(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`COQ ATACATT ATAA
`
`(43) International Publication Date
`22 December 2016 (22.12.2016)
`
`WIPO!) PCT
`
`\SS
`
`(10) International Publication Number
`WO 2016/205068 Al
`
`GD)
`
`International Patent Classification:
`A61K 9/00 (2006.01)
`AGIK 47/24 (2006.01)
`A61K 31/439 (2006.01)
`A61K 47/46 (2006.01)
`A61K 31/4409 (2006.01)
` A61K 47/38 (2006.01)
`A6LK 47/14 (2006.01)
`AG6LK 47/02 (2006.01)
`A61K 47/10 (2006.01)
`AGLK 31/498 (2006.01)
`A61K 47/32 (2006.01)
`A61K 31/4164 (2006.01)
`A61K 47/12 (2006.01)
`AG61K 31/165 (2006.01)
`A6IK 47/18 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2016/036687
`
`(22)
`
`International Filing Date:
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`9 June 2016 (09.06.2016)
`
`English
`
`English
`
`(30)
`
`(71)
`
`(72)
`
`Priority Data:
`14/742,921
`14/742,903
`
`18 June 2015 (18.06.2015)
`18 June 2015 (18.06.2015)
`
`US
`US
`
`Applicant: PRESBYOPIA THERAPIES, LLC [US/US];
`915 Ocean Blvd., Coronado, CA 92118 (US).
`
`Inventors: HORN, Gerald; 1150 Heather Road, Deer-
`ficld, IL 60015 (US). NORDAN,Lee; 26933 Camino De
`Estrella, 2nd Floor, Dana Point, CA 92624 (US).
`
`(74)
`
`(81)
`
`Agents: RAINCROW,Jeremy, D. et al.; Wood, Phillips,
`Katz, Clark & Mortimer, 500 West Madison Street, Suite
`1130, Chicago, IL 60661 (US).
`
`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, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HIN, HR, HU,ID,IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NI NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, 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, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, 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))
`
`(54) Title: STORAGE STABLE COMPOSITIONS AND METHODS FOR THE TREATMENT OF REFRACTIVE ERRORS OF
`THE EYE
`
`(57) Abstract: The invention provides compositions and methods for achieving storage stable aceclidine. The compositions prefer-
`ably comprise aceclidine, a cycloplegic agent, a surfactant, a tonicity adjuster and optionally a viscosity enhancer and an antioxidant.
`The invention further provides methods for treating refractive errors of the eye with a storage stable aceclidine composition.
`
`
`
`WoO2016/205068A1IIITINNIIMTANMIMTIITTITAAACTAAT
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`Storage Stable Compositions and Metheads fer the Treatment of Refractive Errors
`
`
`
`Backeround of the Invention
`
`of the Eye
`
`[001] As a person ages the minimum distance from the eye at which an object will come into
`
`focus, provided distance vision is corrected or is excellent unaided, increases. For example, a 10
`
`year-old can focus on an object or a “focal point” only three inches (0.072 meters) fromtheir eye
`
`while stil retaining excellent distance vision; a 40 year-old at six inches (0.15 meters); and a 60
`
`year-old at an inconvenient 39 inches (1.0 meter}. This condition of increasing minimum focal
`
`length in individuals with excellent unaided distance vision is called presbyapia,
`
`loosely
`
`translated as “old-man eye”.
`
`i902] Excellent unaided distance vision is also known as emmetropia. The inability to focus on
`
`distant focal poinis is known as ovyopia and the inability to focus on near focal points is known
`
`as hyperopia. Specifically, “distance” vision is considered any focal point 1 meter or more fromm
`
`the eye and near vision is any focal point less than | meter from the eye. The minimum focal
`
`length at which an object will come into focus is known as the “near point’. The change in focus
`
`from distance to the near point and any focal point in between is called accommodation.
`
`Accommodation is ofien measured in diopters. Diopters are calculated by taking the reciprocal
`
`of the focal length (in meters}. For example, the decrease in accommodation from a 10 year-old
`
`eve to a 60 year-old eye is about 13 diopters (1 + 0.072 meters = 13.89 diopters; i + i meter = 1
`
`diopter}.
