole active component present in the topical ophthalmic compositions of the invention.
  • brimonidine is present as a pharmaceutically acceptable salt.
  • the compound when brimonidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w brimonidine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w brimonidine.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise brimonidine at a
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 20% w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 2% w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.5 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.25 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.10 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.04 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.02 % w/w.
  • the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w,
  • the topical ophthalmic compositions of the invention comprise epinephrine as an active component.
  • epinephrine is the sole active component present in the topical ophthalmic compositions of the invention.
  • epinephrine is present as a pharmaceutically acceptable salt.
  • the compound when epinephrine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w epinephrine.
  • the topical ophthalmic compositions comprise less than about 0.01% w/w epinephrine. In some embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise epinephrine at a
  • topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic
  • compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
  • the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
  • the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
  • the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
  • the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration of at least about 0.001% w/w,
  • the topical ophthalmic compositions of the invention comprise clonidine as an active component.
  • clonidine is the sole active component present in the topical ophthalmic compositions of the invention.
  • clonidine is present as a pharmaceutically acceptable salt.
  • the compound when clonidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w clonidine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w clonidine.
  • the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.50 % w/w.
  • the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.07 % w/w.
  • the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise clonidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise carbachol as an active component.
  • carbachol is the sole active component present in the topical ophthalmic compositions of the invention.
  • carbachol is present as a pharmaceutically acceptable salt.
  • the compound when carbachol is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w carbachol. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w carbachol.
  • the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.50 % w/w.
  • the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.07 % w/w.
  • the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise carbachol at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise demecarium as an active component.
  • demecarium is the sole active component present in the topical ophthalmic compositions of the invention.
  • demecarium is present as a pharmaceutically acceptable salt.
  • demecarium is present as demecarium bromide.
  • the compound when demecarium is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w demecarium.
  • the topical ophthalmic compositions comprise less than about 0.01% w/w demecarium. In some embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 2% w/w.
  • the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.0 % w/w.
  • the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.09 % w/w.
  • the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise demecarium at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise isoflurophate as an active component.
  • isoflurophate is the sole active component present in the topical ophthalmic compositions of the invention.
  • isoflurophate is present as a pharmaceutically acceptable salt.
  • the compound when isoflurophate is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w isoflurophate.
  • the composition comprises less than about 0.01% w/w isoflurophate.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 20% w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 20% w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1% w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.0 % w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.09 % w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise isoflurophate at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise neostigmine as an active component.
  • neostigmine is the sole active component present in the topical ophthalmic compositions of the invention.
  • neostigmine is present as a pharmaceutically acceptable salt.
  • neostigmine is present as neostigmine bromide.
  • the compound when neostigmine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w neostigmine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w neostigmine. In some embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 20% w/w.
  • the topical ophthalmic compositions comprise neostigmine at a concentration from about 1% w/w to about 5% w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.25 % w/w.
  • the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.10 % w/w.
  • the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.04 % w/w.
  • the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.02 % w/w.
  • the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise physostigmine as an active component.
  • physostigmine is the sole active component present in the topical ophthalmic compositions of the invention.
  • physostigmine is present as a pharmaceutically acceptable salt.
  • the compound when physostigmine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w physostigmine.
  • the topical ophthalmic compositions comprise less than about 0.01% w/w physostigmine. In some embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.2% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.50 % w/w.
  • the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.07 % w/w.
  • the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise physostigmine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise pilocarpine as an active component.
  • pilocarpine is the sole active component present in the topical ophthalmic compositions of the invention.
  • pilocarpine is present as a pharmaceutically acceptable salt.
  • pilocarpine is present as pilocarpine hydrochloride.
  • the compound when pilocarpine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain cases, the ocular condition is presbyopia.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w pilocarpine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w pilocarpine. In some embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise pilocarpine at a
  • the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
  • the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
  • the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
  • the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
  • the topical ophthalmic compositions comprise pilocarpine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise phospholine iodide as an active component, an irreversible acetylcholinesterase inhibitor also known as echothiophate iodide.
  • phospholine iodide is the sole active component present in the topical ophthalmic compositions of the invention.
  • phospholine iodide is present as a pharmaceutically acceptable salt.
  • the compound when phospholine iodide is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w phospholine iodide. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w phospholine iodide. In some embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 20% w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.5 % w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.25 % w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.20 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.05 % w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.02 % w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise phospholine iodide at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.20% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise aceclidine as an active component.
  • aceclidine is the sole active component present in the topical ophthalmic compositions of the invention.
  • aceclidine is present as a pharmaceutically acceptable salt.
  • the compound when aceclidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w aceclidine. In other aspects, the composition comprises less than about 0.01% w/w aceclidine.
  • the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 4% w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.50 % w/w.
  • the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.07 % w/w.
  • the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise aceclidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.2% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention comprise Formula I as an active component.
  • Formula I is the sole active component present in the topical ophthalmic compositions of the invention.
  • Formula I is present as a pharmaceutically acceptable salt.
  • the topical ophthalmic compositions comprise at least about 0.01% w/w Formula I. In other aspects, the composition comprises less than about 0.01% w/w Formula I.
  • the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 5% w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.75 % w/w.
  • the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.50 % w/w.
  • the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.07 % w/w.
  • the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.03 % w/w.
  • the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.01 % w/w.
  • the topical ophthalmic compositions comprise Formula I at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.2% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
  • the topical ophthalmic compositions of the invention also include a suitable buffer.
  • a suitable buffer refers to a component of a solution that resists changes in pH of the solution when an acid or alkali is added to it. Buffers typically involve a weak acid or alkali together with one of its salts.
  • a buffer may comprise one or more of sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide, or hydrochloric acid.
  • the buffer comprises monobasic and dibasic sodium phosphate.
  • the quality of a buffer is determined by its buffer capacity, i.e. its resistance to changes in pH when strong acids or bases are added.
  • the buffer capacity corresponds to the amount of H + or OH- ions that can be neutralized by the buffer.
  • Buffer capacity is related to the buffer concentration.
  • a graph described by the relation of the pH to the addition of H /OH ions is called the titration curve. The point of inflection of the curve corresponds to the pKa value of the buffer.
  • the buffer capacity of a buffer is at its maximum at the pKa value.
  • the pKa value of a buffer therefore corresponds to the mid-point of the pH range covered by the buffer and represents the point at which the concentration of acid and base is the same. In the area of this pH range, therefore, relatively large amounts of H /OH ions result in only small changes in pH. Therefore, a buffer with more than one pKa resists changes to the pH of a solution over a broad range of H + /OH ions.
  • buffers with more than one pKa include, but are not limited to, citrate buffer and phosphate buffer.
  • a buffer suitable for use in the topical ophthalmic compositions described herein is preferably one that stabilizes the stored compositions by maintaining the compositions at a low pH (e.g ., pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5), but that quickly equilibrates to a physiological pH (i.e., the pH of the tear film and/or ocular surface, or a pH of about 7.0) when the compositions are administered to the surface of an eye.
  • suitable buffers include, but are not limited to borate buffer, borate citrate buffer, lactate buffer and citrate buffer.
  • the buffer is a borate buffer.
  • the buffer is present at a concentration of less than about 0.001 mM. In other embodiments, the buffer is present at a concentration of at least about 0.001 mM. In other embodiments, the buffer is present at a concentration from about 0.01 mM to 1 M. In specific embodiments, the buffer is present at a concentration from about 1 mM to about 200 mM. In additional embodiments, the buffer is present at a
  • a buffer may control the pH of the topical ophthalmic compositions of the invention.
  • the topical ophthalmic compositions of the invention have a pH of lower than about 7.4.
  • the topical ophthalmic compositions of the invention have a pH of lower than about 7.0, lower than about 6.5, lower than about 6.0, lower than about 5.5, lower than about 5.0, lower than about 4.5, lower than about 4.0, lower than about 3.5 lower than about 3.0, lower than about 2.5, lower than about 2.0, lower than about 1.5, or lower than about 1.0.
  • the pH of topical ophthalmic compositions of the invention is in the range of about 1.0 to about 7.4, or about 1.5 to 7.4 or about 2.0 to about 7.4, or about 2.5 to about 7.4, or about
  • 6.0 or about 2.0 to about 6.0, or about 2.5 to about 6.0, or about 3.0 to about 6.0, or about 1.0 to about 5.5, or about 1.5 to about 5.5, or about 2.0 to about 5.5, or about 2.5 to about 5.5, or about 3.0 to about 5.5, or about 3.5 to about 5.5, or about 4.0 to about 5.5, or about 4.5 to about 5.5, or about 5.0 to about 5.5, or about 1.0 to 5.0, or about 1.5 to 5.0, or about
  • compositions of the invention is in the range of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5.
  • the pH of topical ophthalmic compositions of the invention is about 4.5.
  • the pH of topical ophthalmic compositions of the invention is about 5.0.
  • the pH of topical ophthalmic compositions of the invention is about 6.0.
  • the pH of the ocular topical ophthalmic compositions of the invention unexpectedly reduces or eliminates the incidence of adverse events and/or ocular discomfort commonly associated with commercially available topical ophthalmic compositions. These adverse events include, without limitation, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
  • the topical ophthalmic compositions of the invention may or may not contain a secondary buffering agent.
  • the secondary buffering agent includes, without limitation, citrate buffer and acetate buffer.
  • the secondary buffering agent is present at a concentration of at least about concentration of less than about 0.001 mM. In other embodiments, the secondary buffering agent is present at a concentration of at least about 0.001 mM. In some embodiments, the secondary buffering agent is present at a concentration from about 0.01 mM to 1 M. In specific embodiments, the secondary buffering agent is present at a concentration from about 1 mM to about 100 mM.
  • viscosity of a topical ophthalmic composition of the invention is used as it normally is used for liquids and means a measure of the liquid’s resistance to deformation at a given rate.
  • viscosity is a quantity expressing the magnitude of internal friction, as measured by the force per unit area resisting a flow in which parallel layers of the topical ophthalmic compositions, unit distance apart, have unit speed relative to one another.
  • a fluid that has no resistance to shear stress is known as an ideal or inviscid fluid.
  • the topical ophthalmic compositions of the invention have a viscosity from about 1 centipoise (cps) to about 10 cps. In certain aspects, the topical ophthalmic compositions of the invention have a viscosity close to that of pure water (1 cps). In specific aspects, the topical ophthalmic compositions of the invention have a viscosity of about 1 cps.
  • viscosity enhancing component refers to any substance that increases the viscosity of the topical ophthalmic compositions of the invention.
  • a viscosity enhancing component may be a polymer including, but not limited to hypromellose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methylcellulose, methyl cellulose 4000, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, pyrrolidone, polyvinyl pyrrolidone, gellan, carrageenan, alignic acid,
  • compositions of the present invention do not contain any of the above-listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement. In other specific embodiments, the compositions of the present invention contain only trace amounts of any of the above-listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement.
  • a trace amount means a concentration of about 100 ppm (100 micrograms per gram o 100 micrograms per milliliter) or less.
  • the compositions of the present invention may contain small amounts of any of the above- listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement, provided that the viscosity of the resulting composition is about 20 cps or less, about 15 cps or less, about 10 cps or less, about 5 cps or less or about 2 cps or less.
  • a viscosity enhancing component may be non-polymeric including, without limitation, gums, such as hydroxypropyl-guar (hp-guar) and xanthan gum, thickeners, such as alginate,
  • compositions of the present invention do not contain any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement. In other specific embodiments, the compositions of the present invention contain only trace amounts of any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement.
  • compositions of the present invention may contain small amounts of any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement, provided that the viscosity of the resulting composition is about 20 cps or less, about 15 cps or less, about 10 cps or less, about 5 cps or less or about 2 cps or less, or about 1 cps.
  • the viscosity of the resulting composition is about 20 cps to about 1 cps, or about 15 cps to about 1 cps, or about 10 cps to about 1 cps, or about 8 cps to about 1 cps, or about 6 cps to about 1 cps, or about 5 cps to about 1 cps, or about 4 cps to about 1 cps, or about 3 cps to about 1 cps, or about 2 cps to about 1 cps, or about 10 cps to about 2 cps, or about 8 cps to about 2 cps, or about 6 cps to about 2 cps, or about 5 cps to about 2 cps, or about 4 cps to about 2 cps, or about 3 cps to about 2 cps, or about 10 cps to about 3 cps, or about 3
  • the topical ophthalmic compositions of the invention may further include one or more osmolality agents in an amount that renders the topical ophthalmic compositions of the invention roughly isotonic.
  • “Osmolality” is a measure of the total number of dissolved particles in a given volume of a solution.
  • the term“osmolality agent” include any compound or substance useful for adjusting the osmolality of a topical ophthalmic composition.
  • osmolality agents include, but are not limited to, salts, particularly sodium chloride or potassium chloride, organic compounds such as propylene glycol, mannitol, sorbitol, dextrose, and glycerin.
  • the osmolality agents of the topical ophthalmic compositions of the invention include, but are not limited to, glycerin, propylene glycol, mannitol, sorbitol, sodium chloride, potassium chloride and dextrose.
  • “Tonicity” is a measure of the effective osmotic pressure gradient, as defined by the water potential of two solutions separated by a semipermeable membrane.
  • tonicity is the relative concentration of solutes dissolved in solution which determine the direction and extent of diffusion. The term is commonly used when describing the response of cells immersed in an external solution.
  • tonicity is influenced only by solutes that cannot cross the membrane, as only these exert an effective osmotic pressure. Solutes able to freely cross the membrane do not affect tonicity because they will always be in equal concentrations on both sides of the membrane.
  • a solution is“isotonic” when its effective osmole concentration is the same as that of another solution.
  • the solutions on either side of a cell membrane for example, are isotonic if the concentration of solutes outside the cell is equal to the concentration of solutes inside the cell.
  • the amount of osmolality agent may vary depending upon whether the topical ophthalmic compositions are isotonic, hypertonic, or hypotonic.
  • the amount of an osmolality agent such as those listed above may be at least about 0.0001% w/w up to about 0.05% w/w, about 0.10% w/w, 0.35% w/w, 0.40% w/w, about 0.50% w/w, about 0.95% w/w, about 1% w/w, about 2% w/w, about 5% w/w, about 10% w/w, or about 20% w/w, as well as between any of these concentrations.
  • at least one of the one or more osmolality agents is present at a
  • the one or more osmolality agents are each present at a concentration of at least about 0.0001% w/w. In other embodiments, the one or more osmolality agents are each present at a concentration of at least about 0.0001% w/w. In some embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 20% w/w. In other embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 20% w/w. In additional embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 5% w/w.
  • the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 5% w/w. In yet other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 2.5% w/w. In additional embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 2.5% w/w. In still other
  • At least one of the one or more osmolality agents is present at a
  • the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 1% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.95% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.95% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.50% w/w.
