(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`19) World Intellectual Propert
`=
`
`ower Organization “pens
`
`=
`International Bureau
`——
`(43) International Publication Date
`——
`17 December2020 (17.12.2020) WIPO! PCT
`
`UIIUAISMTANANEYT
`(10) International Publication Number
`WO 2020/252057 Al
`
`(51) International Patent Classification:
`AGIK 31/498 (2006.01)
`AGIK 31/27 (2006.01)
`AG1K 9/00 (2006.01)
`AGIP 27/10 (2006.01)
`(21) International Application Number:
`PCT/US2020/037042
`
`(22) InternationalFiling Date:
`
`10 June 2020 (10.06.2020)
`
`(25) Filing Language:
`or
`(26) Publication Language:
`(30) Priority Data:
`62/859,678
`62/913,794
`62/963,891
`62/970,155
`
`US
`10 June 2019 (10.06.2019)
`US
`11 October 2019 (11.10.2019)
`US
`21 January 2020 (21.01.2020)
`04 February 2020 (04.02.2020) US
`
`English
`.
`English
`
`[US/US];
`(71) Applicant: VISUS THERAPEUTICS, INC.
`500 Yale Avenue N., Seattle, Washington 98112 (US).
`(72) Inventors: SAMBURSKY,Robert P.; 7410 Mizner Re-
`serve Court, Lakewood Ranch, Florida 34202 (US). KAUF-
`MAN, Herbert E.;, 35 Watergate Drive, Sarasota, Florida
`34236 (US).
`
`(74) Agent: WOOD, Lynda M. et al.; 118 North Tioga Street,
`Suite 400, Ithaca, New York 14850 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnational 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, FI, GB, GD, GE, GII, GM, GT, TIN,
`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, NI, NO, NZ,
`
`G4) Title: USING PARASYMPATHOMIMETIC DRUGS ALONE OR, IN COMBINATION WITH ONE OR MORE ALPHA
`AGONISTS IN PSEUDOPHAKIC PATIENTS, TO CREATE MULTI-FOCALITY
`
`Fig. 22
`
`[_] 2.25% Carb + Brim
`ERY 3% Carb + Brim
`
`inNVA(Jaeger)
`
`
`
`Meanchange
`
`Time (hrs)
`
`(57) Abstract: Using one or more parasy mpathomimetic drugs alone or together, or in combination with one or more alpha agonists
`to create optically beneficial miosis to temporarily create multifocality in a pseudophakic patient to treat presbyopia. A pharmaceutical
`preparation comprising a therapeutically effective amount of one or more parasympathomimetic drugs or cholinesterase inhibitors, alone
`or in combination with or a pharmaceutically acceptable salt thereof, in combination with one or more alpha agonists or antagonists,
`or a pharmaceutically acceptable salt thereof. A method for creating multifocality in a pseudophakic patient, reducing symptoms of
`ptesbyopia in a patient having an eye or both eyes through administering to an eye or eyes a pharmaceutically effective amount of the
`ophihalmic preparationis also disclosed.
`
`[Continued on nextpage]
`
`
`
`
`
`
`
`wo2020/252057Ad.ITNMITUNIITAIACUNTTIMTMAAAA
`
`

`

`WO 2020/252057 AL |IMMNTIMITTNININTNI ANTMTM TMATAATAU AATA
`
`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 ofregional 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,
`TM), 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, SL SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM,ML, MR,NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`— ofinventorship (Rule 4.17(iv))
`Published:
`
`— with international search report (Art. 21(3))
`— before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48. 2(h))
`
`

`

`WO 2020/252057
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`1
`
`USING PARASYMPATHOMIMETIC DRUGS ALONE OR, IN COMBINATION
`
`WITH ONE OR MORE ALPHA AGONISTS IN PSEUDOPHAKIC PATIENTS, TO
`
`CREATE MOLTEPOCALITY
`
`BACKGROUNDOF THE INVENTION
`
`FIELD OF THE INVENTION
`
`[0001] The invention pertains to the field of treating optical disorders. More particularly,
`
`the invention pertains to the use of one or more parasympathomimetic drugs or a
`
`cholinesterase inhibitor alone or in combination with one or more alpha agonists or
`
`antagonist to create optically beneficial miosis to induce multifocality in a pseudopkaic
`
`10
`
`patient, for example, to temporarily treat presbyopia.