`
`{9031 The highest incidence of first complaint of presbyopia occurs in people ages 42-44.
`
`Presbyopia occurs because as a person ages the eye’s acconumodative ability which uses near
`
`reflex-pupil constriction, convergence of the eyes and particularly ciliary muscle contraction,
`
`decreases. This reduction in accommodation results in an inadequate change in the normal
`
`thickening and increased curvature of the anterior surface of the Jens that is necessary for the
`
`shift
`
`in focus from distant objects to near objects.
`
`Important near focus tasks affected by
`
`presbvopia include viewing computer screens (21 inches} and reading print (16 inches).
`
`[04] Presbyopia is a normal and inevitable effect of ageing and is the first unmistakable sign
`
`for many in their forties that they are getting older. One study found that more than | billion
`
`people worldwide were presbyopic in 2005. This same study predicted that number to almost
`
`double by the year Z0S0.
`
`[Uf everyoric over the age of 45 is considered to be presbyopic, then an
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`estimated 122 million people in the United States alone had presbyopia in 2010. As baby
`
`boomers reach the critical age, this numberis only going to increase.
`
`[OOS] Presbyopia carries with it a stigmaresulting from the limitation in ability to quickly
`
`function at many tasks requiring focusing at both distant and near points, which once occurred
`
`almost immediately.
`
`In the presbyopic patient, these tasks can be performed only by the use of
`
`eveglasses, contact lenses or after undergoing invasive surgery. One such optical modification,
`
`the monovision procedure, can be executed with the use of glasses, contact lenses or even
`
`surgery. The monovision procedure corrects one eye for near focus and the other eye for
`
`distance focus. However, monovision correction is normally accompanied by loss of depth
`
`perception and distance vision particularly in dim light (c.g. night}. Other surgical procedures
`
`that have been developed to relieve presbyopia include: (1) the implantation of intraocular lenses
`(INTRACOR®, registered trademark of Technolas Perfect Vision GMBH); (2) reshaping of the
`
`caomea (PresbyLASIS. and conductive keratoplasty}; G)} seleral band expansion; end (4)
`implantation of cormeal inlays (Flexivue Microlens®; registered trademark of PresbiBiio LLC,
`Kamra®;
`registered trademark of AcuFocus,
`Inc. and Vue+})
`Eamra® comeal
`inlays
`
`manufactured by AcuFocus work by inlaying a pinhole on the cornea to increase the depth of
`
`focus, A similar effect can be achieved with general miotic agents, such as pilocarpine (a non-
`
`selective muscarinic acetyichcline receptor agonist}, carbachol
`
`(a non-selective mruscarmic
`
`acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase imhibitor).
`
`These general miotic
`
`agents
`
`trigger
`
`imereased ciliary muscle contraction and induce
`
`accommodation of any remaining reserves, bmproyimng near vision at the expense of distance
`
`vision in individuals who still retain some accommodative Ametion. While these general miotic
`
`agents also create improved depth of focus vie a pinhole effect induced by pupillary miosis (Le.
`
`constriction}, to the degree accommodation occurs, the pinhole effect only partially offsets the
`
`induced accommodative myopia for distance.
`
`In some cases, such as with pilocarpine or
`
`carbachol, the induced accommodation may create up to 5 diopters or more of induced myopia
`
`resulting in induced myopia causing blurred distance vision generally and during shift of the
`
`focal point from distance to near. These general miotic agents also cause substantial redness,
`
`severe nasal congestion and create cillary muscle spasms, which commonly induces discomfort
`
`that can be severe and long-lasting.
`
`In extreme cases, such cillary muscle spasms can result in
`
`retinal detachment.
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`{G06} Miotic agents have been described in various patent and patent applications for the
`
`treatment of presbyopia.