  • the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.50% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.40% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.40% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.35% w/w.
  • the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.35% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.10% w/w. In further embodiments, the one or more osmolality agents are each present at a
  • the topical ophthalmic compositions of the invention may further include a strong acid or a strong base.
  • strong acids and strong bases are well known in the art and include, without limitation, NaOH, KOH, HC1, and H2SO4.
  • the topical ophthalmic compositions of the invention further comprise NaOH or HC1.
  • the topical ophthalmic compositions of the invention may be packaged for single use, and contain no preservative or essentially no preservative.
  • the topical ophthalmic compositions of the invention may be packaged for multiple uses, and comprise a suitable preservative to prevent contamination over multiple uses.
  • the term“preservative” means any substance that prevents or retards contamination in the form of bacterial or fungal growth in the topical ophthalmic solutions of the invention. Examples of suitable preservatives include, but are not limited to,
  • benzalkonium chloride BAK
  • Polyquaternium-1 Poly quad®
  • chlorobutanol stabilized chlorine dioxide
  • a stabilized oxychloro complex comprising chlorite, chlorate and chlorine dioxide.
  • Stabilized chlorine dioxide also known as Purite®
  • Purite® may be described as an aqueous solution of sodium chlorite (NaCICh).
  • U.S. Patent Number 5,424,078, which is incorporated herein by reference in its entirety, further discusses the use of stabilized chlorine dioxide as a preservative for topical ophthalmic compositions.
  • the preservative is present at a concentration of at least about 1 ppm. In other embodiments, the preservative is present at a concentration of less than about 1 ppm. In some aspects, the preservative is present at a concentration from about 1 ppm to about 1000 ppm. In other aspects, the preservative is present at a concentration from about 10 ppm to about 300 ppm. In specific embodiments, the preservative is present at a concentration from about 10 ppm to about 200 ppm. In certain aspects, the preservative is present at a concentration of at least about 0.001% w/w. In specific aspects, the preservative is present at a concentration of at least about 0.0075% w/w.
  • the topical ophthalmic compositions of the present invention may be prepared by techniques known to those skilled in the art.
  • the topical ophthalmic compositions of the invention may be an aqueous solution, emulsion or suspension or may be a dried preparation.
  • the topical ophthalmic compositions of the invention may be desiccated or lyophilized, for example, by freeze-drying or spray drying for storage or formulations purposes.
  • a solid composition of the invention is subsequently reconstituted into liquid compositions by the addition of an appropriate liquid carrier prior to administering to a subject in need thereof.
  • the topical ophthalmic compositions of the invention may be administered at several intervals in order to sustain therapeutic levels.
  • the topical ophthalmic compositions of the invention may be administered once daily, twice daily (BID), four times daily (QID) or more.
  • the topical ophthalmic compositions of the invention are administered once daily.
  • the topical ophthalmic compositions of the invention are applied twice daily.
  • the topical ophthalmic compositions of the invention have a duration of action of at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 24 hours, as well as all intervening time points.
  • the topical ophthalmic compositions of the invention have a duration of action greater than 10 hours, for example 12 hours, or even 24 hours.
  • The“duration of action” refers to the duration of time that an administered topical ophthalmic composition has an effect on at least one vision parameter or ocular condition (e.g ., myopia) in a subject in need thereof.
  • the invention further relates to methods of treating an ocular condition in a subject in need of treatment thereof, comprising administering one or more topical ophthalmic compositions of the invention.
  • treating refers to both therapeutic measures and prophylactic or preventative measures, wherein the objective is to prevent, slow down (lessen), or ameliorate an undesired ophthalmic change or condition or disorder, such as the progression of myopia.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishing the extent of disease, stabilized (i.e., not worsening) state of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, and reversing the disease (whether partial or total).
  • the term“ocular condition” may refer to any condition, disease, or impairment, which affects or involves the eye or one of the parts or regions of the eye, and includes optical issues causing refractive errors in the eye.
  • Ocular conditions include, but are not limited to myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery ( e.g ., glare, halos or starbursts around lights), presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil, or other causes of parasympathetic denervation, complications arising after refractive surgery,
  • the term“subject” refers to any individual, e.g., a mammal, for whom diagnosis, prognosis, or therapy is desired.
  • the term“subject” may mean a human or non-human mammal affected, likely to be affected, or suspected to be affected with an ocular condition or disease.
  • topical ophthalmic compositions provided herein are principally directed to compositions which are suitable for administration to humans, the skilled artisan will understand that such compositions are generally suitable for administration to subjects of all sorts. In certain aspects, the subject is a mammal.
  • a mammal includes, without limitation, primates, such as humans, monkeys and apes, and non-primates such as domestic animals, including laboratory animals, sports animals, farm animals, and household pets (e.g., cats, dogs, swine, cattle, cows, sheep, goats, horses, guinea pigs, rabbits, rats, mice), and non-domestic animals, such as wildlife, birds, or the like.
  • primates such as humans, monkeys and apes
  • non-primates such as domestic animals, including laboratory animals, sports animals, farm animals, and household pets (e.g., cats, dogs, swine, cattle, cows, sheep, goats, horses, guinea pigs, rabbits, rats, mice), and non-domestic animals, such as wildlife, birds, or the like.
  • the term“a subject in need thereof’ includes subjects, such as mammalian subjects, that would benefit from administration of a topical ophthalmic composition of the invention.
  • Subjects in need of treatment include, without limitation, those already with the condition or disorder as well as those prone to having the condition or disorder, or those in which the condition or disorder is to be prevented, ameliorated, or reversed.
  • the term“administer,” or“administering” as it applies to, for example, a subject in need of the topical ophthalmic compositions of the invention refers to contact of, for example, the topical ophthalmic composition of the invention to at least one eye of the subject.
  • administration includes contact (e.g., in vitro or ex vivo) of the topical ophthalmic compositions of the invention to the cell, as well as contact of the topical ophthalmic compositions of the invention with a fluid, where the fluid is in contact with the cell.
  • the topical ophthalmic compositions of the present invention have good stability.
  • A“stable” composition is one which retains physical and/or chemical stability upon storage. The storage period is generally selected based on the intended shelf-life of the composition.
  • Various analytical techniques for measuring stability are available in the art, such as the procedure and methods outlined in Example 4. Stability can be measured at a selected temperature and relative humidity (“RH”) for a selected time period, for example at 5°C, 25°C/40% RH, and 40°C/25% RH for 1 month, or 2 months, or 3 months, or 6 months, or 10 months, or 12 months, or 18 months, or 24 months, or 36 months, or any other time period
  • RH temperature and relative humidity
  • Tests may be conducted at ambient humidity, no humidity, and ranges from 0-100% relative humidity, including for example 25% or 40% RH.
  • a stable composition in accordance with the present invention can be substantially clear and colorless at temperatures of, for example, 5°C, 25° C, and 40°C, for durations of time of, for example, 1 month, or 2 months, or 3 months, or 6 months, or 10 months, or 12 months, or 15 months, or 18 months, or 24 months, or 30 months, or 36 months.
  • a stable composition in accordance with the present invention may exhibit only a slight decrease in pH throughout the storage duration, thereby maintaining its desired therapeutic effect. For instance, at 5°C, the pH may decrease by only about 4% or less (e.g., about 1% to about 4%, or about 2% to about 3.75%, or about 2.25% to about 3.6%) after 6 months. For example, at 5°C, the pH may decrease by only about 7.25% or less (e.g., about 1.5% to about 7.25%, or about 2.5% to about 7%, or about 3% to about 6.5%) after 12 months.
  • the pH may decrease by only about 12% or less (e.g., about 3% to about 12%, or about 4% to about 11%, or about 5% to about 10%) after 6 months.
  • the pH may decrease by only about 16% or less (e.g., about 3% to about 16%, or about 4.5 to about 15.5%, or about 6% to about 15%) after 12 months.
  • the pH may decrease by only about 13.5% or less (e.g., about 1% to about 13.5%, or about 2.5% to about 13%, or about 4% to about 12.5%) after about 3 months.
  • the pH may decrease by only about 17.5% or less (e.g., about 5% to about 17.5%, or about 5.5% to about 17%, or about 6.5% to about 16.5%) after 6 months.
  • a stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.2 to about 4.7, or about 4.3 to about 4.7, or about 4.4 to about 4.7 or about 4.5 to about 4.7 at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months.
  • a stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.2 to about 4.7, or about 4.3 to about 4.6, or about 4.4 to about 4.6 at 25°C after 6 or 12 months.
  • a stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.0 to about 4.7, or about 4.1 to about 4.6, or about 4.1 to about 4.5 at 40°C after 3 or 6 months.
  • a stable composition in accordance with the present invention may exhibit only a slight increase in osmolality throughout the storage duration.
  • the osmolality can increase by only about 1.25% or less (e.g., about 0.25% to about 1.25%, or about 0.3% to about 1.1%, or about 0.35% to about 1.05% after 6 months.
  • the osmolality can increase by only about 0.85% or less (e.g., about 0.25% to about 0.85%, or about 0.30% to about 0.80%, or about 0.35% to about 0.75%) after 12 months.
  • the osmolality can increase by only about 2.35% or less (e.g., about 0.8% to about 2.35%, or about 0.9% to about 2.25%, or about 1% to about 2.15%) after 6 months.
  • the osmolality can increase by only about 2.35% or less (e.g., about 1% to about 2.35%, or about 1.2% to about 2.25%, or about 1.4% to about 2.15%) after 12 months.
  • the osmolality can increase by only about 4% or less (e.g., about 1.5% to about 4%, or about 1.6% to about 3.5%, or about 1.75% to about 3.25%) after 3 months.
  • the osmolality can increase by only about 6.0% or less (e.g., about 3% to about 6.0%, or about 3.5% to about 5.8%, or about 3.75% to about 5.7%) after 6 months.
  • a stable composition in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 290 mOsm/kg, or about 282 mOsm/kg to about 289 mOsm/kg, or about 284 mOsm/kg to about 298 mOsm/kg, or about 285 mOsm/kg to about 287 mOsm/kg at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months.
  • a stable composition in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 292 mOsm/kg, or about 282 mOsm/kg to about 291 mOsm/kg, or about 284 mOsm/kg to about 290 mOsm/kg at 25°C after 6 months or 12 months.
  • a stable formulation in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 305 mOsm/kg, or about 282 mOsm/kg to about 303 mOsm/kg, or about 286 mOsm/kg to about 300 mOsm/kg, or about 289 mOsm/kg to about 300 mOsm/kg at 40°C after 6 months or 12 months.
  • a stable composition in accordance with the present invention may result in formation of only a very amount of total impurities during storage.
  • the total impurities are about 0.30% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10% w/w or less, at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months.
  • the total impurities are about 0.40% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10% w/w or less, at 5°C after 12 months.
  • the total impurities are about 1% w/w or less, or about 0.9% w/w or less, or about 0.8% w/w or less, or about 0.6% w/w or less, at 25°C after 6 months. In an embodiment, the total impurities are about 2% w/w or less, or about 1.75% w/w or less, or about 1.6% w/w or less, or about 1.5% w/w or less, or about 1.3% w/w or less, at 25°C after 12 months.
  • the total impurities are about 2.1%, w/w or less, or about 2% w/w or less, or about 1.75% w/w or less, or about 1.5% w/w or less, at 40°C after 3 months. In an embodiment, the total impurities are about 4% w/w or less, or about 3.8% w/w or less, or about 3.5% w/w or less, or about 3.1% w/w or less, or about 3% w/w or less, or about 2.75% w/w or less at 25°C after 12 months. [0063] A stable composition in accordance with the present invention that contains atropine may result in formation of only a slight amount of tropic acid.
  • the total amount of tropic acid in the composition is about 0.25% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10%, w/w or less, or about 0.06% w/w or less, at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months.
  • the total amount of tropic acid in the composition is about 0.30% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10%, w/w or less, or about 0.09% w/w or less, at 5°C after 12 months.
  • the total amount of tropic acid in the composition about 0.35% w/w or less, or about 0.32% w/w or less, or about 0.29% w/w or less, or about 0.25% w/w or less, at 25°C/ after 6 months. In an embodiment, the total amount of tropic acid in the
  • composition is about 0.60% w/w or les, or about 0.55% w/w or less, or about 0.50% w/w or less, or about 0.48% w/w or less, or about 0.45% w/w or less, at 25°C after 12 months.
  • the total amount of tropic acid in the composition is about 0.70% w/w or less, or about 0.66% w/w or less, or about 0.60% w/w or less, or about 0.55% w/w or less, or about 0.52% w/w or less, or about 0.50% w/w or less at 40°C after 3 months.
  • the total amount of tropic acid in the composition is about 1.2% w/w or less, or about 1% w/w or less, or about 0.90% w/w or less, or about 0.80% w/w or less, or about 0.75% w/w or less, at 40°C after 6 months.
  • a stable composition in accordance with the present invention may include at least one preservative, such as benzalkonium chloride (BAK).
  • BAK benzalkonium chloride
  • the amount thereof remains unchanged when stored for 6 months at 5°C, 25°C, and 40°C.
  • the amount of benzalkonium chloride (as % w/w of the composition) may increase or decrease by only about 4% or less (e.g., about 0.1% to about 4%, or about 0.2% to about 3.95%) when stored for 6 months at 5°C, 25°C/40%
  • the amount of benzalkonium chloride may be at least about 0.0060% w/w, or about 0.0065% w/w, or about 0.0066% w/w, or about 0.0067% w/w, about 0.0068% w/w, or about 0.0069% w/w, or about 0.0071 % w/w when stored for 6 months at 5°C, 25°CRH, and 40°C.
  • the topical ophthalmic compositions of the invention are administered to only one eye of a subject in need thereof.
  • the topical ophthalmic compositions of the invention are administered to at least one eye of a subject.
  • the topical ophthalmic compositions of the invention are administered to both eyes of a subject.
  • the topical ophthalmic compositions of the invention are administered to a non-dominant eye of a subject.
  • the topical ophthalmic compositions of the invention are administered to a dominant eye of a subject.
  • the topical ophthalmic compositions of the invention are administered to a dominant eye of a subject.
  • the topical ophthalmic compositions of the invention are administered to both the non-dominant eye and the dominant eye of the subject.
  • the topical ophthalmic compositions of the invention do not cause, or do not significantly cause vision blur when administered to a subject in need thereof. Additionally, when administered to subjects, the topical ophthalmic compositions of the invention do not cause, or do not significantly cause one or more one adverse effect that include, but are not limited to, ocular blurring, ocular discomfort, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
  • the topical ophthalmic compositions of the invention reduce incidence of at least one adverse effect compared to topical administration of a second ophthalmic composition comprising a viscosity-enhancing component and one or more active components selected from the group consisting of atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, pilocarpine, physostigmine, and any pharmaceutically acceptable salt thereof.