`
`DESCRIPTION OF RELATED ART
`
`[0002] Presbyopia is typically age-related eye deterioration. Young, properly
`
`functioning, eyes are able to see al near distances, an ability that deteriorates as one ages.
`
`Presbyopia normally develops as a person ages, and is associated with a natural
`
`15
`
`progressive loss of accommodation with naturally occurring stiffening of the crystalline
`
`lens with age. A presbyopic eye loses the ability to rapidly and easily focus on objects at
`
`near distances. Presbyopia progresses over the lifetime of an individual, usually becoming
`
`noticeable after the age of 45 years. By the age of 65 years, the crystalline lens has often
`
`lost almost all elastic properties and has only limited ability to change shape.
`
`20
`
`[0003] Use of over the counter reading glasses is a very common wayof addressing the
`
`vision problems associated with presbyopia. Reading glasses allow the eye to focus on
`
`near objects and maintain a clear image. This approach is similar to that of treating
`
`hyperopia, or farsightedness.
`
`[0004] Many presbyopesare also prescribed bi-focal eyeglasses, where one portion of
`
`25
`
`the lens is corrected for distance vision and another portion of the lens is corrected for near
`
`vision. When peering down throughthe bifocals, the individual looks through the portion
`
`of the lens corrected for near vision. When viewing distant objects, the individual looks
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`2
`
`higher, through the portion of the bi-focals corrected for distance vision. Contact lenses
`
`and intra-ocular lenses (IOLs) have also been used to treat presbyopia, for example, by
`
`relying on monovision (where one eye is corrected for distance-vision, while the other eye
`
`is corrected for near-vision) or bilateral correction with either bi-focal or multi-focal
`
`lenses. Laser ablation has also been used to treat presbyopia. All these procedures seek to
`
`correct the problem for long term purposes using drastic steps (surgery, laser ablation,
`
`etc.) or require wearing corrective lenses.
`
`[09005] Numerous research studies have tried to determine the exact reasons for the
`
`development of presbyopia and different attempts have been made to decrease the effects
`
`10
`
`of presbyopia with glasses and contact lenses. These have been of limited usefulness. The
`
`use of pinhole spectacles has also been unsatisfactory since the pinhole does not move
`
`with the eye andthefield of vision of the eye is restricted. Pinhole spectacles often also
`
`cause dimness wheninsufficient light reaches the retina.
`
`[0006] Surgical approaches to relieve presbyopia include monovision, laser ablation,
`
`15
`
`intraocular lenses, and refractive lens replacement. Refractive corneal inlays increase the
`
`corneal power, usually in the non-dominant eye. These inlays require surgery. An
`
`intraocular lens (OL)is an artificial lens. It replaces the eye's natural lens that is removed
`
`during cataract surgery. The most commontype of lens used with cataract surgery is
`
`called a monofocal IOL.It has one focusing distance. It is set to focus for up close,
`
`20
`
`medium range or distance vision. Most people have them set for clear distance vision.
`
`Since these lenses do not correct for presbyopia, patients typically wear eyeglasses for
`
`reading or close work after surgery. Special IOLs, called multifocal and accommodative
`
`IOLs, have different focusing powers within the same lens. These IOLs reduce the
`
`postoperative dependence on reading glasses by providing increased near vision along
`
`25
`
`with distance vision.
`
`[0007] Another surgical approach to treat presbyopia is the AcuFocus™ implant, which
`
`is a corneal implant with a small] central artificial pupil. The AcuFocus implantis similar
`
`to a washer with a hole in the middle, whichis inserted underthe flap of the cornea during
`
`a surgical procedure. This procedure restores reading vision through increased depth of
`
`30
`
`focus. Operating only on the non-dominant eye seems Lo avoid dimness problems that are
`
`seen when the pupil in both eyes is made small.