`
`US Patent Nos. 6,291,466 and 6,410,544 deseribe the use of
`
`pllocarpine to regulate the contraction of ciliary muscles to restore the eye to its resting state and
`
`potentially restore its accommodative abilities.
`
`{0071 US Patent Application Publication No. 2010/0016395 describes the use of pilocarpme
`
`with the non-steroidal anti-inflammatory, diclofenac, to reduce brow ache from ciliary spasm and
`
`increase the time in which the ciliary muscle contraction is regulaicd.
`
`International PCT
`
`Application Publication WO/2013/041967 describes the use of pilocarpine with oxymetazoline
`
`or meloxicam to temporarily overcome ocular conditions such as presbyopia.
`
`[808] US Patent No. 8,299,079 (HEKDevelopment LLC) describes the use of direct acting
`
`general miotic agents such as pllocarpine, carbachol and phospholine iodide with briumonidine at
`
`a concentration from 0.05%to 3.0%wiv. However, the use of brimonidine concentrations at or
`
`above 0.05% w/v results in increased rebound hyperemia. For example, rebound redness occurs
`in 25% of patients using brimonidine 0.20% w/v (Alphagan®, registered trademark of Allergan,
`
`Inc.) twice daily.
`
`[908] These attempts at miotic treatrment for presbyopia all induce transient myopia of several
`
`diopters reducing distance vision to about legal blindness or worse at the expense of improved
`
`near vision for the full duration of their action, typically lasting several hours.
`
`{0610} Further, aceclidine is unstable in solution. Normally, aceclidine is stored in a two-boitle
`
`system one bottle containing the lyophilized aceclidine and the second bottle containing the
`
`difuent necessary to reconstitute the lyophilized aceclidine before topical instillation. This two
`
`container system poses the risk of improper reconstitution and therefor improper treatment of
`
`presbyopia.
`
`iG1i} Thus,
`
`there is a need in the art for a treatrnent of presbyopia that is non-imvasive and
`
`convenient with minimal side effects. Specifically, there is a need for an ophthalmological
`
`composition that will allow a person suffering from presbyopia to focus om near objects without
`significant side effects such as diminished distance vision, blurred vision, pain, redness, impaired
`night driving or incapacitating dim light vision,
`induced nasal congestion, or risk of retinal
`
`detachment. Further, there is a need in the art for storage stable acechdine compositions.
`
`fihe lovention,
`Summary
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`{912]
`
`In certain embodimenis, the present invention is directed to compositions and methods
`
`for the treatment of presbyopia.
`
`[G13]
`
`In certain embodiments, the present invention is directed to compositions and methods
`
`for the treatment of presbyopia comprising a muscarinic agonist, wherein the muscarinic agonist
`
`preferentially activates Mi and M3 muscarinic acetylcholine receptors.
`
`In still more preferred
`
`embodiments the muscarinic agonist is more highly selective for Mi
`
`than M3.
`
`In certain
`
`embodiments, the present invention is directed to compositions and methods for the treatment of
`
`presbyopia comprising a muscarinic agonist that preferentially activates MI and M3 muascarimc
`
`acetylcholine receptors.
`
`i014]
`
`In certain embodiments, the present invention is directed to conypositions and methods
`
`for the treatment of presbyopia comprising a muscarinic agonist selected from the group
`
`consisting of aceclidine,
`
`talsaclidine,
`
`sabcomeline, cevimeline, WAY-132983, AFB267B
`
`(NGX267), AC-42, AC-260584, 77-LH-28-1,
`
`and LY593039 or
`
`any pharmaceutically
`
`acceptable salts, esters, analogues, prodrugs or derivatives thereof.
`
`i015]
`
`Im certain embodiments, the present invention is directed to compositions and methods
`
`for the treatment of presbyopia comprising a muscarinic agonist
`
`that activates only Mi
`
`muscarinic acetylcholine receptors.
`
`{G16]
`
`In certain cther embodiments, the present invention is directed to an ophthalmological
`
`composition for the treatment of presbyopia comprising aceclidine.