  • the adverse effects include, without limitation, ocular blurring, ocular discomfort, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
  • the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to the reduced viscosity of the compositions. In other aspects, the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to the acidic pH of the compositions. In yet other aspects, the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to both the reduced viscosity and the acidic pH of the compositions.
  • the invention additionally relates to methods of treating myopia in a subject in need thereof, comprising administering to at least one eye of the subject one or more topical ophthalmic compositions of the invention.
  • “Myopia” or nearsightedness is a vision condition in which people can see close objects clearly, but objects farther away appear blurred. Myopia occurs if the eyeball is too long or the cornea (the clear front cover of the eye) is too curved. As a result, the light entering the eye is not focused correctly, and distant objects look blurred. Myopia affects nearly 30 percent of the U.S. population. While the exact cause of myopia is unknown, there is significant evidence that many people inherit myopia, or at least the tendency to develop myopia. If one or both parents are nearsighted, there is an increased chance their children will be nearsighted. Even though the tendency to develop myopia may be inherited, its actual development may be affected by how a person uses his or her eyes.
  • myopia Individuals who spend considerable time reading, working at a computer, or doing other intense close visual work may be more likely to develop myopia. Generally, myopia first occurs in school-age children. Because the eye continues to grow during childhood, it typically progresses until about age 20. However, myopia may also develop in adults due to visual stress or health conditions such as diabetes.
  • the invention further provides methods of improving at least one vision parameter in a subject in need thereof, comprising administering to at least one eye of the subject one or more topical ophthalmic compositions of the invention.
  • vision parameter refers to any characteristic in a subject’s vision that may be measured and is susceptible to being improved by the topical ophthalmic compositions and methods described herein.
  • Vision parameters include, but are not limited to, near vision acuity, intermediate visual acuity, distance visual acuity, night vision, day vision, optical aberrations ( e.g ., glare, light scattering), and uncorrected refractive errors. Additional examples of vision parameters include, without limitation, night time glare, post-LASIK “star burst” glare, visual“halos” seen around light sources, and accommodative insufficiency.
  • “Improving vision parameter,” includes, but is not limited to, near, intermediate, and/or distance visual acuity, and may for example be reflected in the increase of number of letters correctly read at any time point post dosing, the increase in the average letter change, or 2-line or 3 -line improvement, all from baseline (i.e., from pre-treatment).
  • Night vision improvement may be reflected in visual improvement for subjects in dim or dark lighting (e.g., under mesopic or scotopic conditions).
  • Day vision improvement may be reflected in visual improvement for subjects in bright lighting as found during daylight hours or in sunshine (e.g., under photopic conditions).
  • Vision improvement using the methods described herein may also be achieved in combination with or when using other visual aids and devices (e.g., those used for treating myopia), including but not limited to reading glasses, lens modifying medications, and surgical myopic options.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected near visual acuity (UNVA).
  • photopic vision is the vision of the eye under well-lit conditions (luminance level 10 to 10 8 cd/m 2 ). In humans and other animals, photopic vision allows color perception, mediated by cone cells, and a significantly higher visual acuity and temporal resolution than available with scotopic vision (the vision of the eye under low- light conditions; luminance level 10 3 to 10 6 cd/m 2 ).
  • the term“uncorrected near visual acuity” refers to a subject’s ability, without any vision aid (such as eyeglasses or contact lenses), to see the details of objects within arm’s distance from the body (e.g., at 33-41 cm away from the eye).
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast UNVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast UNVA.
  • the term“improvement from baseline” refers to the increase from pre-treatment in the number of letters correctly read at certain post treatment time point.
  • the term“2-line improvement from baseline” or“3 -line improvement from baseline” or similar improvement from baseline refers to a subject’s ability to read 2 or 3 more lines of letters on a standard chart (e.g., Snellen, ETDRS, Logarithmic Visual Acuity Chart, etc.) after treatment with a topical ophthalmic composition of the invention when comparing to the number of lines readable before treatment.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast UNVA.
  • mesopic vision refers to a combination of photopic vision and scotopic vision in low but not quite dark lighting situations. Mesopic light levels range from luminances of approximately 0.001 to 3 cd m -2 . Most night-time outdoor and traffic lighting scenarios are in the mesopic range. The human eye uses scotopic vision under low-light conditions and mesopic vision in intermediate conditions. Humans see differently at different light levels. This is because under high light levels typical during the day (photopic vision), the eye uses cones to process light.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast UNVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast UNVA.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected distance visual acuity (UDVA).
  • UDVA uncorrected distance visual acuity
  • the term“uncorrected distance visual acuity” (UDVA) refers to a subject’s ability, without any vision aid (such as eyeglasses or contact lenses), to see the details of objects beyond arm’s distance from the body (e.g., greater than 4 meters away from the eye).
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast UDVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast UDVA.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast distance-corrected near visual acuity (DCNVA).
  • DCNVA high contrast distance-corrected near visual acuity
  • DCNVA distance corrected near visual acuity
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast DCNVA.
  • methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast DCNVA.
  • methods described herein result in an at least 3 -line improvement from baseline under the condition of photopic, high contrast DCNVA.
  • methods described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast DCNVA.
  • methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast DCNVA.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast distance-corrected intermediate visual acuity (DCIVA).
  • DCIVA distance-corrected intermediate visual acuity
  • the term“distance-corrected intermediate visual acuity” (DCIVA) may be used to refer to a subject’s ability to see the details of objects at intermediate distances with the use of vision aids such as eyeglasses or contact lenses that correct for distance vision issues.
  • methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast DCIVA.
  • methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast DCIVA.
  • methods described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast DCIVA.
  • methods described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast DCIVA.
  • methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast DCIVA.
  • Example 1 Topical Ophthalmic Compositions of the Invention
  • the topical ophthalmic compositions of the invention may contain one or more of the drug substances listed below.
  • Buffers the topical ophthalmic compositions of the invention may contain any one of the buffers listed below.
  • Secondary buffering agents the topical ophthalmic compositions of the invention may or may not contain any one of the secondary buffering agents listed below.
  • Osmolality agents the topical ophthalmic compositions of the invention may contain one or more osmolality agents listed below.
  • the one or more osmolality agents are used in an amount that renders the topical ophthalmic compositions of the invention roughly isotonic.
  • Preservatives the topical ophthalmic compositions of the invention may or may not contain any one or a combination of preservatives listed below.
  • topical ophthalmic compositions of the invention include any combinations of active ingredients, buffers, secondary buffering agents, osmolality agents and/or preservatives taken from Table 1-5, such that the topical ophthalmic compositions preferably have a low pH when stored, but will quickly equilibrate to a physiological pH (such as that of the tear film) and/or become roughly isotonic when applied to surface of the eye.
  • Simulated tear fluid was prepared using sodium chloride (0.9% w/w), calcium chloride dihydrate (0.015% w/w), sodium phosphate dibasic heptahydrate (0.028% w/w), human lysozyme (0.19% w/w), bovine albumin (0.020% w/w), bovine submaxillary mucin (0.020% w/w), human gamma globulin (0.010% w/w), and water, with a pH of 7.2.
  • the formulation was filled at 5mL and lOmL fill volume into 5mL multi-dose and lOmL multi-dose preservative free (MDPF) container closure system, respectively.
  • MDPF multi-dose preservative free
  • Table 22 Tests and Stability Intervals for the 5°C and 25°C/40% RH Storage Conditions
  • X denotes that stability testing was performed at this time interval
  • X denotes that stability testing was performed at this time interval
  • Table 28 Stability Data for Formulation II at 5°C
  • Table 29 Stability Data for Formulation II at 25°C/40% RH
  • Table 32 Stability Data for Formulation III at 25°C/40% RH
  • Table 33 Stability Data for Formulation III at 40°C/25% RH
  • Formulation I had an initial (To) pH of 4.74, which decreased to 4.52 at the 5°C, 12 month time point, to 4.41 at the 25°C/40% RH, 12 month time point and to 4.37 at the 40°C/25% RH, 6 month time point.
  • Formulation II had an initial (To) pH of 4.80, which decreased to 4.64 at the 5°C, 12 month time point, to 4.51 at the 25°C/40% RH, 12 month time point and to 4.49 at the 40°C/25% RH, 6 month time point.
  • Formulation III had an initial (To) pH of 4.79, which decreased to 4.48 at the 5°C, 12 month time point, to 4.07 at the 25°C/40% RH, 12 month time point and to 4.00 at the 40°C/25% RH time point. [00161] 3.3. Osmolality
  • BAK Benzalkonium Chloride

Abstract

The present invention is related to topical ophthalmic compositions comprising one or more active components. The active components in the topical ophthalmic compositions include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof. Moreover, the topical ophthalmic compositions may include a buffer and do not contain a viscosity-enhancing component. Also described herein are methods for the treatment of ocular conditions and for the improvement of vision parameters using the topical ophthalmic compositions.

Description

COMPOSITIONS AND METHODS FOR TREATMENT OF OCULAR CONDITIONS
Background of the Invention
[0001] The present application claims the benefit of U.S. provisional application No. 62/838,155, filed April 24, 2019, the entire disclosure of which is incorporated by reference herein.
Field of the Invention
[0002] The invention generally relates to topical ophthalmic compositions comprising one or more active components, a buffer, wherein the topical ophthalmic compositions have a pH of about 3.0 to 7.4 and generally do not contain a viscosity-enhancing component.
Background of the Invention
[0003] To improve patient compliance, the comfort of the topical ophthalmic
compositions should be maximized as much as possible, although sometimes formulation considerations ( e.g ., drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Currently available commercial ophthalmic formulations are typically formulated with viscosity enhancing polymers (Ritch et al, The Glaucomas, Mosby (St. Louis), p. 517, 1989). Unfortunately, the viscosity due to added polymers in such ophthalmic formulations result in adverse effects such as vision blur that limit their use (Hall et ah, Optom. Vis. Sci., 88, pp. 872-880,
2011). Additionally, most commercially available topical ophthalmic formulations have been reported to cause adverse events such as eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching. These adverse effects result in decreased patient compliance. [0004] Thus, there is a need in the art for improved topical ophthalmic compositions that optimize ocular comfort and improve patient compliance by reducing or eliminating the adverse effects commonly associated with currently available commercial ophthalmic formulations, while not compromising therapeutic potency. The present disclosure addresses this need.
Summary of the Invention
[0005] The invention relates to topical ophthalmic compositions comprising one or more active components. The active components in the topical ophthalmic compositions include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I (as defined below), and pharmaceutically acceptable salts thereof. Moreover, the topical ophthalmic compositions include a buffer, have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity enhancing component.
[0006] The invention further provides topical ophthalmic compositions comprising one or more active components. The active components in the topical ophthalmic composition include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof. Moreover, the topical ophthalmic compositions include a buffer, have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps.
[0007] The invention further provides topical ophthalmic compositions comprising one or more active components. The active components in the topical ophthalmic composition include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof. Moreover, the topical ophthalmic compositions include a buffer, have a pH of about about 3.0 to 7.4, or about 3.0 to about 6.0, or 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps without the need for including a viscosity-enhancing agent.
[0008] The invention also provides methods of treating an ocular condition in a subject in need of treatment thereof, comprising administering one or more topical ophthalmic compositions of the invention.
[0009] The invention further provides methods of treating myopia in a subject in need thereof. The method comprises administering to at least one eye of the subject topical ophthalmic compositions comprising atropine and have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity-enhancing component.
[0010] The invention additionally provides methods of improving at least one vision parameter in a subject in need thereof. The methods comprise administering to at least one eye of the subject a topical ophthalmic composition comprising atropine and have a pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5 and do not contain a viscosity-enhancing component. The vision parameter includes, but is not limited to, intermediate vision acuity, distance vision acuity and night vision.
[0011] The invention also provides topical ophthalmic compositions for use in treating, or for preparing a medicament for treating, ocular conditions in a subject in need of treatment thereof, including myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery, presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil or other causes of parasympathetic denervation, complications arising after refractive surgery, decentered ablations following LASIK or PRK, LASIK undercorrections, LASIK overcorrections, corneal scars, hazing, and refractive errors. Detailed Description of the Invention
[0012] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter pertains.
[0013] As used in this specification and the appended claims, the singular forms“a,”“an” and“the” include plural referents unless the context clearly dictates otherwise.
[0014] The invention provides topical ophthalmic compositions comprising one or more active components. The term“topical” as used herein refers to a composition intended for direct application to the corneal surface of an eye of a subject in need thereof. The term topical does not include injections to the eye of a subject ( e.g ., anterior chamber injections).
[0015] The term“ophthalmic composition” or“ophthalmic compositions of the invention” as used herein refers to compositions suitable for application to an eye of a subject, which are in such form as to permit the biological activity of the one or more active components (e.g., atropine) to be effective, and which contain no additional components that are unacceptably toxic to the subject to which the composition would be administered. Such ophthalmic compositions will generally be sterile. Thus, for topical application to the eye, the ophthalmic compositions of the present invention will generally be formulated as sterile aqueous compositions (e.g., suspensions, solutions, emulsions or the like) and typically include at least 70 w/w %, more typically 80 w/w % and even more typically at least 90 or 95 w/w % purified water. Such ophthalmic compositions may be in the form of liquid preparations, e.g., eye drops. The ophthalmic compositions may be suitable for single-dose or multiple-dose topical application. The ophthalmic compositions suitable for multi-dose topical application are often disposed in a dispenser (e.g., an eye dropper), which can dispense the ophthalmic composition (e.g., as individual drops) to the corneal surface of the eye.
[0016] As used herein, the term“active component” refers to a component of the topical ophthalmic compositions of the invention which is responsible for the therapeutic effect of the composition, whereas the other components of the composition (e.g., excipients, carriers, and diluents) are not responsible for the therapeutic effect of the composition, even if they have other functions in the composition which are necessary or desired as part of the formulation (such as lubrication, pH control, emulsification, stabilization, preservation, and other functions). In some embodiments, the active components have therapeutic activity for the treatment of an ocular condition or for improving a vision parameter.
[0017] The active components in the topical ophthalmic compositions of the invention include, but are not limited to atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, pilocarpine, physostigmine, phospholine iodide, aceclidine, and the compound of Formula I. In some embodiments, the topical ophthalmic compositions do not include pilocarpine. In additional
embodiments, the topical ophthalmic compositions do not include physostigmine. In further embodiments, the topical ophthalmic compositions do not include both pilocarpine and physostigmine.