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`[0008] Other refractive errors include myopia (nearsightedness), hyperopia (a condition
`
`where rays of light reach the retina before they converge in a focused way, resulting in
`
`general blurriness) and astigmatism (an imperfection in the curvature of the eye). Man-
`
`maderetractive errors or visual distortions also often occur after laser surgery or when the
`
`natural lens is replaced with an artificial intraocular lens (for example during cataract
`
`surgery).
`
`[0009] A cataract is a clouding of the lens in the eye that affects vision. Before a cataract
`
`develops, the lens is a clear structure that helps to focus light, or an image, on theretina.
`
`Most cataracts are related to aging. Most people develop cataracts after age 50 years, and
`
`10
`
`presbyopia has already occurred. Cataracts are very commonin older people. A cataract
`
`can occurin either or both eyes.
`
`[0010] Canadian patent, CA 2747095, entitled “Optical Correction” by Anant Sharma
`
`discusses a medicament for topical administration to the eye to improve visual acuity for
`
`several hours and provide benefit to users with presbyopia, myopia, hypermetropia,
`
`15
`
`stigmatism and/or impaired night vision. The medicament includes two pharmacologically
`
`active agents — a parasympathetic agonist and either a sympathetic antagonist ora
`
`sympathetic agonist. The parasympathetic agonist is pilocarpine, the sympathetic
`
`antagonist is selected from dapiprazole or thymoxamine and the sympathetic agonistis
`
`selected from brimonidine or iopidine. Eye drop formulations were prepared and tested on
`
`20
`
`three individuals.
`
`[0011] Each of the three individuals tested received both the first and the second eye
`
`drop formulations. The first eye drop formulation was 0.5% by weight dapiprazole and
`
`0.5% by weight pilocarpine. The second eye drop formulation was 0.1% by weight
`
`brimonidine and 0.25% by weight pilocarpine.
`
`[0012] Visions tests were conducted before and after the drop formulations were
`
`administered. In each case, effects were maintained for at least two hours and somefor at
`
`least four hours.
`
`[0013] The first individual was a 63 year old emmetropenot requiring glasses for
`
`functional distance. Within twenty minutes of administration, the patient's unaided
`
`30
`
`distance vision in each eye had improved by a line on the Snellen chart, from 6/6 to 6/5,
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`The refraction did not change. The patient's unaided reading vision improved from N12 to
`
`N4.5 at a reading distance of one third of a meter. The patient's night vision improved
`
`qualitatively as described by the patient.
`
`[0014] The second individual was a 50 year old with a -4 Dioptre myope (requiring
`
`glasses for functional distance vision). Within half an hour of administration, the patient's
`
`unaided distance vision improved from being able to count fingers (but not to read the
`
`Snellen chart) to 6/36 on the Chart. Wearing distance-corrected glasses, the patient's
`
`reading vision at a distance of one third of a meter improved from N12 to N4.5. The
`
`refraction did not change. Quality of night vision improvedas the patient noted less haloes
`
`10
`
`and glare, and night vision also improved quantitatively [rom 6/6 to 6/5 in dim conditions.
`
`[0015] The third individual was a 49 year old with +4 Dioptre hypermetrope (longsighted
`
`and requiring glasses for useful reading vision). Within half an hour of administration, the
`
`patient's unaided distance vision improved on the Snellen chart from 6/60 to 6/24. The
`
`patient's unaided reading vision at one third of a meter improved from N18 to N4.5. The
`
`15
`
`refraction did not change. Quality of night vision improved, the patient noting less haloes
`
`and glare, and night vision also improved quantitatively from 6/6 to 6/5 in dim conditions.
`
`[0016] The only side effects discussed in CA 2747095 were red eye, which were not
`
`suffered by any of the individuals tested.
`
`[0017] The inventor of CA 2747095 hypothesized that the combination of the
`
`20
`
`parasympathetic agonists and sympathetic agonists and antagonists havelittle or no effect
`
`on the ciliary muscles of the eye which act to alter the shape and hence refraction of the
`
`lens. Ciliary muscles as discussed below however, is responsible for brow ache.