`
`iG17,
`
`In certain other embodiments the present invention is directed to an ophthalmological
`
`composition for the treatment of presbyopia comprising aceclidine and a cycloplegic agent.
`
`{818}
`
`In certain other embodiments, the present invention is directed to an ophthalmological
`
`composition for the treatment of presbyopia comprising aceclidine and a selective a-2 adrenergic
`
`receptor agonist.
`
`[O19]
`
`In certain other embodiments, the present invention is directed to an ophthalmological
`
`composition for the treatment of presbyopia comprising aceclidine, a cycloplegic agent and a
`
`selective a-2 adrenergic receptor agonist.
`
`[O20]
`
`In certain other embodiments, the present invention is directed to an ophthalmological
`
`composition for the treatrnent of presbyopia comprising a general miotic agent and a cyclaplegic
`
`agent.
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`[921]
`
`In certain other embodiments, the present invention is directed to an ophthalmological
`
`composition of the present invention comprising:
`
`[022]
`
`a general miotic agent, a muscarinic agonist or aceclidine;
`
`optionally a cycloplegic agent;
`
`optionally a selective a-2 adrenergic receptor agonist;
`
`a Viscosity enhancer; and
`
`a surfactant selected from the group consisting of an anionic surfactant, a nonionic surfactant,
`
`and a combination thereof,
`
`{023}
`
`In one embodiment, the present invention is directed to an ophthalmological composition
`
`for the treatment of presbyopia comprising:
`
`iG24]
`
`aceclidine at a concentration from about 0.25%to about 2.0% w/v;
`
`i028}
`
`a cycloplegic agent at a concentration from about 0.025%to about 0.1%w/y, preferably
`
`selected from plirenzepine,
`
`tropicamide, cyclopentolate hydrochloride, 4-diphenylacetoxy-N-
`
`methylpiperidine methiodide (4-DAMP), AF-DX 384, methoctramine, tripitramine, darifenacin,
`
`solifenacin,
`
`tolterodine, oxybutynin,
`
`ipratrophum, oxitropium,
`
`tiotrophim, otenzepad and a
`
`combination thereof and more preferably tropicamide;
`
`i026{
`
`a surfactant, preferably selected from polyoxyl 40 stearate, a gamma cyclodextrin,
`
`sulfobutylether B-cyclodextrin, 2-hydroxypropy! cyclodextrin, sodium lauryl sulfate, sodium
`
`ester lauryl sulfate, a poloxamer, a polysorbate, sorbitan monolaurate, sorbitan monopalmitaie,
`
`sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, a cyclodextrin and combinations
`
`thereof and more preferably polyoxyl 40 stearate;
`
`i027]
`
`a tonicity adjustor, preferably selected from mannitol, sodium chloride, potassium
`
`chioride, glycerin and combinations thereof and more preferably mannitol; and
`
`i028] optionally a viscosity enhancer, preferably the viscosity enhanceris not a polysaccharide,
`
`{029]
`
`In another embodiment,
`
`the present invention is directed to an an ophthalmological
`
`composition for the treatment of presbyopia comprising:
`
`030]
`
`aceclidine at a concentration from about 0.25%to about 2.0% w/v;
`
`[ {
`
`031}
`
`acycloplegic agent at a concentration from about 0.025%to about 0.1% wy;
`
`(632]
`
`asurfactant;
`
`{033]
`
`atonicity adjustor; and
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`one or more excipients selected from a viscosity enhancer selected from the group
`[034]
`consisting of guar gum, hydroxypropyl-guar, xanthan gum,
`alginate, chitosan, gelrite,
`
`hyauluronic acid, dextran, and a carbomer, preferably carbomer 934 or carbomer 940 wherein
`
`the viscosity is from about | ic about 5,000 centipoise (“eps”) priar to topical installation and
`
`from about 1 to about 50 cps upon topical installation, preferably from about 1 to about 5,000
`
`cps at
`
`from about 2 to about $ °C and an antioxidant selecied from citrate, citric acid
`
`monohydrate
`
`ethylenediaminctetraacetic
`
`acid,
`
`disodiurn
`
`ethylenediaminecictraacetic
`
`acid,
`
`dicaicium diethylenctriamine pentaacetic acid and combinations thereof, preferably citme acid
`
`monohydrate.