[0018] In some embodiments, the active component or components in the topical ophthalmic compositions of the invention include a compound of Formula I:
Figure imgf000006_0001
Formula I or a pharmaceutically acceptable salt thereof
[0019] In certain embodiments, at least one of the one or more active components in the compositions of the present invention is/are present at a concentration of at least about 0.01% w/w. In other embodiments, at least one of the one or more active components is present at a concentration of less than about 0.01% w/w. In additional embodiments, the one or more active components are each present at a concentration of at least about 0.01% w/w. In certain aspects, at least one of the one or more active components is present at a concentration from about 0.001% w/w to about 20% w/w. In other aspects, the one or more active components are each present at a concentration from about 0.001% w/w to about 20% w/w. In certain aspects, at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 20% w/w. In other aspects, the one or more active components are each present at a concentration from about 0.01% w/w to about 20% w/w. In some embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 10% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to about 10% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 2% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 2% w/w. In certain embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 1.75 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.75% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 1.5 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.5% w/w. In certain
embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 1.25 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1.25% w/w. In additional embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 1% w/w. In further embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 1% w/w. In certain embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 0.50% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.50% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.30% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.30% w/w. In certain
embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 0.10% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.10% w/w to at least about 0.10% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.09% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.09% w/w. In certain
embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 0.07% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.07% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.05% w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.05% w/w. In certain
embodiments, at least one of the one or more active components is present at a
concentration from about 0.01% w/w to at least about 0.04 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.04% w/w. In certain embodiments, at least one of the one or more active components is present at a concentration from about 0.01% w/w to at least about 0.03 % w/w. In other embodiments, the one or more active components are each present at a concentration from about 0.01% w/w to at least about 0.03% w/w. In certain embodiments, at least one of the one or more active components is present at a
concentration from about 0.001% w/w to at least about 0.03 % w/w. In other
embodiments, the one or more active components are each present at a concentration from about 0.001% w/w to at least about 0.03% w/w. In other embodiments, at least one of the one or more active components is present at a concentration of at least about 0.001% w/w, 0.01% w/w, 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.1% w/w, 0.3% w/w, 0.5% w/w, 0.7% w/w, 0.9% w/w, 1.0% w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w and 2% w/w, as well as between any of these concentrations. In other embodiments, the one or more active components is present at a concentration of at least about 0.001% w/w, 0.01% w/w, 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.1% w/w, 0.3% w/w, 0.5% w/w, 0.7% w/w, 0.9% w/w, 1.0% w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w and 2% w/w, as well as between any of these concentrations. In other embodiments, at least one of the one or more active components is present at a concentration from about 1% w/w to about 5% w/w. In other embodiments, the one or more active components are each present at a concentration from about 1% w/w to about 5% w/w.
[0020] The topical ophthalmic compositions may also include pharmaceutically acceptable salts of the active components. As used herein, the term“pharmaceutically acceptable salts” refers to salts of the one or more active agents of the topical ophthalmic compositions of the invention that are substantially non-toxic to living organisms, e.g., subjects in need of the topical ophthalmic compositions. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the one or more active components of the invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the one or more active components of the invention.
[0021] Inorganic acids which may be used to prepare pharmaceutically acceptable salts of the active components include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like. Organic acids which may be used to prepare pharmaceutically acceptable salts include, without limitation, aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl-heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like. Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include, but are not limited to, hydrochloride,
hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate, p- toluenesulfonate, methanesulfonate, and maleate. Suitable pharmaceutically acceptable salts may also be formed by reacting the active components with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like. Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups that may be found on some of the active components and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium. All of these salts may be prepared by conventional means from the active components of the invention by reacting, for example, the appropriate acid or base with the active components of the invention.
[0022] In specific embodiments, the topical ophthalmic compositions of the invention comprise atropine as an active component. In certain aspects, atropine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, atropine is present as a pharmaceutically acceptable salt. In certain cases, the pharmaceutically acceptable salt of atropine includes, without limitation, atropine sulfate, atropine hydrochloride, atropine nitrate, atropine hydrobromide, atropine pyrosulfate, atropine bisulfate, atropine sulfite, atropine bisulfite, atropine hydroiodide, atropine hydrofluoride, atropine acetate, atropine formate, atropine oxalate, atropine citrate, atropine lactate, atropine toluenesulfonate, atropine methanesulfonate, atropine maleate, atropine monohydrogenphosphate, atropine dihydrogenphosphate, atropine metaphosphate, atropine pyrophosphate, and atropine phosphate. In specific
embodiments, atropine is present as atropine sulfate. In some embodiments, when atropine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain embodiments, the ocular condition is myopia.
[0023] In certain aspects, topical ophthalmic compositions of the invention comprise at least about 0.01% w/w atropine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w atropine. In some embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise atropine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise atropine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations. [0024] In other embodiments, the topical ophthalmic compositions of the invention comprise oxymetazoline as an active component. In certain aspects, oxymetazoline is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, oxymetazoline is present as a pharmaceutically acceptable salt. In some embodiments, when oxymetazoline is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions of the invention comprise at least about 0.01% w/w
oxymetazoline. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w oxymetazoline. In some embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise oxymetazoline at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0025] In yet other embodiments, the topical ophthalmic compositions of the invention comprise brimonidine as an active component. In certain aspects, brimonidine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, brimonidine is present as a pharmaceutically acceptable salt. In some embodiments, when brimonidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w brimonidine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w brimonidine. In some embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise brimonidine at a
concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise brimonidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w,
1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0026] In still other embodiments, the topical ophthalmic compositions of the invention comprise epinephrine as an active component. In certain aspects, epinephrine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, epinephrine is present as a pharmaceutically acceptable salt. In some embodiments, when epinephrine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w epinephrine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w epinephrine. In some embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise epinephrine at a
concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic
compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a
concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise epinephrine at a concentration of at least about 0.001% w/w,
0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w,
1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0027] In further embodiments, the topical ophthalmic compositions of the invention comprise clonidine as an active component. In certain aspects, clonidine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, clonidine is present as a pharmaceutically acceptable salt. In some embodiments, when clonidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w clonidine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w clonidine. In some embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise clonidine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise clonidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0028] In additional embodiments, the topical ophthalmic compositions of the invention comprise carbachol as an active component. In certain aspects, carbachol is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, carbachol is present as a pharmaceutically acceptable salt. In some embodiments, when carbachol is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w carbachol. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w carbachol. In some embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise carbachol at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise carbachol at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0029] In other embodiments, the topical ophthalmic compositions of the invention comprise demecarium as an active component. In certain aspects, demecarium is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, demecarium is present as a pharmaceutically acceptable salt. In certain aspects, demecarium is present as demecarium bromide. In some embodiments, when demecarium is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w demecarium. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w demecarium. In some embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise demecarium at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise demecarium at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0030] In other embodiments, the topical ophthalmic compositions of the invention comprise isoflurophate as an active component. In certain aspects, isoflurophate is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, isoflurophate is present as a pharmaceutically acceptable salt. In some embodiments, when isoflurophate is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w isoflurophate. In other aspects, the composition comprises less than about 0.01% w/w isoflurophate. In some embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1% w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise isoflurophate at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0031] In yet other embodiments, the topical ophthalmic compositions of the invention comprise neostigmine as an active component. In certain aspects, neostigmine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, neostigmine is present as a pharmaceutically acceptable salt. In certain aspects, neostigmine is present as neostigmine bromide. In some embodiments, when neostigmine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w neostigmine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w neostigmine. In some embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 1% w/w to about 5% w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise neostigmine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0032] In still other embodiments, the topical ophthalmic compositions of the invention comprise physostigmine as an active component. In certain aspects, physostigmine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, physostigmine is present as a pharmaceutically acceptable salt. In some embodiments, when physostigmine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w physostigmine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w physostigmine. In some embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.2% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.75 % w/w.
In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise physostigmine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0033] In other embodiments, the topical ophthalmic compositions of the invention comprise pilocarpine as an active component. In certain aspects, pilocarpine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, pilocarpine is present as a pharmaceutically acceptable salt. In certain aspects, pilocarpine is present as pilocarpine hydrochloride. In some embodiments, when pilocarpine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain cases, the ocular condition is presbyopia. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w pilocarpine. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w pilocarpine. In some embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 20% w/w. In specific embodiments, the topical ophthalmic compositions comprise pilocarpine at a
concentration from about 0.2% w/w to about 10% w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise pilocarpine at a
concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise pilocarpine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0034] In other embodiments, the topical ophthalmic compositions of the invention comprise phospholine iodide as an active component, an irreversible acetylcholinesterase inhibitor also known as echothiophate iodide. In certain aspects, phospholine iodide is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, phospholine iodide is present as a pharmaceutically acceptable salt.
In some embodiments, when phospholine iodide is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w phospholine iodide. In other aspects, the topical ophthalmic compositions comprise less than about 0.01% w/w phospholine iodide. In some embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 2% w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.20 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise phospholine iodide at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.20% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0035] In other embodiments, the topical ophthalmic compositions of the invention comprise aceclidine as an active component. In certain aspects, aceclidine is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, aceclidine is present as a pharmaceutically acceptable salt. In some embodiments, when aceclidine is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w aceclidine. In other aspects, the composition comprises less than about 0.01% w/w aceclidine. In some embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 4% w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise aceclidine at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.2% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0036] In other embodiments, the topical ophthalmic compositions of the invention comprise Formula I as an active component. In certain aspects, Formula I is the sole active component present in the topical ophthalmic compositions of the invention. In some embodiments, Formula I is present as a pharmaceutically acceptable salt. In some embodiments, when Formula I is part of a topical ophthalmic composition, the compound is the sole active component, which has therapeutic activity for the treatment of an ocular condition or for improving a vision parameter. In certain aspects, the topical ophthalmic compositions comprise at least about 0.01% w/w Formula I. In other aspects, the composition comprises less than about 0.01% w/w Formula I. In some embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 20% w/w. In some embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 10% w/w. In specific embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 5% w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.75 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.5 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.25 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 1.0 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.50 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.09 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.07 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.05 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.04 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.03 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.01% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.02 % w/w. In certain embodiments, the topical ophthalmic compositions comprise Formula I at a concentration from about 0.001% w/w to about 0.01 % w/w. In other embodiments, the topical ophthalmic compositions comprise Formula I at a concentration of at least about 0.001% w/w, 0.01% w/w 0.02% w/w, 0.03% w/w, 0.04% w/w, 0.05% w/w, 0.06% w/w, 0.07% w/w, 0.08% w/w, 0.09% w/w, 0.10% w/w, 0.15% w/w, 0.2% w/w, 0.25% w/w, 0.5% w/w, 1.0 % w/w, 1.25% w/w, 1.5% w/w, 1.75% w/w, and 2% w/w, as well as between any of these concentrations.
[0037] The topical ophthalmic compositions of the invention also include a suitable buffer. As used herein, the term“buffer” refers to a component of a solution that resists changes in pH of the solution when an acid or alkali is added to it. Buffers typically involve a weak acid or alkali together with one of its salts. For example, a buffer may comprise one or more of sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide, or hydrochloric acid. In certain
embodiments, the buffer comprises monobasic and dibasic sodium phosphate. The quality of a buffer is determined by its buffer capacity, i.e. its resistance to changes in pH when strong acids or bases are added. In other words, the buffer capacity corresponds to the amount of H+ or OH- ions that can be neutralized by the buffer. Buffer capacity is related to the buffer concentration. A graph described by the relation of the pH to the addition of H /OH ions is called the titration curve. The point of inflection of the curve corresponds to the pKa value of the buffer. The buffer capacity of a buffer is at its maximum at the pKa value. The pKa value of a buffer therefore corresponds to the mid-point of the pH range covered by the buffer and represents the point at which the concentration of acid and base is the same. In the area of this pH range, therefore, relatively large amounts of H /OH ions result in only small changes in pH. Therefore, a buffer with more than one pKa resists changes to the pH of a solution over a broad range of H+/OH ions. Examples of buffers with more than one pKa include, but are not limited to, citrate buffer and phosphate buffer.
[0038] A buffer suitable for use in the topical ophthalmic compositions described herein is preferably one that stabilizes the stored compositions by maintaining the compositions at a low pH ( e.g ., pH of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5), but that quickly equilibrates to a physiological pH (i.e., the pH of the tear film and/or ocular surface, or a pH of about 7.0) when the compositions are administered to the surface of an eye. Examples of suitable buffers include, but are not limited to borate buffer, borate citrate buffer, lactate buffer and citrate buffer. In specific embodiments, the buffer is a borate buffer.
[0039] In certain embodiments, the buffer is present at a concentration of less than about 0.001 mM. In other embodiments, the buffer is present at a concentration of at least about 0.001 mM. In other embodiments, the buffer is present at a concentration from about 0.01 mM to 1 M. In specific embodiments, the buffer is present at a concentration from about 1 mM to about 200 mM. In additional embodiments, the buffer is present at a
concentration from about 1 mM to about 100 mM.