`
`[0018] CA 2747095’s data is problematic as it was tested on only three individuals, some
`
`of which wear corrective lens and some which do not. Additionally, no measurements
`
`25
`
`were taken as to the effects of the drops at time incrementsafter they were received.
`
`Furthermore, a control was not tested on the individuals as a comparison to rule out
`
`placebo effect.
`
`[0019] Thus, there remains a need for new ways of ameliorating or reducing refractive
`
`errors including, but not limited to, presbyopia, hyperopia, myopia, pseudophakes, and
`
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`5
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`disruptions due to laser surgery for patients that do not wish to undergo surgery (IOLs,
`
`laser ablation, etc.) or use corrective glasses. For people who use corrective lenses, there
`
`remains a need to temporarily treat these disorders without the use of corrective lenses.
`
`SUMMARYOF THE INVENTION
`
`[0020] A pharmaceutical preparation includes one or more parasympathomimetic drugs
`
`alone or in combination with one or more sympatholytics. Sympatholytics inhibit
`
`sympathetic activity and include alpha-1 agonists and alpha-? agonists. In one
`
`embodiment, an ophthalmic topical preparation is provided, comprising a therapeutically
`
`effective amount of one or more parasympathomimetic drugs, or pharmaceutically
`
`10
`
`acceptable salts thereof, alone or in combination with and one or more alpha agonists or
`
`antagonists, or pharmaceutically acceptable salts thereof which creates optically beneficial
`
`miosis to induce multifocality in a pseudopkaic patient, for example, to temporarily treat
`
`presbyopia.
`
`[0021] Methods for ameliorating or reducing optical errors in patients having al least one
`
`15
`
`eye comprise administering to at least one eye a therapeutically effective amount of an
`
`ophthalmic preparation comprising one or more parasympathomimetic drugs, or their
`
`pharmaceutically acceptable salts, alone or in combination with and one or more alpha
`
`agonists or antagonists, or their pharmaceutically acceptable salts.
`
`[0022] Methods for ameliorating or reducing refractive errors and creating multi-focality
`
`20
`
`in pseudophakic patients having at least one eye comprise administering to at least one eye
`
`a therapeutically effective amount of an ophthalmic preparation comprising one or more
`
`parasympathomimetic drugs, or their pharmaceutically acceptable salts, alone or in
`
`combination with and one or more alpha agonists or antagonists, or their pharmaceutically
`
`acceptable salts.
`
`25
`
`[0023] The invention also provides for a method of producing ocular miosis in a subject
`
`which comprises administering to the subject an amount of a preparation comprising one
`
`or more parasympathomimetic, or their pharmaceutically acceptable salts, and one or more
`
`alpha agonists or antagonists, or their pharmaceutically acceptable salts, effective to
`
`produce ocular miosis and one or more alpha agonists or antagonists.
`
`

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`WO 2020/252057
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`6
`
`[0024] The invention also provides for a method of producing ocular miosis to induce
`
`multi-focality in a subject which comprises administering to the subject an amountof a
`
`preparation comprising one or more parasympathomimetic, or their pharmaceutically
`
`acceptable salts, alone or in combination with and one or more alpha agonists or
`
`antagonists, or their pharmaceutically acceptable salts, effective to produce ocular miosis
`
`and one or more alpha agonists or antagonists.
`
`[0025] A method for ameliorating or reducing at least one refractive error selected from
`
`the group consisting of myopia, hyperopia, pseudophakia and astigmatism of a patient
`
`includes administering to at least one eye of the patient an ophthalmic preparation
`
`10
`
`comprising a therapeutically effective amount of one or more parasympathomimetic drugs,
`
`or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of an
`
`alpha agonist or an alpha antagonist, or pharmaceutically acceptable salts thereof.
`
`[0026] A method of inducing multi-focality in a subject through ocular miosis of patient
`
`with at least one refractive error selected from the group consisting of myopia, hyperopia,
`
`15
`
`and astigmatism of a pseudophakic patient includes administering to at least one eye of the
`
`patient an ophthalmic preparation comprising a therapeutically effective amount of one or
`
`more parasympathomimetic drugs, or pharmaceutically acceptable salts thereof alone or in
`
`combination with a therapeutically effective amount of an alpha agonist or an alpha
`
`antagonist, or pharmaceutically acceptable salts thereof.
