(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`19) World Intellectual Propert
`=
`
`=
`eeOrganization
`=
`International Bureau
`=——
`(43) International Publication Date
`29 October 2020 (29.10.2020) WIPO!|PCT
`
`UU TT AT ATAATT
`(10) International Publication Number
`WO 2020/219707 Al
`
`(51) International Patent Classification:
`AG61K 9/00 (2006.01)
`
`(21) International Application Number:
`PCT/US2020/029566
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`23 April 2020 (23.04.2020)
`
`English
`
`English
`
`(30) Priority Data:
`62/838,155
`
`24 April 2019 (24.04.2019)
`
`US
`
`(71) Applicant: ALLERGAN, INC. [US/US]; 2525 Dupont
`Drive, Irvine, California 92612 (US).
`
`(72) Inventors: ROBINSON, Michael, R.; 200 Pacific Coast
`Highway, #147, Huntington Beach, California 92606 (US).
`GIYANANI, Jaya; 25 Palatine, Apt. 254, Irvinc, Califor-
`nia 92612 (US). GORE, Anuradha; 12 DoveStreet, Aliso
`Viejo, California 92656 (US).
`
`(74) Agent: SIDDIQT, Lorenz et al., ALLERGAN, INC., 2525
`Dupont Drive, Irvine, California 92612 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN,
`HR, HU,ID, IL, IN,IR,IS, JO, JP. KE, KG,KH, KN, KP,
`KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL, NO, NZ,
`OM,PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA,
`SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`T4), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FL FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM,ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— with international search report (Art. 21(3))
`
`G4) Title: COMPOSITIONS AND METHODS FOR TREATMENT OF OCULAR CONDITIONS
`
`(57) Abstract: The present inventionis related to topical ophthalmic compositions comprising one or more active components. The ac-
`tive components in the topical ophthalmic compositions include, but are not limited to atropine, oxymetazoline, brimonidine, epineph-
`rinc, clonidine, carbachol, ncostigminc, dcmccarium, isoflurophatc, phospholinc iodide, accclidinc, Formula I, and pharmaccutically
`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.
`
`
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`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 ofthe 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
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`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 muchaspossible, although sometimes formulation
`
`considerations(e.g., drug stability) may necessitate less than optimal comfort. In the case
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`that comfort cannot be maximized, the liquid should be formulated such that the liquid 1s
`
`tolerable to the patient for topical ophthalmic use. Currently available commercial
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`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 1n adverse effects
`
`such as vision blur that limit their use (Hall ef al., 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
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`sensitivity, ocular stinging, and ocular itching. These adverse effects result in decreased
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`patient compliance.
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`[0004] Thus, there 1s a need in the art for improved topical ophthalmic compositions that
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`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 inventionrelates 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,
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`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
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`about 3.0 to about 6.0, or 3.0 to about 5.5 and a viscosity from about | centipoise (cps) to
`
`about 10 cps without the need for including a viscosity-enhancing agent.
`
`[0008] The invention also provides methodsof 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 ofabout 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 medicamentfor 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 symptomspost 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.
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`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.
`
`2? <<
`
`”
`
`[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 componentsthat are
`
`unacceptably toxic to the subject to which the composition would be administered. Such
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`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 besuitable 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 componentofthe 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,
`
`4
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`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,
`
`phospholineiodide, 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 componentsin the topical
`
`ophthalmic compositions of the invention include a compound of FormulaI:
`
`Me
`H
`N
`~sCI
`
`N
`
`yy
`
`H
`
`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 1s
`
`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 componentsis presentat a
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`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/wto 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 componentsare 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 componentsis present at a concentration from about 0.01% w/w toat 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 toat 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/wto at least about 0.50% w/w. In certain embodiments, at least one of the one or more
`
`active componentsis present at a concentration from about 0.01% w/wto at least about
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`0.30% w/w. In other embodiments, the one or more active components are each present at
`
`a concentration from about 0.01% w/wto 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 componentsare 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 presentat
`
`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/wto 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 componentsare 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 componentsis present at a concentration ofat 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
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`concentrations. In other embodiments, the one or more active components is presentat 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% wiw, 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 componentsis 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 moreactive 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 moreactive
`
`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
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`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 someof 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 componentsof 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 compositionsof the invention
`
`comprise atropine as an active component. In certain aspects, atropine is the sole active
`
`componentpresent 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 compoundis 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
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`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 atropineat 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 atropineat 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 atropineat 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 atropineat 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.
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`[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 oxymetazolineis part of a topical ophthalmic composition, the
`
`compound is the sole active component, which hastherapeutic 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
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`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, brimonidineis the sole
`
`active componentpresent in the topical ophthalmic compositions of the invention. In
`
`some embodiments, brimonidine is present as a pharmaceutically acceptable salt. In some
`
`embodiments, when brimonidineis part of a topical ophthalmic composition, the
`
`compoundis 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 brimonidineat 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
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`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 brimonidineat 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 brimonidineat 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 brimonidineat a
`
`concentration from about 0.01% w/w to about 0.10 % w/w. In certain embodiments, the
`
`topical ophthalmic compositions comprise brimonidineat a concentration from about
`
`0.01% w/w to about 0.09 % w/w. In certain embodiments, the top