[0040] A buffer may control the pH of the topical ophthalmic compositions of the invention. In certain embodiments, the topical ophthalmic compositions of the invention have a pH of lower than about 7.4. In other embodiments, the topical ophthalmic compositions of the invention have a pH of lower than about 7.0, lower than about 6.5, lower than about 6.0, lower than about 5.5, lower than about 5.0, lower than about 4.5, lower than about 4.0, lower than about 3.5 lower than about 3.0, lower than about 2.5, lower than about 2.0, lower than about 1.5, or lower than about 1.0. In certain aspects, the pH of topical ophthalmic compositions of the invention is in the range of about 1.0 to about 7.4, or about 1.5 to 7.4 or about 2.0 to about 7.4, or about 2.5 to about 7.4, or about
3.0 to about 7.4, or about 1.0 to about 6.5, or about 1.0 to about 6.0, or about 1.5 to about
6.0, or about 2.0 to about 6.0, or about 2.5 to about 6.0, or about 3.0 to about 6.0, or about 1.0 to about 5.5, or about 1.5 to about 5.5, or about 2.0 to about 5.5, or about 2.5 to about 5.5, or about 3.0 to about 5.5, or about 3.5 to about 5.5, or about 4.0 to about 5.5, or about 4.5 to about 5.5, or about 5.0 to about 5.5, or about 1.0 to 5.0, or about 1.5 to 5.0, or about
2.0 to about 5.0, or about 2.5 to about 5.0, or about 3.0 to about 5.0, or about 3.5 to about
5.0, or about 3.6 to about 5.0, or about 3.7 to about 5.0, or about 3.8 to about 5.0, or about 3.9 to about 5.0, or about 4.0 to about 5.0, or about 4.1 to about 5.0, or about 4.2 to about 5.0, or about 4.3 to about 5.0, or about 4.4 to about 5.0, or 4.5 or about 5.0, or about 4.6 to about 5.0 or about 4.7 to about 5.0, or about 1.0 to about 4.7, or about 1.5 to 4.7, or about 2.0 to about 4.7, or about 2.5 to about 4.7, or about 3.0 to about 4.7, or about 3.5 to about 4.7, or about 3.6 to about 4.7, or about 3.7 to about 4.7, or about 3.8 to about 4.7, or about 3.9 to about 4.7, or about 4.0 to about 4.7, or about 4.1 to about 4.7, or about 4.2 to about 4.7, or about 4.3 to about 4.7, or about 4.4 to about 4.7, or about 4.5 or about 4.7, or about 1.0 to about 4.5, or about 1.5 to 4.5, or about 2.0 to about 4.5, or about 2.5 to about 4.5, or about 3.0 to about 4.5, or about 3.5 to about 4.5, or about 3.6 to about 4.5, or about 3.7 to about 4.5, or about 3.8 to about 4.5, or about 3.9 to about 4.5, or about 4.0 to about 4.5, or about 4.1 to about 4.5, or about 4.2 to about 4.5, or about 4.3 to about 4.5, or about 1.0 to about 4.3, or about 1.5 to 4.3, or about 2.0 to about 4.3, or about 2.5 to about 4.3, or about 3.0 to about 4.3, or about 3.5 to about 4.3, or about 3.3 to about 4.3, or about 3.7 to about 4.3, or about 3.8 to about 4.3, or about 3.9 to about 4.3, or about 4.0 to about 4.3, or about 4.1 to about 4.3, or about 1.0 to about 4.1, or about 1.5 to 4.1, or about 2.0 to about 4.1, or about 2.5 to about 4.1, or about 3.0 to about 4.1, or about 3.5 to about 4.1, or about 3.3 to about 4.1 , or about 3.7 to about 4.1, or about 3.8 to about 4.1 , or about 3.9 to about 4.1 , or about 1.0 to about 3.7, or about 1.5 to about 3.7, or about 2.0 to about 3.7, or about 2.5 to about 3.7, or about 3.0 to about 3.7, or about 3.5 to about 3.7, or about 3.3 to about 3.7, or about 3.5 to about 3.7. In certain embodiments, the pH of topical ophthalmic
compositions of the invention is in the range of about 3.0 to 7.4, or about 3.0 to about 6.0, or about 3.0 to about 5.5. In specific embodiments, the pH of topical ophthalmic compositions of the invention is about 4.5. In specific embodiments, the pH of topical ophthalmic compositions of the invention is about 5.0. In specific embodiments, the pH of topical ophthalmic compositions of the invention is about 6.0. The pH of the ocular topical ophthalmic compositions of the invention unexpectedly reduces or eliminates the incidence of adverse events and/or ocular discomfort commonly associated with commercially available topical ophthalmic compositions. These adverse events include, without limitation, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
[0041] The topical ophthalmic compositions of the invention may or may not contain a secondary buffering agent. In certain aspects, the secondary buffering agent includes, without limitation, citrate buffer and acetate buffer. In certain embodiments, the secondary buffering agent is present at a concentration of at least about concentration of less than about 0.001 mM. In other embodiments, the secondary buffering agent is present at a concentration of at least about 0.001 mM. In some embodiments, the secondary buffering agent is present at a concentration from about 0.01 mM to 1 M. In specific embodiments, the secondary buffering agent is present at a concentration from about 1 mM to about 100 mM.
[0042] Contrary to most currently available commercial topical ophthalmic compositions, specific embodiments of some of the topical ophthalmic compositions of the invention preferably do not contain viscosity enhancing components. As used herein, the term “viscosity” of a topical ophthalmic composition of the invention is used as it normally is used for liquids and means a measure of the liquid’s resistance to deformation at a given rate. Thus, viscosity is a quantity expressing the magnitude of internal friction, as measured by the force per unit area resisting a flow in which parallel layers of the topical ophthalmic compositions, unit distance apart, have unit speed relative to one another. A fluid that has no resistance to shear stress is known as an ideal or inviscid fluid. Zero viscosity is observed only at very low temperatures in superfluids. Otherwise, the second law of thermodynamics requires all fluids to have positive viscosity; such fluids are technically said to be viscous or viscid. A fluid with a relatively high viscosity, such as pitch, may appear to be a solid. In certain embodiments, the topical ophthalmic compositions of the invention have a viscosity from about 1 centipoise (cps) to about 10 cps. In certain aspects, the topical ophthalmic compositions of the invention have a viscosity close to that of pure water (1 cps). In specific aspects, the topical ophthalmic compositions of the invention have a viscosity of about 1 cps.
[0043] As used herein, the term“viscosity enhancing component” refers to any substance that increases the viscosity of the topical ophthalmic compositions of the invention. A viscosity enhancing component may be a polymer including, but not limited to hypromellose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, methylcellulose, methyl cellulose 4000, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906, carboxypropylmethyl cellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, pyrrolidone, polyvinyl pyrrolidone, gellan, carrageenan, alignic acid,
carboxyvinyl polymer, glycerol, acrylic polymers ( e.g ., carbomer, polycarbophil), or combinations thereof. In specific embodiments, the compositions of the present invention do not contain any of the above-listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement. In other specific embodiments, the compositions of the present invention contain only trace amounts of any of the above-listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement.
As used herein, a trace amount means a concentration of about 100 ppm (100 micrograms per gram o 100 micrograms per milliliter) or less. In other specific embodiments, the compositions of the present invention may contain small amounts of any of the above- listed polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement, provided that the viscosity of the resulting composition is about 20 cps or less, about 15 cps or less, about 10 cps or less, about 5 cps or less or about 2 cps or less. In other aspects, a viscosity enhancing component may be non-polymeric including, without limitation, gums, such as hydroxypropyl-guar (hp-guar) and xanthan gum, thickeners, such as alginate,
polysaccharides, such as chitosan and dextran, natural polymers, such as gelrite, glycosaminoglycans, such as hyaluronic acid, or any combination thereof. In specific embodiments, the compositions of the present invention do not contain any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement. In other specific embodiments, the compositions of the present invention contain only trace amounts of any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement. In other specific embodiments, the compositions of the present invention may contain small amounts of any of the above- listed non-polymeric viscosity enhancing agents, even if the compound(s) could be used to serve another purpose other than viscosity enhancement, provided that the viscosity of the resulting composition is about 20 cps or less, about 15 cps or less, about 10 cps or less, about 5 cps or less or about 2 cps or less, or about 1 cps. In other embodiments, the viscosity of the resulting composition is about 20 cps to about 1 cps, or about 15 cps to about 1 cps, or about 10 cps to about 1 cps, or about 8 cps to about 1 cps, or about 6 cps to about 1 cps, or about 5 cps to about 1 cps, or about 4 cps to about 1 cps, or about 3 cps to about 1 cps, or about 2 cps to about 1 cps, or about 10 cps to about 2 cps, or about 8 cps to about 2 cps, or about 6 cps to about 2 cps, or about 5 cps to about 2 cps, or about 4 cps to about 2 cps, or about 3 cps to about 2 cps, or about 10 cps to about 3 cps, or about 8 cps to about 3 cps, or about 6 cps, to about 3 cps, or about 5 cps to about 3 cps, or about 4 cps to about 3 cps, or about 10 cps to about 4 cps, or about 8 cps to about 4 cps, or about 6 cps to about 4 cps, or about 5 cps to about 4 cps, or about 10 cps to about 5 cps.
[0044] The topical ophthalmic compositions of the invention may further include one or more osmolality agents in an amount that renders the topical ophthalmic compositions of the invention roughly isotonic. “Osmolality” is a measure of the total number of dissolved particles in a given volume of a solution. As used here, the term“osmolality agent” include any compound or substance useful for adjusting the osmolality of a topical ophthalmic composition. Examples of osmolality agents include, but are not limited to, salts, particularly sodium chloride or potassium chloride, organic compounds such as propylene glycol, mannitol, sorbitol, dextrose, and glycerin. In certain embodiments, the osmolality agents of the topical ophthalmic compositions of the invention include, but are not limited to, glycerin, propylene glycol, mannitol, sorbitol, sodium chloride, potassium chloride and dextrose.
[0045]“Tonicity” is a measure of the effective osmotic pressure gradient, as defined by the water potential of two solutions separated by a semipermeable membrane. In other words, tonicity is the relative concentration of solutes dissolved in solution which determine the direction and extent of diffusion. The term is commonly used when describing the response of cells immersed in an external solution. Unlike osmotic pressure, tonicity is influenced only by solutes that cannot cross the membrane, as only these exert an effective osmotic pressure. Solutes able to freely cross the membrane do not affect tonicity because they will always be in equal concentrations on both sides of the membrane. There are three classifications of tonicity that one solution can have relative to another: hypertonic, hypotonic, and isotonic. A solution is“isotonic” when its effective osmole concentration is the same as that of another solution. In biology, the solutions on either side of a cell membrane, for example, are isotonic if the concentration of solutes outside the cell is equal to the concentration of solutes inside the cell.
[0046] The amount of osmolality agent may vary depending upon whether the topical ophthalmic compositions are isotonic, hypertonic, or hypotonic. In certain embodiments, the amount of an osmolality agent such as those listed above may be at least about 0.0001% w/w up to about 0.05% w/w, about 0.10% w/w, 0.35% w/w, 0.40% w/w, about 0.50% w/w, about 0.95% w/w, about 1% w/w, about 2% w/w, about 5% w/w, about 10% w/w, or about 20% w/w, as well as between any of these concentrations. In some embodiments, at least one of the one or more osmolality agents is present at a
concentration of at least about 0.0001% w/w. In other embodiments, the one or more osmolality agents are each present at a concentration of at least about 0.0001% w/w. In some embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 20% w/w. In other embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 20% w/w. In additional embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 5% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 5% w/w. In yet other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 2.5% w/w. In additional embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 2.5% w/w. In still other
embodiments, at least one of the one or more osmolality agents is present at a
concentration from about 0.001% w/w to about 1% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 1% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.95% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.95% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.50% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.50% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.40% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.40% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.35% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.35% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.10% w/w. In further embodiments, the one or more osmolality agents are each present at a
concentration from about 0.001% w/w to about 0.10% w/w. In other embodiments, at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 0.05% w/w. In further embodiments, the one or more osmolality agents are each present at a concentration from about 0.001% w/w to about 0.05% w/w.
[0047] The topical ophthalmic compositions of the invention may further include a strong acid or a strong base. Examples of strong acids and strong bases are well known in the art and include, without limitation, NaOH, KOH, HC1, and H2SO4. In specific aspects, the topical ophthalmic compositions of the invention further comprise NaOH or HC1.
[0048] The topical ophthalmic compositions of the invention may be packaged for single use, and contain no preservative or essentially no preservative. Alternatively, the topical ophthalmic compositions of the invention may be packaged for multiple uses, and comprise a suitable preservative to prevent contamination over multiple uses. As used herein, the term“preservative” means any substance that prevents or retards contamination in the form of bacterial or fungal growth in the topical ophthalmic solutions of the invention. Examples of suitable preservatives include, but are not limited to,
benzalkonium chloride (BAK), Polyquaternium-1 (Poly quad®), chlorobutanol, stabilized chlorine dioxide, and a stabilized oxychloro complex comprising chlorite, chlorate and chlorine dioxide. Stabilized chlorine dioxide, also known as Purite®, may be described as an aqueous solution of sodium chlorite (NaCICh). U.S. Patent Number 5,424,078, which is incorporated herein by reference in its entirety, further discusses the use of stabilized chlorine dioxide as a preservative for topical ophthalmic compositions.
[0049] In certain embodiments, the preservative is present at a concentration of at least about 1 ppm. In other embodiments, the preservative is present at a concentration of less than about 1 ppm. In some aspects, the preservative is present at a concentration from about 1 ppm to about 1000 ppm. In other aspects, the preservative is present at a concentration from about 10 ppm to about 300 ppm. In specific embodiments, the preservative is present at a concentration from about 10 ppm to about 200 ppm. In certain aspects, the preservative is present at a concentration of at least about 0.001% w/w. In specific aspects, the preservative is present at a concentration of at least about 0.0075% w/w. While chelators such as EDTA (ethylenediaminetetraacetic acid) may be used in certain embodiments, these may sometimes show poor tolerability. Accordingly, certain embodiments of preferred compositions do not include chelators such as EDTA. The topical ophthalmic compositions of the present invention may be prepared by techniques known to those skilled in the art. The topical ophthalmic compositions of the invention may be an aqueous solution, emulsion or suspension or may be a dried preparation. In some aspects, the topical ophthalmic compositions of the invention may be desiccated or lyophilized, for example, by freeze-drying or spray drying for storage or formulations purposes. In certain aspects, a solid composition of the invention is subsequently reconstituted into liquid compositions by the addition of an appropriate liquid carrier prior to administering to a subject in need thereof.
[0050] The topical ophthalmic compositions of the invention may be administered at several intervals in order to sustain therapeutic levels. For example, the topical ophthalmic compositions of the invention may be administered once daily, twice daily (BID), four times daily (QID) or more. In some embodiments, the topical ophthalmic compositions of the invention are administered once daily. In other embodiments, the topical ophthalmic compositions of the invention are applied twice daily. In certain aspects, the topical ophthalmic compositions of the invention have a duration of action of at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, at least about 10 hours, at least about 11 hours, at least about 12 hours, at least about 24 hours, as well as all intervening time points. In specific embodiments, the topical ophthalmic compositions of the invention have a duration of action greater than 10 hours, for example 12 hours, or even 24 hours. The“duration of action” refers to the duration of time that an administered topical ophthalmic composition has an effect on at least one vision parameter or ocular condition ( e.g ., myopia) in a subject in need thereof.
[0051] The invention further relates to methods of treating an ocular condition in a subject in need of treatment thereof, comprising administering one or more topical ophthalmic compositions of the invention. As used herein, the term“treating” refers to both therapeutic measures and prophylactic or preventative measures, wherein the objective is to prevent, slow down (lessen), or ameliorate an undesired ophthalmic change or condition or disorder, such as the progression of myopia. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishing the extent of disease, stabilized (i.e., not worsening) state of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, and reversing the disease (whether partial or total). [0052] As used herein, the term“ocular condition” may refer to any condition, disease, or impairment, which affects or involves the eye or one of the parts or regions of the eye, and includes optical issues causing refractive errors in the eye. Ocular conditions include, but are not limited to myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery ( e.g ., glare, halos or starbursts around lights), presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil, or other causes of parasympathetic denervation, complications arising after refractive surgery, such as decentered ablations following LASIK or PRK, LASIK undercorrections, LASIK overcorrections, corneal scars, hazing, and refractive errors.