`
`20
`
`[0027] A method oftreating at least one refractive error in a patient that has had ocular
`
`surgery includes administering to at least one eye of the patient an ophthalmic preparation
`
`comprising a therapeutically effective amount of one or more parasympathomimetic drugs,
`
`or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of an
`
`alpha agonist or an alpha antagonist, or pharmaceutically acceptable salts thereof. In some
`
`25
`
`embodiments, the refractive error may include, but is not limited to, myopia, hyperopia,
`
`astigmatism, and any combination of myopia, hyperopia, and astigmatism in a
`
`pseudophakic patient. The ocular surgery can include cataract surgery, surgery to alter at
`
`least one eye with an intraocular lens or lens replacement.
`
`[0028] A method of treating pseudophakiain a patient includes administering to al least
`
`30
`
`one eye of the patient an ophthalmic preparation comprising a therapeutically effective
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`PCT/US2020/037042
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`7
`
`amount of one or more parasympathomimetic drugs, or pharmaceutically acceptable salts
`
`thereof; alone or in combination with a therapeutically effective amountof an alpha
`
`agonist or an alpha antagonist, or pharmaceutically acceptable salts thereof.
`
`[0029]
`
`In some embodiments, the one or more parasympathomimetic drugs is carbachol
`
`or pilocarpine, and the alpha agonist is brimonidine or phentolamine.
`
`[0030]
`
`In some embodiments, the alpha agonist is brimonidine, or its pharmaceutically
`
`acceptable salt, is present in an amountless than about 0.05%, 0.2%, 0.15% or 0.10%. In
`
`other embodiments, the alpha antagonist is phentolamine, or its pharmaceutically
`
`acceptable salt, is present in an amount of less than 2%. In some further embodiments, the
`
`10
`
`one or more parasympathomimetic drugs is carbachol, or its pharmaceutically acceptable
`
`salt, which is present in the preparation in an amount of about 0.50%- 5%. In other
`
`embodiments, the one or more parasympathomimemtic drugs is pilocarpine,orits
`
`pharmaceutically acceptable salt, which is present in the preparation in an amount of about
`
`25% -1.5%. In yet other embodiments, the one or more parasympathomimemtic drugs is
`
`15
`
`pilocarpine, or its pharmaceutically acceptable salt, which is present in the preparation in
`
`an amount of about .25% -4.0%. In other embodiments, the pilocarpine,or its
`
`pharmaceutically acceptable salt, is present in an amountofless than 0.1%.
`
`[0031]
`
`In some embodiments, the ophthalmic preparation includes a permeation
`
`enhancer such as benzalkonium chloride (BAC or BAK)in an amount of 0.005-0.3%.
`
`20
`
`More preferably, benzalkonium chloride is present in an amount of 0.005-0.1%.
`
`[0032] Use of alpha adrenergic simulation such as from brimonidine can be used to
`
`improve scotopic and mesopic vision when combined with topical parasympathomimetics
`
`medications for pseudophakia.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`25
`
`[0033] FIG. 1 shows changein visual acuity at 1 hr, 2 hrs, and 4 hrs after administration
`
`of 0.25% pilocarpine alone, 0.5% pilocarpine alone, 1.0% pilocarpine alone, 0.25%
`
`pilocarpine combined with 0.2% brimonidine, 0.5%, pilocarpine combined with 0.2%
`
`brimonidine, or 1.0% pilocarpine combined with 0.2% brimonidine.
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`8
`
`[0034] FIG. 2 showsthe average changein visual acuity at 1, 2, 4, 8, and 10 hoursafter
`
`administration for the active drug and placebo arms. The solid squares represent the
`
`average change in visual acuity for the active drug arm whereasthe solid triangles
`
`represent the average changein visual acuity for the placebo arm.
`
`[0035] FIG. 3 showsthe distribution of mean changein near visual acuity (Jaeger) over
`
`time for presbyopic subjects >50 years (2.25% carbachol plus brimonidine versus
`
`placebo).