`{G35}
`In a preferred embodiment, the present invention is directed to en an ophthalmological
`
`composition for the treatment of presbyopia comprising:
`
`G36]
`
`aceclidine at a concentration from about 0.25%to about 2.0% w/v;
`
`O37)
`
`tropicamide at a concentration from about 0.025% to about 0.1%wi/v;;
`
`
`
`
`
`one,pennypinning046]
`
`039] mannitol at a concentration from about 0.5%to about 6.0%w/v;
`
`G38] polyoxyl 40 stearate at a concentration from about 2.0%to about 10.0% w/v;
`3
`
`a buffer selected from acetate buffer, citrate butter, phosphate butfer and citrophosphate
`
`aceclidine at a concentration from about 0.25% to about 2.0% w/y;
`
`trepicamide at a concentration from about 0.025%to about 0.1% w/y;;
`
`buffer at a concentration of about 3 millamelar;
`
`[041] optionally citric acid monohydrate at a concentration from about 0.1% to about 0.2%
`
`wiv;
`
`[942] optionally a viscosity enhancer selected from carbomer 934 and carbomer 940 at a
`
`concentration from about 0.01%ta about 1.0% wy; and
`
`[043] optionally benzalkoniurm chloride (“BAK”) at a concentration of about 0.02% w/y,
`
`1044) wherein the pH of the composition is frorn about 4.75 to about 5.0 and wherethe
`
`viscosity of the cornposition is from about 1 to about 50 cps upon topical installation.
`
`[045]
`
`In another preferred embodiment,
`
`the present
`
`invention is directed to an an
`
`ophthalmological composition for the treatment of presbyopia comprising:
`
`046}
`
`O47]
`
`[ i [
`
`048]
`
`polyoxyl] 40 stearate at a concentration of about 4.0%w/v;
`
`{G49} mannitol at a concentration from about 0.5% to about 6.0%w/v;
`
`i O50]
`
`citric acid monchydrate at a concentration from about 0.1%to about 0.2% w/v,
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`[651]
`[652]
`
`carbomer 934 at a concentration from about 0.01%to about 1.0% w/v, and
`a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate
`
`buffer at a concentration of about 3 millimolar,
`
`[Q53] wherein the pH of the composition is about 4.75 and wherein the viscosity of the
`composition is from about 1 to about 5,000 cps at from about 2 to about § °C.
`[054]
`In another preferred embodiment,
`the present
`invention is directed to an an
`ophthalmological composition for the treatment of presbyopia comprising:
`i058]
`aceclidine at a concentration from about 0.25%to about 2.6% wry,
`[O56]
`twopicamide at a concentration from about 0.025%to about 0.1%w/v;;
`{G57] polyoxyl 40 stearate at a concentration of about 3.5%w/v;
`
`{G58] mannitol! at a concentration of about 4.0% w/v, and
`{959]
`a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate
`buffer at a concentration of about 3 millimolar,
`|
`i060] wherein the pH of the composition is about 3.0.
`invention is directed to an an
`[661]
`In another preferred embodiment,
`the present
`ophthalmological composition for the treatment of presbyopia comprising:
`062]
`aceclidine at a concentration from about 0.25% to about 2.0%w/v;
`063]
`tropicamide at a concentration from about 0.025% to about 0.1% w/v;;
`064]
`polyoxyil 40 stearate at a concentration of about 5.5% w/v;
`068] mannitol at a concentration of about 0.5%to about
`6% w/v;
`[066]
`citric acid monohydrate at a concentration from about 0.3%to about 0.2%w/v;
`{G67}
`carbomer 940 at a concentration from about 0.01%to about 1.0% w/v, and
`{068]
`a buffer selected from acetate buffer, citrate buffer, phosphate buffer and citrophosphate
`
`[ [ [ [
`
`buffer at a concentration of about 3 millimolar,
`
`{069} wherein the pH of the composition is from about 4.75 to about 5.0 and the viscosity of
`the composition is from about 1
`to about 5,000 cps at from about 2 to about 8 °C . In some
`preferred embodiments of the above formulations the aceclidine concentration is about 1.33%to
`about 1.75%w/v, the mannitol concentration is about 1.0% to 2.5%w/v, and the carbomer 940
`
`concentration is about 0.09% to 1.0% w/v
`
`{or equivalent viscosity using any other non-
`
`polysaccharide viscosity agent such as carbomer 934).