[0053] As used herein, the term“subject” refers to any individual, e.g., a mammal, for whom diagnosis, prognosis, or therapy is desired. The term“subject” may mean a human or non-human mammal affected, likely to be affected, or suspected to be affected with an ocular condition or disease. Although the topical ophthalmic compositions provided herein are principally directed to compositions which are suitable for administration to humans, the skilled artisan will understand that such compositions are generally suitable for administration to subjects of all sorts. In certain aspects, the subject is a mammal. In some aspects, a mammal includes, without limitation, primates, such as humans, monkeys and apes, and non-primates such as domestic animals, including laboratory animals, sports animals, farm animals, and household pets (e.g., cats, dogs, swine, cattle, cows, sheep, goats, horses, guinea pigs, rabbits, rats, mice), and non-domestic animals, such as wildlife, birds, or the like.
[0054] As used herein, the term“a subject in need thereof’ includes subjects, such as mammalian subjects, that would benefit from administration of a topical ophthalmic composition of the invention. Subjects in need of treatment include, without limitation, those already with the condition or disorder as well as those prone to having the condition or disorder, or those in which the condition or disorder is to be prevented, ameliorated, or reversed. [0055] The term“administer,” or“administering” as it applies to, for example, a subject in need of the topical ophthalmic compositions of the invention, refers to contact of, for example, the topical ophthalmic composition of the invention to at least one eye of the subject. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of the topical ophthalmic compositions of the invention to the cell, as well as contact of the topical ophthalmic compositions of the invention with a fluid, where the fluid is in contact with the cell.
[0056] This invention has numerous advantages. For example, the topical ophthalmic compositions of the present invention have good stability. A“stable” composition is one which retains physical and/or chemical stability upon storage. The storage period is generally selected based on the intended shelf-life of the composition. Various analytical techniques for measuring stability are available in the art, such as the procedure and methods outlined in Example 4. Stability can be measured at a selected temperature and relative humidity (“RH”) for a selected time period, for example at 5°C, 25°C/40% RH, and 40°C/25% RH for 1 month, or 2 months, or 3 months, or 6 months, or 10 months, or 12 months, or 18 months, or 24 months, or 36 months, or any other time period
(intervening or otherwise). Tests may be conducted at ambient humidity, no humidity, and ranges from 0-100% relative humidity, including for example 25% or 40% RH.
[0057] A stable composition in accordance with the present invention can be substantially clear and colorless at temperatures of, for example, 5°C, 25° C, and 40°C, for durations of time of, for example, 1 month, or 2 months, or 3 months, or 6 months, or 10 months, or 12 months, or 15 months, or 18 months, or 24 months, or 30 months, or 36 months.
[0058] A stable composition in accordance with the present invention may exhibit only a slight decrease in pH throughout the storage duration, thereby maintaining its desired therapeutic effect. For instance, at 5°C, the pH may decrease by only about 4% or less (e.g., about 1% to about 4%, or about 2% to about 3.75%, or about 2.25% to about 3.6%) after 6 months. For example, at 5°C, the pH may decrease by only about 7.25% or less (e.g., about 1.5% to about 7.25%, or about 2.5% to about 7%, or about 3% to about 6.5%) after 12 months. For example, at 25°CRH, the pH may decrease by only about 12% or less (e.g., about 3% to about 12%, or about 4% to about 11%, or about 5% to about 10%) after 6 months. For example, at 25°C/40% RH, the pH may decrease by only about 16% or less (e.g., about 3% to about 16%, or about 4.5 to about 15.5%, or about 6% to about 15%) after 12 months. For example, at 40°C, the pH may decrease by only about 13.5% or less (e.g., about 1% to about 13.5%, or about 2.5% to about 13%, or about 4% to about 12.5%) after about 3 months. For example, at 40°C/25% RH, the pH may decrease by only about 17.5% or less (e.g., about 5% to about 17.5%, or about 5.5% to about 17%, or about 6.5% to about 16.5%) after 6 months.
[0059] A stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.2 to about 4.7, or about 4.3 to about 4.7, or about 4.4 to about 4.7 or about 4.5 to about 4.7 at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months. A stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.2 to about 4.7, or about 4.3 to about 4.6, or about 4.4 to about 4.6 at 25°C after 6 or 12 months. A stable composition in accordance with the present invention may have pH of about 4.0 to about 4.8, or about 4.0 to about 4.7, or about 4.1 to about 4.6, or about 4.1 to about 4.5 at 40°C after 3 or 6 months.
[0060] A stable composition in accordance with the present invention may exhibit only a slight increase in osmolality throughout the storage duration. At 5°C, the osmolality can increase by only about 1.25% or less (e.g., about 0.25% to about 1.25%, or about 0.3% to about 1.1%, or about 0.35% to about 1.05% after 6 months. At 5°C, the osmolality can increase by only about 0.85% or less (e.g., about 0.25% to about 0.85%, or about 0.30% to about 0.80%, or about 0.35% to about 0.75%) after 12 months. At 25°C/, the osmolality can increase by only about 2.35% or less (e.g., about 0.8% to about 2.35%, or about 0.9% to about 2.25%, or about 1% to about 2.15%) after 6 months. At 25°C, the osmolality can increase by only about 2.35% or less (e.g., about 1% to about 2.35%, or about 1.2% to about 2.25%, or about 1.4% to about 2.15%) after 12 months. At 40°C, the osmolality can increase by only about 4% or less (e.g., about 1.5% to about 4%, or about 1.6% to about 3.5%, or about 1.75% to about 3.25%) after 3 months. At 40°C, the osmolality can increase by only about 6.0% or less (e.g., about 3% to about 6.0%, or about 3.5% to about 5.8%, or about 3.75% to about 5.7%) after 6 months.
[0061] A stable composition in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 290 mOsm/kg, or about 282 mOsm/kg to about 289 mOsm/kg, or about 284 mOsm/kg to about 298 mOsm/kg, or about 285 mOsm/kg to about 287 mOsm/kg at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months. A stable composition in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 292 mOsm/kg, or about 282 mOsm/kg to about 291 mOsm/kg, or about 284 mOsm/kg to about 290 mOsm/kg at 25°C after 6 months or 12 months. A stable formulation in accordance with the present invention may have an osmolality of about 280 mOsm/kg to about 305 mOsm/kg, or about 282 mOsm/kg to about 303 mOsm/kg, or about 286 mOsm/kg to about 300 mOsm/kg, or about 289 mOsm/kg to about 300 mOsm/kg at 40°C after 6 months or 12 months.
[0062] A stable composition in accordance with the present invention may result in formation of only a very amount of total impurities during storage. In an embodiment, the total impurities are about 0.30% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10% w/w or less, at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months. In an embodiment, the total impurities are about 0.40% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10% w/w or less, at 5°C after 12 months. In an embodiment, the total impurities are about 1% w/w or less, or about 0.9% w/w or less, or about 0.8% w/w or less, or about 0.6% w/w or less, at 25°C after 6 months. In an embodiment, the total impurities are about 2% w/w or less, or about 1.75% w/w or less, or about 1.6% w/w or less, or about 1.5% w/w or less, or about 1.3% w/w or less, at 25°C after 12 months. In an embodiment, the total impurities are about 2.1%, w/w or less, or about 2% w/w or less, or about 1.75% w/w or less, or about 1.5% w/w or less, at 40°C after 3 months. In an embodiment, the total impurities are about 4% w/w or less, or about 3.8% w/w or less, or about 3.5% w/w or less, or about 3.1% w/w or less, or about 3% w/w or less, or about 2.75% w/w or less at 25°C after 12 months. [0063] A stable composition in accordance with the present invention that contains atropine may result in formation of only a slight amount of tropic acid. In an embodiment, the total amount of tropic acid in the composition is about 0.25% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10%, w/w or less, or about 0.06% w/w or less, at 5°C after 6 months, or 12 months, or 18 months, or 24 months, or 36 months. In an embodiment, the total amount of tropic acid in the composition is about 0.30% w/w or less, or about 0.20% w/w or less, or about 0.15% w/w or less, or about 0.10%, w/w or less, or about 0.09% w/w or less, at 5°C after 12 months. In an
embodiment, the total amount of tropic acid in the composition about 0.35% w/w or less, or about 0.32% w/w or less, or about 0.29% w/w or less, or about 0.25% w/w or less, at 25°C/ after 6 months. In an embodiment, the total amount of tropic acid in the
composition is about 0.60% w/w or les, or about 0.55% w/w or less, or about 0.50% w/w or less, or about 0.48% w/w or less, or about 0.45% w/w or less, at 25°C after 12 months. In an embodiment, the total amount of tropic acid in the composition is about 0.70% w/w or less, or about 0.66% w/w or less, or about 0.60% w/w or less, or about 0.55% w/w or less, or about 0.52% w/w or less, or about 0.50% w/w or less at 40°C after 3 months. In an embodiment, the total amount of tropic acid in the composition is about 1.2% w/w or less, or about 1% w/w or less, or about 0.90% w/w or less, or about 0.80% w/w or less, or about 0.75% w/w or less, at 40°C after 6 months.
[0064] In certain embodiment, a stable composition in accordance with the present invention may include at least one preservative, such as benzalkonium chloride (BAK). In an embodiment the amount thereof remains unchanged when stored for 6 months at 5°C, 25°C, and 40°C. In an embodiment, the amount of benzalkonium chloride (as % w/w of the composition) may increase or decrease by only about 4% or less (e.g., about 0.1% to about 4%, or about 0.2% to about 3.95%) when stored for 6 months at 5°C, 25°C/40%
RH, and 40°C/25% RH. In another embodiment, the amount of benzalkonium chloride may be at least about 0.0060% w/w, or about 0.0065% w/w, or about 0.0066% w/w, or about 0.0067% w/w, about 0.0068% w/w, or about 0.0069% w/w, or about 0.0071 % w/w when stored for 6 months at 5°C, 25°CRH, and 40°C. [0065] In certain embodiments, the topical ophthalmic compositions of the invention are administered to only one eye of a subject in need thereof. In other embodiments, the topical ophthalmic compositions of the invention are administered to at least one eye of a subject. In yet other embodiments, the topical ophthalmic compositions of the invention are administered to both eyes of a subject.
[0066] Normally a subject has a dominant eye and a non-dominant eye. The“dominant eye” is the eye that has a greater visual acuity and, therefore, dominates the depth vision. The“non-dominant eye” usually dominates the peripheral and spatial vision. Their interaction causes the brain to receive a three-dimensional image. Usually the dominant eye is the eye that is used to look through a microscope, a camera, or for any task in which only one eye is used. In certain embodiments, the topical ophthalmic compositions of the invention are administered to a non-dominant eye of a subject. In other embodiments, the topical ophthalmic compositions of the invention are administered to a dominant eye of a subject. In yet other embodiments, the topical ophthalmic compositions of the invention are administered to both the non-dominant eye and the dominant eye of the subject.
[0067] When administered to subjects, the topical ophthalmic compositions of the invention do not cause, or do not significantly cause vision blur when administered to a subject in need thereof. Additionally, when administered to subjects, the topical ophthalmic compositions of the invention do not cause, or do not significantly cause one or more one adverse effect that include, but are not limited to, ocular blurring, ocular discomfort, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
[0068] In certain embodiments, the topical ophthalmic compositions of the invention reduce incidence of at least one adverse effect compared to topical administration of a second ophthalmic composition comprising a viscosity-enhancing component and one or more active components selected from the group consisting of atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, pilocarpine, physostigmine, and any pharmaceutically acceptable salt thereof. In certain cases, the adverse effects include, without limitation, ocular blurring, ocular discomfort, eye pain, brow ache, blurry vision, light sensitivity, ocular stinging, and ocular itching.
[0069] In certain aspects, the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to the reduced viscosity of the compositions. In other aspects, the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to the acidic pH of the compositions. In yet other aspects, the improved comfort associated with administering the topical ophthalmic compositions of the invention is due to both the reduced viscosity and the acidic pH of the compositions.
[0070] The invention additionally relates to methods of treating myopia in a subject in need thereof, comprising administering to at least one eye of the subject one or more topical ophthalmic compositions of the invention.
[0071]“Myopia” or nearsightedness is a vision condition in which people can see close objects clearly, but objects farther away appear blurred. Myopia occurs if the eyeball is too long or the cornea (the clear front cover of the eye) is too curved. As a result, the light entering the eye is not focused correctly, and distant objects look blurred. Myopia affects nearly 30 percent of the U.S. population. While the exact cause of myopia is unknown, there is significant evidence that many people inherit myopia, or at least the tendency to develop myopia. If one or both parents are nearsighted, there is an increased chance their children will be nearsighted. Even though the tendency to develop myopia may be inherited, its actual development may be affected by how a person uses his or her eyes. Individuals who spend considerable time reading, working at a computer, or doing other intense close visual work may be more likely to develop myopia. Generally, myopia first occurs in school-age children. Because the eye continues to grow during childhood, it typically progresses until about age 20. However, myopia may also develop in adults due to visual stress or health conditions such as diabetes.
[0072] The invention further provides methods of improving at least one vision parameter in a subject in need thereof, comprising administering to at least one eye of the subject one or more topical ophthalmic compositions of the invention. As used herein, the term “vision parameter” refers to any characteristic in a subject’s vision that may be measured and is susceptible to being improved by the topical ophthalmic compositions and methods described herein. Vision parameters include, but are not limited to, near vision acuity, intermediate visual acuity, distance visual acuity, night vision, day vision, optical aberrations ( e.g ., glare, light scattering), and uncorrected refractive errors. Additional examples of vision parameters include, without limitation, night time glare, post-LASIK “star burst” glare, visual“halos” seen around light sources, and accommodative insufficiency.
[0073]“Improving vision parameter,” includes, but is not limited to, near, intermediate, and/or distance visual acuity, and may for example be reflected in the increase of number of letters correctly read at any time point post dosing, the increase in the average letter change, or 2-line or 3 -line improvement, all from baseline (i.e., from pre-treatment).
Night vision improvement may be reflected in visual improvement for subjects in dim or dark lighting (e.g., under mesopic or scotopic conditions). Day vision improvement may be reflected in visual improvement for subjects in bright lighting as found during daylight hours or in sunshine (e.g., under photopic conditions). Vision improvement using the methods described herein may also be achieved in combination with or when using other visual aids and devices (e.g., those used for treating myopia), including but not limited to reading glasses, lens modifying medications, and surgical myopic options.
[0074] In certain embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected near visual acuity (UNVA). As used herein, the term“photopic” vision is the vision of the eye under well-lit conditions (luminance level 10 to 108 cd/m2). In humans and other animals, photopic vision allows color perception, mediated by cone cells, and a significantly higher visual acuity and temporal resolution than available with scotopic vision (the vision of the eye under low- light conditions; luminance level 10 3 to 10 6 cd/m2).
[0075] As used herein, the term“uncorrected near visual acuity” (UNVA) refers to a subject’s ability, without any vision aid (such as eyeglasses or contact lenses), to see the details of objects within arm’s distance from the body (e.g., at 33-41 cm away from the eye).