`
`[0036] FIG. 4 showsin near visual acuity (Jaeger) over time for presbyopic subjects <50
`
`years (2.25% carbachol plus brimonidine versus placebo).
`
`10
`
`[0037] FIG. 5 showsthe distribution of mean change in near visual acuity (J) over time
`
`for emmetropic presbyopes (carbachol 2.25% plus brimonidine vs placebo vs
`
`brimonidine).
`
`[0038] FIG. 6 showsthe distribution of mean change in near visual acuity (J) over time
`
`for myopic presbyopes (carbachol 1.5% plus brimonidine vs placebo vs brimonidine)
`
`15
`
`[0039] FIG. 7 showsthe distribution of mean change in near visual acuity (J) over time
`
`for hyperopic presbyopes (carbachol 3% plus brimonidine vs placebo vs brimonidine)
`
`[0040] FIGS. 8a-8b showsthe data from a study comparing 3% carbachol plus 0.2 %
`
`brimonidine eye drops administered to the same subjects in a combined formulation versus
`
`separate administration.
`
`20
`
`[0041] FIG. 9 showsthe distribution of mean change in near visual acuity (J) over time
`
`for the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in both
`
`combined and separate forms.
`
`[0042] FIG. 10 showsthe distribution of mean change in pupil size (mm) over time for
`
`the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in both
`
`25
`
`combined and separate forms.
`
`[0043] FIG.11 shows the distribution of mean change in near visual acuity (J) over time
`
`in all groups.
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`[0044] FIG. 12 shows the relationship between change in pupil diameter and Near
`
`LogMar VA.
`
`9
`
`[0045] FIG. 13 shows the change in LogMar near UCVA from pretreatment baseline.
`
`[0046] FIG. 14 shows the change from baseline near LogMar VAfor carbachol plus
`
`brimonidine (0.2%) compared to placebo.
`
`[0047] FIG. 15 showstheside effects of carbachol plus brimonidine over seven days.
`
`[0048] FIG. 16 shows the responses to a survey regarding whether patients would use the
`
`drops in the future.
`
`[0049] FIG. 17 shows visual measures of PD (pupil dilation) over time for B
`
`10
`
`(brimonidine), P (pilocarpine) and PB (brimonidine plus pilocarpine).
`
`[0050] FIG. 18 shows visual measures of NV (near vision) over time for B
`
`(brimonidine), P (pilocarpine) and PB (brimonidine plus pilocarpine).
`
`[0051] FIG. 19 shows visual measures of [TV Gntermediate vision) over time for B
`
`(brimonidine), P (pilocarpine) and PB (brimonidine plus pilocarpine).
`
`15
`
`[0052] FIG. 20 showsthe responses to a survey regarding whether patients would use the
`
`drops in the future.
`
`[0053] FIG. 21 shows data from 15 patients treated with combination drops after
`
`intraocular lens replacement.
`
`[0054] FIG. 22 shows distribution of mean change in near visual acuity (Jaeger) over
`
`20
`
`time for group 1 receiving 2.25% carbachol plus brimonidine versus group 2 receiving 3%
`
`carbachol plus brimonidine.
`
`[0055] FIG. 23 showsdistribution of mean change in pupil size (Jaeger) over time for
`
`group 1 receiving 2.25% carbachol plus brimonidine versus group 2 receiving 3%
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`carbachol plus brimonidine.
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`25
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`[0056] FIG. 24 shows mean pupil size over ime for emmetropic presbyopic subjects
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`receiving combined 3% carbachol plus 0.2% brimonidine with 100 ppm of benzalkonium
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`10
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`chloride drops, separate administration of 3% carbachol with 50 ppm of benzalkonium
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`chloride and then administration of 0.2% brimonidine, administration of just 3% carbachol
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`with 50 ppm of benzalkonium chloride, and administration of just 0.2% brimonidine with
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`50 ppm.