[0076] In some embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast UNVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast UNVA.
[0077] The term“improvement from baseline” refers to the increase from pre-treatment in the number of letters correctly read at certain post treatment time point. As used herein, the term“2-line improvement from baseline” or“3 -line improvement from baseline” or similar improvement from baseline refers to a subject’s ability to read 2 or 3 more lines of letters on a standard chart (e.g., Snellen, ETDRS, Logarithmic Visual Acuity Chart, etc.) after treatment with a topical ophthalmic composition of the invention when comparing to the number of lines readable before treatment.
[0078] In certain embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast UNVA. As used herein, the term“mesopic” vision refers to a combination of photopic vision and scotopic vision in low but not quite dark lighting situations. Mesopic light levels range from luminances of approximately 0.001 to 3 cd m-2. Most night-time outdoor and traffic lighting scenarios are in the mesopic range. The human eye uses scotopic vision under low-light conditions and mesopic vision in intermediate conditions. Humans see differently at different light levels. This is because under high light levels typical during the day (photopic vision), the eye uses cones to process light. Under very low light levels, corresponding to moonless nights without electric lighting (scotopic vision), the eye uses rods to process light. At many night-time levels, a combination of both cones and rods supports vision. Photopic vision facilitates excellent color discrimination ability, whereas colors are indiscriminable under scotopic vision. Mesopic vision falls between these two extremes. In most night time environments, there is enough ambient light at night to prevent true scotopic vision. [0079] In some embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast UNVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast UNVA.
[0080] In certain embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected distance visual acuity (UDVA). As used herein, the term“uncorrected distance visual acuity” (UDVA) refers to a subject’s ability, without any vision aid (such as eyeglasses or contact lenses), to see the details of objects beyond arm’s distance from the body (e.g., greater than 4 meters away from the eye).
[0081] In some embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast UDVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast UDVA.
[0082] In certain embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast distance-corrected near visual acuity (DCNVA).
As used herein, the term“distance corrected near visual acuity” (DCNVA) refers to a subject’s ability to see the details of objects within arm’s distance from the body (e.g., at 33-41 cm away from the eye), with the use of vision aids such as eyeglasses or contact lenses that correct for distance vision issues.
[0083] In some embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast DCNVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast DCNVA. In yet other embodiments, methods described herein result in an at least 3 -line improvement from baseline under the condition of photopic, high contrast DCNVA. In additional embodiments, methods described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast DCNVA. In further embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast DCNVA.
[0084] In certain embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 2-line improvement from baseline under the condition of mesopic, high contrast distance-corrected intermediate visual acuity (DCIVA). As used herein, the term“distance-corrected intermediate visual acuity” (DCIVA) may be used to refer to a subject’s ability to see the details of objects at intermediate distances with the use of vision aids such as eyeglasses or contact lenses that correct for distance vision issues.
[0085] In some embodiments, methods of treatment using the topical ophthalmic compositions described herein result in an at least 3-line improvement from baseline under the condition of mesopic, high contrast DCIVA. In other embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of mesopic, high contrast DCIVA. In yet other embodiments, methods described herein result in an at least 2-line improvement from baseline under the condition of photopic, high contrast DCIVA. In additional embodiments, methods described herein result in an at least 3-line improvement from baseline under the condition of photopic, high contrast DCIVA. In further embodiments, methods described herein result in an increase in the average letter change from baseline under the condition of photopic, high contrast DCIVA.
Examples
[0086] Example 1: Topical Ophthalmic Compositions of the Invention
[0087] The following Tables list the components of the topical ophthalmic compositions of the invention. [0088] Table 1: Active Ingredients: the topical ophthalmic compositions of the invention may contain one or more of the drug substances listed below.
Figure imgf000052_0001
[0089] Table 2: Buffers: the topical ophthalmic compositions of the invention may contain any one of the buffers listed below.
Figure imgf000052_0002
[0090] Table 3: Secondary buffering agents: the topical ophthalmic compositions of the invention may or may not contain any one of the secondary buffering agents listed below.
Figure imgf000053_0001
[0091] Table 4: Osmolality agents: the topical ophthalmic compositions of the invention may contain one or more osmolality agents listed below.
Figure imgf000053_0002
[0092] The one or more osmolality agents are used in an amount that renders the topical ophthalmic compositions of the invention roughly isotonic.
[0093] Table 5: Preservatives: the topical ophthalmic compositions of the invention may or may not contain any one or a combination of preservatives listed below.
Figure imgf000053_0003
[0094] Examples of topical ophthalmic compositions of the invention include any combinations of active ingredients, buffers, secondary buffering agents, osmolality agents and/or preservatives taken from Table 1-5, such that the topical ophthalmic compositions preferably have a low pH when stored, but will quickly equilibrate to a physiological pH (such as that of the tear film) and/or become roughly isotonic when applied to surface of the eye.
[0095] Example 2 Exemplary Formulations
[0096] The following Tables disclose exemplary topical ophthalmic formulations.
[0097] Table 6: Atropine Formulation 1
Figure imgf000054_0001
[0098] Table 7: Atropine Formulation 2
Figure imgf000054_0002
[0099] Table 8: Atropine Formulation 3
Figure imgf000054_0003
[00100] Table 9: Atropine Formulation 4
Figure imgf000055_0001
[00101] Table 10: Pilocarpine Formulation 5
Figure imgf000055_0002
[00102] Table 11: Pilocarpine Formulation 6
Figure imgf000055_0003
[00103] Table 12: Pilocarpine Formulation 7
Figure imgf000056_0001
[00104] Example 3 Simulated Tear Fluid Study with Pilocarpine Solutions
[00105] 1. Introduction
[00106] The quantity of simulated tear fluid (STF) required to bring the pH of a sample of pilocarpine solution to near neutral was compared for two pilocarpine samples, Formula A and Formula B (containing 1.25% and 1.0% w/w pilocarpine, respectively, as described in Formulations 5 and 6 above), and a marketed comparator of 1.0% w/w pilocarpine containing hydroxy propyl methyl cellulose (hypromellose 2910), a viscosity-enhancing polymer (Isoptocarpine®, Alcon), as described below in Table 13. The time taken to reach an equilibrated pH following mixing of the pilocarpine solution with equal volume of STF was also noted for each sample.
[00107] Table 13: Materials used
Figure imgf000056_0002
Figure imgf000057_0001
[00108] Simulated tear fluid (STF) was prepared using sodium chloride (0.9% w/w), calcium chloride dihydrate (0.015% w/w), sodium phosphate dibasic heptahydrate (0.028% w/w), human lysozyme (0.19% w/w), bovine albumin (0.020% w/w), bovine submaxillary mucin (0.020% w/w), human gamma globulin (0.010% w/w), and water, with a pH of 7.2.
[00109] 2. Methods
[00110] 2.1. Titration Experiment
[00111] Titration of STF solution into a sample of pilocarpine solution was used to determine the quantity of STF needed to neutralize the pH of the drug solution. A small quantity of pilocarpine solution (1 gram) was aliquoted in a glass beaker with a small stir bar and mixed gently (120 rpm). STF was gradually titrated in to the beaker and the pH was continuously monitored. The final quantity of STF added to reach pH 6.75 was noted for each sample.
[00112] 2.2. Equilibration Time
[00113] The time required for the pH of a 1 : 1 mixture of pilocarpine solution and STF to equilibrate was measured. A small volume of pilocarpine solution (250 pL) was pipetted at the bottom of a sample cup and to that was added 250 pL of STF on top. A micro pH probe was inserted into the sample cup to the bottom to record the pH. After monitoring for 5 min, the pH reached was noted.
[00114] 3. Results
[00115] As shown in Table 14, for each of the three pilocarpine solutions titrated with STF, there was no significant difference in quantity of STF needed to reach a final pH of 6.75. A 30 to 32-fold dilution with STF was required in each case. [00116] Table 14: Results of the titration experiment
Figure imgf000058_0001
[00117] As shown in Table 15, the time needed for Formula A and STF mixture to equilibrate to a final pH however was much shorter as compared to the Sandoz product. Formula A required less than a minute (approximately 15 - 20 seconds) to reach the final pH while the pH of the Sandoz product had not yet equilibrated up to 5 minutes after addition of the STF to it.
[00118] Table 15: Results of the equilibration time experiment
Figure imgf000058_0002
There was no significant difference between Formula A, Formula B, and the Sandoz product in the quantity of STF needed to reach a final pH of 6.75. However, the time needed for Formula A to equilibrate to a final pH however was much shorter (approximately 15 - 20 seconds) as compared to the Sandoz product (greater than 5 minutes). [00119] Example 4 Simulated Tear Fluid Study with Atropine Solutions
[00120] 1. Introduction
[00121] The time taken to reach an equilibrated pH following mixing of an atropine solution with simulated tear fluid (STF) was compared for an atropine sample of 1% w/w atropine sulfate, Formula C, and a marketed comparator, Isopto Atropine with 1% w/w atropine sulfate and hydroxy propyl methyl cellulose, a viscosity enhancing polymer (Table 16).
[00122] Table 16: Materials used
Figure imgf000059_0001
[00123] Table 17: Atropine Formulation C
Figure imgf000059_0002
[00124] 2. Methods
[00125] 2.1. Equilibration Time [00126] The time required for the pH of a mixture of atropine solution and STF to equilibrate was measured. A small volume of atropine solution (250 pL) was pipetted at the bottom of a 15 mL centrifuge tube. A micro pH probe was inserted into the sample at the bottom of the centrifuge tube to record the pH. Approximately 7.5 mL of STF was gently added to the centrifuge tube. No mixing was conducted. The pH was monitored for 20 minutes.
[00127] 3. Results
[00128] As shown in Table 18, the time needed for Formula C and STF mixture to equilibrate to a final pH was much shorter as compared to the Isopto atropine product. Formula C required approximately a minute to reach the final pH, while the pH of the commercial Isopto atropine product had not yet equilibrated up to 20 minutes after addition of the STF to it.
[00129] Table 18: Results of the equilibration time experiment
Figure imgf000060_0001
[00130] Thus, the time needed for Formula C to equilibrate to a final pH was much shorter (less than one minute) as compared to the commercial Isopto Atropine product (greater than 5 minutes).
[00131] Example 5: Stability Tests for Atropine Formulations [00132] 1. Introduction
[00133] The following Table discloses exemplary topical ophthalmic formulations containing atropine as the active ingredient. [00134] Table 19: Atropine Formulations
Figure imgf000061_0001
[00135] The ingredients listed in each formulation described above were dissolved in purified water at room temperature using low shear impeller mixer. The pH of each formulation was adjusted with IN HC1 and/or IN NaOH prior to QS step with purified water to target a formulation of pH 4.5. The formulations were then passed through sterile fdtration with 0.2 micron PES membrane into sterile containers for a final bulk formulation.
[00136] The formulation was filled at 5mL and lOmL fill volume into 5mL multi-dose and lOmL multi-dose preservative free (MDPF) container closure system, respectively. The container closure information for Formulation I and II are detailed in Table 20.
[00137] Table 20: Container Closure Information
Figure imgf000062_0001
[00138] The container closure information for Formulation III is detailed in Table 21.
[00139] Table 21: Container Closure Information
Figure imgf000062_0002
[00140] 2. Methods
[00141] The bottled samples of Formulations I-III were used in a stability study evaluation. Samples were placed at 5°C, 25°C/40% RH, and 40°C/25% RH. The 5°C and 25°C/40% RH storage conditions were selected as potential long term storage conditions while the 40°C/25% RH storage condition was selected as an accelerated condition.
Samples were pulled from the storage conditions and tested at designated intervals as detailed in Tables 22 and 23. [00142] Table 22: Tests and Stability Intervals for the 5°C and 25°C/40% RH Storage Conditions
Figure imgf000063_0001
a Formulation III only.
X denotes that stability testing was performed at this time interval
— denotes that no stability testing was performed at this time interval
[00143] Table 23: Tests and Stability Intervals for the 40 °C/25% RH Storage Conditions
Figure imgf000063_0002
a Formulation III only.
X denotes that stability testing was performed at this time interval
— denotes that no stability testing was performed at this time interval
[00144] The techniques and methods used for the analysis of the Atropine Sulfate 0.03% ophthalmic solutions are detailed in Table 24. [00145] Table 24: Techniques and Methods used for the Analysis of Atropine Sulfate 0.03% (w/w) Ophthalmic Solutions
Figure imgf000064_0001
[00146] 3. Results
[00147] Stability data generated for Formulations I-III.
[00148] Table 25: Stability Data for Formulation I at 5 °C
Figure imgf000065_0001
[00149] Table 26: Stability Data for Formulation I at 25°C/40% RH
Figure imgf000065_0002
[00150] Table 27: Stability Data for Formulation I at 40°C/25% RH
Figure imgf000066_0001
[00151] Table 28: Stability Data for Formulation II at 5°C
Figure imgf000066_0002
[00152] Table 29: Stability Data for Formulation II at 25°C/40% RH
Figure imgf000067_0001
[00153] Table 30: Stability Data for Formulation II at 40°C/25% RH
Figure imgf000067_0002
[00154] Table 31: Stability Data for Formulation III at 5°C
Figure imgf000068_0001
[00155] Table 32: Stability Data for Formulation III at 25°C/40% RH
Figure imgf000068_0002
[00156] Table 33: Stability Data for Formulation III at 40°C/25% RH
Figure imgf000069_0001
[00157] 3.1. Physical Appearance
[00158] No changes were observed in the physical appearance of Formulation I-III at 5°C and 25°C/40% RH through 12 months or at 40°C/25% RH through 6 months. All three formulations were reported as clear, colorless solutions through the periods of study.
[00159] 3.2. pH
[00160] Each of Formulations I-III exhibited a downward trend in pH at all storage conditions (5°C, 25 °C/40% RH, and 40°C/25% RH) through the study durations.
Formulation I had an initial (To) pH of 4.74, which decreased to 4.52 at the 5°C, 12 month time point, to 4.41 at the 25°C/40% RH, 12 month time point and to 4.37 at the 40°C/25% RH, 6 month time point. Formulation II had an initial (To) pH of 4.80, which decreased to 4.64 at the 5°C, 12 month time point, to 4.51 at the 25°C/40% RH, 12 month time point and to 4.49 at the 40°C/25% RH, 6 month time point. Formulation III had an initial (To) pH of 4.79, which decreased to 4.48 at the 5°C, 12 month time point, to 4.07 at the 25°C/40% RH, 12 month time point and to 4.00 at the 40°C/25% RH time point. [00161] 3.3. Osmolality
[00162] At 5°C, the osmolality of each of Formulations I-III remained relatively unchanged compared to the initial/To time point through 12 months with values for all three Formulations ranging from 283 to 287 mOsm/kg. Slight increases in osmolality were observed for each of Formulations I-III through 12 months at 25°C/40% RH
(Formulations I and II both increased from 284 to 290 mOsm/kg while Formulation III increased from 284 to 288 mOsm/kg) and through 6 months at 40°C/25% RH
(Formulation I increased from 284 to 295 mOsm/kg while Formulations II and III both increased from 284 to 300 mOsm/kg).
[00163] 3.4. Atropine Assay and Impurities
[00164] The Atropine assay for each of Formulations I-III remained relatively unchanged compared to the initial/To time point through 12 months at 5°C and 25 °C/40% RH. Small increases in Atropine assay were observed through 6 months at 40°C/25% RH for Formulation I (97.6% to 99.7% (w/w)), Formulation II (97.5% to 100.9% (w/w)) and Formulation III (98.8% to 101.7% (w/w)). An upward trend in Tropic Acid (the primary known impurity of Atropine Sulfate) was observed at all three storage conditions for all three lots; the results are summarized in the Table 31.
[00165] Table 34: Tropic Acid Impurity Levels in Atropine Sulfate 0.03% (w/w) Ophthalmic Solutions
Figure imgf000071_0001
'The final time point for the 5 °C and 25 °C/60% RH storage conditions was 12 months and the final time point for the
40 °C/75% RH storage condition was 6 months.
[00166] The total impurities for each of Formulations I-III were observed to increase relative to the increase in the number of impurities other than tropic acid through the periods of study at both 25°C/40% RH and 40°C/25% RH. At 5°C, impurities other than tropic acid were observed intermittently at levels very close to the method’s limit of quantitation (0.05%, w/w). Additionally, independent of this development study, aliquots from the bulk samples of each of Formulations I-III were stored in glass vials at 40°C/25% RH for approximately 4.5 months and subsequently analyzed for Atropine assay and impurities. The analysis of these samples indicated that some of the impurities other than tropic acid observed in the stability samples at 25°C/40% RH and 40°C/25% RH are likely container closure leachables (e.g., the stability samples were delivered with white printer labels adhered to the samples and, it is now believed that these labels should have been removed prior to the initiation of the development study).
[00167] 3.5. Benzalkonium Chloride (BAK)
[00168] Through 6 months, the amount of BAK in Formulation III remained generally unchanged compared to the initial/To time point at 5°C, 25°C/40% RH and 40°C/25% RH with values ranging from 0.0066% to 0.0069% (w/w).
[00169] 4. Conclusion [00170] Evaluation of the data indicates that, physical appearance, osmolality, and assay results were generally unchanged for all three formulations of Atropine Sulfate 0.03% ophthalmic solution through 12 months at 5°C and 25°C/40% RH and through 6 months at 40°C/25% RH. A slight downward trend in the pH was observed for all 3 formulations with the trend being slightly more pronounced at higher temperatures. Furthermore, all three formulations demonstrated the best stability through 12 months at 5°C as indicated by the 5°C storage condition producing the lowest levels of Tropic Acid when compared to the 25°C/40% RH and 40°C/25% RH storage conditions.
[00171] While certain embodiments of the invention have been described, other embodiments may exist. While the specification includes a detailed description, the invention’s scope is indicated by the following claims. Furthermore, while the specification has been described in language specific to structural features and/or methodological acts, the claims are not limited to the features or acts described above. Rather, the specific features and acts described above are disclosed as illustrative aspects and embodiments of the invention. Various other aspects, embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention or the scope of the claimed subject matter.

Claims

What is claimed is:
1. A topical ophthalmic composition comprising one or more active components selected from the group consisting of atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof, and a buffer, wherein the composition has a pH of about 3.0 to about 5.5 and does not contain a viscosity-enhancing component.
2. A topical ophthalmic composition comprising one or more active components selected from the group consisting of atropine, oxymetazoline, brimonidine, epinephrine, clonidine, carbachol, neostigmine, demecarium, isoflurophate, phospholine iodide, aceclidine, Formula I, and pharmaceutically acceptable salts thereof, a buffer, one or more osmolality agents, wherein the composition has a pH of about 3.0 to about 5.5 and a viscosity from about 1 centipoise (cps) to about 10 cps, or about 1 cps to about 8 cps, or about 1 cps to about 5 cps, or about 1 cps to about 4 cps, or about 1 cps to about 3 cps.
3. The topical ophthalmic composition of any one of claims 1 to 2, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 20% w/w.
4. The topical ophthalmic composition of claim 3, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 10% w/w.
5. The topical ophthalmic composition of claim 4, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 2% w/w.
6. The topical ophthalmic composition of claim 5, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 1% w/w.
7. The topical ophthalmic composition of claim 6, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 0.5% w/w.
8. The topical ophthalmic composition of claim 7, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 0.10% w/w.
9. The topical ophthalmic composition of claim 8, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 0.05% w/w.
10. The topical ophthalmic composition of claim 9, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 0.04% w/w.
11. The topical ophthalmic composition of claim 10, wherein at least one of the one or more active components is present at a concentration from about 0.01% w/w to about 0.03% w/w
12. The topical ophthalmic composition of claim 3, wherein at least one of the one or more active components is present at a concentration from about 0.1% w/w to about 5% w/w, or about 0.1% w/w to about 3% w/w, or about 0.1% w/w to about 2% w/w, or about 0.1% w/w to about 1.5% w/w, or about 0.1% w/w to about 1.25% w/w, or about 0.1% w/w to about 1% w/w, or about 0.1% w/w to about 0.5%.
13. The topical ophthalmic composition of any preceding claim, wherein the buffer is
selected from the group consisting of phosphate buffer, borate buffer, borate citrate buffer, and lactate buffer.
14. The topical ophthalmic composition of claim 13, wherein the buffer is present at a
concentration from about 0.01 mM to 1 M.
15. The topical ophthalmic composition of claim 14, wherein the buffer is present at a concentration from about 1 mM to about 100 mM.
16. The topical ophthalmic composition of any one of claims 13-15, wherein the buffer is in an amount that equilibrates to a physiological pH within about sixty seconds after application to a mammalian eye.
17. The topical ophthalmic composition of any preceding claim, further comprising one or more osmolality agents in an amount that renders the ophthalmic composition roughly isotonic within about sixty seconds after application to a mammalian eye.
18. The topical ophthalmic composition of claim 17, wherein the one or more osmolality agents is selected from the group consisting of glycerin, propylene glycol, mannitol, sorbitol, sodium chloride, potassium chloride and dextrose.
19. The topical ophthalmic composition of claim 17 or 18, wherein at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 20% w/w.
20. The topical ophthalmic composition of claim 19, wherein at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 5% w/w.
21. The topical ophthalmic composition of claim 20, wherein at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 2.5% w/w.
22. The topical ophthalmic composition of claim 21, wherein at least one of the one or more osmolality agents is present at a concentration from about 0.001% w/w to about 1% w/w.
23. The topical ophthalmic composition of any preceding claim, further comprising a preservative.
24. The topical ophthalmic composition of claim 23, wherein the preservative is selected from the group consisting of benzalkonium chloride and a stabilized oxychloro complex comprising chlorite, chlorate and chlorine dioxide.
25. The topical ophthalmic composition of claim 23 or 24, wherein the preservative is present at a concentration from about 1 ppm to about 1000 ppm.
26. The topical ophthalmic composition of any one of claims 23-25 , wherein the
preservative is present at a concentration from about 10 ppm to about 300 ppm.
27. The topical ophthalmic composition of claim 26, wherein the preservative is present at a concentration from about 10 ppm to about 200 ppm.
28. The topical ophthalmic composition of any preceding claim, further comprising a
secondary buffering agent.
29. The topical ophthalmic composition of claim 28, wherein the secondary buffering agent is selected from the group consisting of citrate buffer and acetate buffer.
30. The topical ophthalmic composition of claim 28 or 29, wherein the secondary buffering agent is present at a concentration from about 0.01 mM to about 1 M.
31. The topical ophthalmic composition of claim 30, wherein the secondary buffering agent is present at a concentration from about 1 mM to about 100 mM.
32. The topical ophthalmic composition of any preceding claim, further comprising NaOH or HC1.
33. The topical ophthalmic composition of any preceding claim, wherein the composition comprises atropine as an active component.
34. The topical ophthalmic composition of claim 33, wherein the composition comprises at least about 0.01% w/w atropine.
35. The topical ophthalmic composition of claim 33, wherein the composition comprises atropine at a concentration from about 0.01% w/w to about 2% w/w, or about 0.1% w/w to about 1.5% w/w, or about 0.01% w/w to about 1.25% w/w, or about 0.01% w/w to about 1% w/w, or about 0.01% w/w to about 0.5% w/w, or about 0.01% w/w to about 0.1% w/w, or about 0.01% w/w to about 0.09% w/w, or about 0.01% w/w to about 0.08% w/w, or about 0.01% w/w to about 0.07% w/w, or about 0.01% w/w to about 0.06% w/w, or about 0.01% w/w to about 0.05% w/w, or about 0.01% w/w to about 0.04% w/w, or about 0.01% w/w to about 0.03% w/w.
36. The composition of claim 33, wherein atropine is the sole active component.
37. The composition of any one of claims 1-36, wherein the composition is applied once daily.
38. The composition of any one of claims 1-37, wherein the composition is applied twice daily.
39. The composition of any one of claims 1-38, wherein the composition is administered to both eyes of a subject.
40. The composition of any one of claims 1-38, wherein the composition is administered to a nondominant eye of a subject.
41. The composition of any one of claims 1-38, wherein the composition is administered to a dominant eye of a subject.
42. A method of treating an ocular condition in a subject in need of treatment thereof,
comprising administering the topical ophthalmic composition of any of claims 1-41 to the subject.
43. The method of claim 42, wherein the ocular condition is selected from the group
consisting of myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery, presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil or other causes of
parasympathetic denervation, complications arising after refractive surgery, decentered ablations following LASIK or PRK, LASIK undercorrections, LASIK overcorrections, corneal scars, hazing, and refractive errors.
44. The method of claim 42 or 43, wherein the ocular condition is myopia.
45. The method of claim 42 or 43, wherein the ocular condition is hyperopia.
46. A method of treating myopia in a subject in need thereof, comprising administering to at least one eye of the subject a topical ophthalmic composition comprising atropine at a concentration from about 0.01% w/w to about 2% w/w, or about 0.1% w/w to about 1.5% w/w, or about 0.01% w/w to about 1.25% w/w, or about 0.01% w/w to about 1% w/w, or about 0.01% w/w to about 0.5% w/w, or about 0.01% w/w to about 0.1% w/w, or about 0.01% w/w to about 0.09% w/w, or about 0.01% w/w to about 0.08% w/w, or about
0.01% w/w to about 0.07% w/w, or about 0.01% w/w to about 0.06% w/w, or about
0.01% w/w to about 0.05% w/w, or about 0.01% w/w to about 0.04% w/w, or about
0.01% w/w to about 0.03% w/w, wherein the topical ophthalmic composition has a pH of about 3.0 to about 5.5 and does not contain a viscosity-enhancing component.
47. A method of improving at least one vision parameter in a subject in need thereof, comprising administering to at least one eye of the subject a topical ophthalmic composition comprising atropine at a concentration from about 0.01% w/w to about 2% w/w, or about 0.1% w/w to about 1.5% w/w, or about 0.01% w/w to about 1.25% w/w, or about 0.01% w/w to about 1% w/w, or about 0.01% w/w to about 0.5% w/w, or about 0.01% w/w to about 0.1% w/w, or about 0.01% w/w to about 0.09% w/w, or about 0.01% w/w to about 0.08% w/w, or about 0.01% w/w to about 0.07% w/w, or about 0.01% w/w to about 0.06% w/w, or about 0.01% w/w to about 0.05% w/w, or about 0.01% w/w to about 0.04% w/w, or about 0.01% w/w to about 0.03% w/w, wherein the topical ophthalmic composition has a pH of about 3.0 to about 5.5 and does not contain a viscosity-enhancing component, and wherein the at least one vision parameter is selected from the group consisting of intermediate vision acuity, distance vision acuity and night vision.
48. The method of any one of claims 42 to 47, wherein the method results in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected distance visual acuity (UDVA).
49. The method of any one of claims 42 to 47, wherein the method results in an at least 3 -line improvement from baseline under the condition of mesopic, high contrast distance- corrected near visual acuity (DCNVA).
50. The method of any one of claims 42 to 47, wherein the method results in an at least 3 -line improvement from baseline under the condition of photopic, high contrast DCNVA.
51. The method of any one of claims 42 to 47, wherein the method results in an at least 3 -line improvement from baseline under the condition of mesopic, high contrast distance- corrected intermediate visual acuity (DCIVA).
52. The method of any one of claims 42 to 47, wherein the method results in an at least 3-line improvement from baseline under the condition of photopic, high contrast DCIVA.
53. A topical ophthalmic composition, substantially as herein described.
54. A method of treating an ocular condition in a subject in need of treatment thereof,
substantially as herein described.
55. A method of treating myopia in a subject in need thereof, substantially as herein
described.
56. The topical ophthalmic composition of any one of claims 1-41, for use in treatment of an ocular condition in a subject in need of treatment thereof.
57. The topical ophthalmic composition of any one of claims 56, for use in treatment of myopia, progressive myopia, pathologic myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, night vision symptoms post refractive surgery, presbyopia, accommodative esotropia, glaucoma, ocular hypertension, accommodative insufficiency, hyperopia, anisocoria, astigmatism, amblyopia, Adie’s tonic pupil or other causes of parasympathetic denervation, complications arising after refractive surgery, decentered ablations following LASIK or PRK, LASIK undercorrections, LASIK overcorrections, corneal scars, hazing, and refractive errors.
58. The topical ophthalmic composition of claim 56, wherein the ocular condition is myopia.
59. The topical ophthalmic composition of claim 56, wherein the ocular condition is
hyperopia.
60. The topical ophthalmic composition of any one of claims 1-41, for improving at least one vision parameter in a subject in need thereof, wherein the at least one vision parameter is selected from the group consisting of intermediate vision acuity, distance vision acuity and night vision.
61. The topical ophthalmic composition of claim 60, wherein the improvement is in an at least 2-line improvement from baseline under the condition of photopic, high contrast uncorrected distance visual acuity (UDVA).
62. The topical ophthalmic composition of claim 60, wherein the improvement is an at least
3 -line improvement from baseline under the condition of mesopic, high contrast distance- corrected near visual acuity (DCNVA).
63. The topical ophthalmic composition of claim 60, wherein the improvement is an at least
3 -line improvement from baseline under the condition of mesopic, high contrast distance- corrected intermediate visual acuity (DCIVA).
64. The topical ophthalmic composition of claim 60, wherein the improvement is an at least 3-line improvement from baseline under the condition of photopic, high contrast DCIVA.
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