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`[0057] FIG. 25 shows mean near visual acuity in emmetropic presbyopes over time for
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`subjects receiving combined 3% carbachol plus 0.2% brimonidine with 100 ppmof
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`benzalkonium chloride drops, separate administration of 3% carbachol with 50 ppm of
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`benzalkonium chloride and then administration of 0.2% brimonidine, administration of
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`just 3% carbachol with 50 ppm of benzalkonium chloride, and administration of just 0.2%
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`10
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`brimonidine with 50 ppm.
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`[0058] FIG. 26a showseffect of 2.25% carbachol with 0.2% brimonidine versus 3%
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`carbachol with 0.2% brimonidine overtime on pupil size.
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`[0059] FIG.26b shows effect of 2.25% carbachol with 0.2% brimonidine versus 3%
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`carbachol with 0.2% brimonidine over time on near visual acuity.
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`15
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`[0060] FIG. 27 showsa distribution of mean change in near visual acuity for treatment
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`and control groups.
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`[0061] FIG. 28 shows a distribution of mean change in pupil size over time for treatment
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`and control groups.
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`DETAILED DESCRIPTION OF THE INVENTION
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`20
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`[0062] US Patent Nos. 8,299,079 , PREPARATIONS AND METHODS FOR
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`AMELIORATING OR REDUCING PRESB YOPIA, issued October 30, 2012 and
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`8,455,494, PREPARATIONS AND METHODS FOR AMELIORATING OR
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`REDUCING PRESBYOPIA, issued June 4, 2013, and US Patent Publication Nos.
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`2010/0298335, PREPARATIONS AND METHODSFOR AMELIORATING OR
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`25
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`REDUCING PRESBY OPIA,published November 25, 2010 and 2013/0245030,
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`PREPARATIONS AND METHODS FOR AMELIORATING OR REDUCING
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`PRESBYOPIA,published September 19, 2013, all herein incorporated by reference,
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`discuss methods and preparations to reduce presbyopia using parasympathomimemtic
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`drugs and alphagonists.
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`11
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`{9063}
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`In embodiments described herein, an ophthalmic topical preparation is provided
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`comprising a therapeutically effective amount of one or mare parasympathomimetic drugs
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`or One or more cholinesterase inhibitors, or their pharmaceutically acceptable salts, and
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`one or more alpha agonists or antagonists, or their pharmaceutically acceptablesalts.
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`10064]
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`In some embodiments, the one or more parasympathomuimetic drugs is
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`pilocarpine, or carbachol, or their pharmaceutically acceptable salts. In a further
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`embodiment, the one or more alpha agonists is brbmonidine, or a pharmaceutically
`
`10
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`acceptable salt thereof. In a farther embodiment, the one or more parasympathomimetic
`
`drugs are replaced with a cholinesterase inhibitor.
`
`[0065]
`
`In some embodiments, the one or more cholinesterase inhibitar is an
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`organophosphate such as metrifonate, a carbamate such as physostigmine (also knownas
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`eserine), neostigmine (also known as prostigmine), pyricdostigmine, ambenonium,
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`15
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`demarcarium, or rivastigmine; a phenanthrene derivative such as galantamine; a piperidine
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`compound such as donepezil, tacrine (also knownas tetrahydroaminoacridine (THA’)),
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`edrophonium, huperzine A, or ladostigil. fo another embodiment, the cholinesterase
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`inhibitor may be diisopropyl fluorophoasphate or DEPP Cloropry). In other embodiments,
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`the one or more cholimesterase inhibitors is phospholine iodide (also known as
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`20
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`echothiophate)} or physostigmine, or its pharmaceutically acceptable salt.
`
`[0066]
`
`in certain embociments, the one or more alpha antagonists is doxazosin,
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`silodosin, prazosin, tarasulosin, alfuzosin, terazoasin, trimazasin, phonoxybenzamine, or
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`phentolamine, thymoxamine or a pharmaceutically acceptable salt thereof.
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`[0067]
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`In embodiments described herein, pharmaceutical preparations comprise one or
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`25
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`more parasympathomimetic drugs (also known as muscarinic agonists), or cholinesterase
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`inhibitors, alone or in combination with one or more alpha agonists. In one embodiment,
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`the one or more parasympathomimetic drug is pilocarpine. In another embodiment, one or
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`more parasympathomimetic drug is carbachol. In further embodiments, the one or more
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`parasympathomimetic drugs are pilocarpine and carbachol, or a pharmaceutically
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`acceptable salt thereof. In certain embodiments, the one or more alpha agonistsis
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`brimonidine, or phentolamine or a pharmaceutically acceptable salt thereof.
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`12
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`[0068] The ophthalmic preparation may be administered to a subject suffering from
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`myopia, hyperopia, astigmatism, presbyopia or other optical errors as often as needed to
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`cause miosis sufficient to temporarily treat, ameliorate, or reduce these optical errors as
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`well as temporarily create multifocality. These refractive errors all benefit from these
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`drugs to a clinically and practically usable degree which enable patients who needed
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`glasses full time to totally do without them. Thus, the invention further provides a method
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`for temporarily treating, ameliorating, or reducing these optical errors by inducing miosis
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`10
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`as well as temporarily creating mulufocalily.
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`[0069]
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`“Optical errors”, or “refractive errors’, as defined herein, also known as
`
`ammetropia (vision abnormalities), are vision defects or optical imperfections that prevent
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`the eye from properly focusing light, causing blurred vision. The primary refractive errors
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`are myopia (nearsightedness), hyperopia (farsightedness, blurred vision), presbyopia
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`15
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`(whenthe lens in the eye loses flexibility), pseudophakia (a near vision defect created by
`
`the implantation of an artificial intraocular lens) and astigmatism (including regular
`
`astigmatism, irregular astigmatism and high degrees of regular astigmatism). Some
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`refractive errors occur after cataract surgery or laser surgery.
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`[0070] As used herein, the term "parasympathomimetic agent or drug” or “muscarinic
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`20
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`agonist” is intended to include any cholinergic drug that enhances the effects mediated by
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`acetylcholine in the central nervous system, the peripheral nervous system, or both.
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`Examples of these so-called acetylcholine receptor agonists suitable for the preparations
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`and methodsof the present invention include acetylcholine, muscarine, pilocarpine,
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`nicotine, suxamethonium, bethanechol, carbachol, methacholine, phenylpropanolamine,
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`25
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`amphetamine, ephedrine, phentolamine, and fenfluramine.
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`[0071] As used herein, the term "alpha agonist” or "alpha blocker" refers to compounds
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`that preferentially stimulate alpha (both alphal and alpha2) adrenoceptors. Examples of
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`alpha androgenic agonist suitable for the preparations and methods ofthe present
`
`invention include amiloride, apraclonidine, brimonidine, clonidine (and its derivatives
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`30
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`such as p-chloro and amino derivatives), detomidine, dexmedetomidine,
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`dipivalylepinephrine, epinephrine, guanabenz, guanfacine, isoproterenol, medetomidine,
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`metaproterenol, mephentermine, methoxamine, methyldopa, naphazoline, norepinephrine,
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`phentolamine, phenylephrine, rilmenidine, salbutamol, terbutaline, tetrahydrozoline,
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`xylazine, thymoxamine, and their pharmaceutically acceptable salts and prodrugs.
`
`[0072]
`
`In the subject invention a "therapeutically effective amount” is any amount of the
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`one or more active ingredients present in the preparation of the present invention which,
`
`when administered to a subject suffering from a refractive error are effective to cause
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`miosis sufficient to temporarily reduce, ameliorate, or treat the refractive error such that
`
`the vision of the treated eye is temporarily restored partially or completely. A complete
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`10
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`restoration of vision should be sufficient to allow the person to read a Times New Roman
`
`font of size 12 without any other aid at a near distance or a far distance, depending upon
`
`the refractive error being treated. A partial restoration of near vision will allow the treated
`
`eye to see with decreased blurriness. Furthermore, a "therapeutically effective amount"is
`
`any amount of the one or more active ingredients present in the preparation of the present
`
`15
`
`invention which, when administered to a subject suffering from a refractive error are
`
`effective to cause miosis sufficient to temporarily reduce, ameliorate, or treat the refractive
`
`error such that the multifocality of the treated eye is temporarily restored partially or
`
`completely. Multifocality is restored if more than focal length is observed by perso