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`[O70] A method oftreating a refractive error of the eye in a subject in need thereof comprising
`administering to a subject in need thereof apharmaceutically acceptable amount of a composition
`of the present invention wherein the refractive error of the eye is selected from presbyopia,
`rayoria, byperopia, astigmatism or a combination thereat.
`iQ71] Phe present invention is further directed to a method for treating presbyopia comprising
`administering to a patient in need thereof a composition of the present invention,
`{G72} Amethod for treating a refractive error of the eye comprising administering to a patient
`in need thereof apharmaceutically acceptable amount of a composition of the present invention,
`
`wherein the size of the pupil is reduced to from about 1.5 to about 2.5 millimeters, preferably
`
`from about 1.7 to about 2.0 millimeters and wherein the refractive error is selected from the
`
`irregularity, a
`eroup consisting of corneal bregular astigmatism, an ectasia induced comeal
`pellucid induced corneal irregularity, a higher order aberration and a refractive surgery induced
`
`higher order aberration.
`[O73] The present invention is further directed to a method of increasing the visual depth of
`field tie. depth of focus) comprising administering to a subject
`in need thereof a
`pharmaceutically effective amount of an ophthalmological composition of the present mrvention.
`[074] The present Invention is further directed to a method of increasing the visual depth
`perception upon improving near vision unaided comprising administering to a subject in need
`thereof a pharmaceutically effective amount of an ophthalmological composition of the present
`invention in both eyes (binocular vision}, wherein such binocularity further enhances neay vision
`
`beyond that of either eye separately.
`[075] The present invention is further directed to a method of improving vision in 4 subject
`with ammetropia (vision abnormality), comprising administering to a subject in need thereof a
`
`pharmaceutically effective arnount of a composition of the present invention,
`[076] The present invention is further directed to a method of improving vision im a subject
`with armmetropia, comprising administering to a subject in need thereof a pharmaceutically
`effective amount of a cornposition of the present invention, wherein ammetropiais selected from
`the group consisting of nearsightedness,
`farsightedness,
`regular
`astigmatism,
`irregular
`
`astigmatism and high degrees of regular astigmatism.
`[O77] The present invention is further directed at eliminating optical aberrations induced by
`corneal irregularity, opacities, or very high degrees of reguiar astigmatism that include regions
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`adiacent or peripheral to the central 1.5 mm optical zone, and thereby inducing improved visual
`
`acuity and quality of vision by filtering out these aberrant optics in those suffering from irregular
`
`astigrnatism or high degrees of more regular astigmatism, such as occurs in conditions such as
`
`keratoconus, photorefractive keratectomy induced cormeal haze, diffuse lamellar keratitis
`
`DLE”) (post-lasik DLE),
`
`other iatrogenic corncal
`
`induced irregularity such as cataract
`
`incision, glaucoma filtering blebs, implanted glaucoma valves, corneal inlays with or without
`
`removal, ectasia post corneal surgery (lasik), and secondary to infection.
`
`{O78] The present
`
`invention is further directed at
`
`improving acuity relative to existing
`
`uncorrected refractive error. Upon this improved acuity, patients now requiring toric contact
`
`lenses for astigmatism with reduced comfort and optics that may shift during each blink mayin
`
`many cases require only non-toric soft contact lenses or no contact lenses. Further, those
`
`requiring gas permeable contact lenses may no longer require contact lenses or only require
`
`much more comfortable soft contact lenses. Patients with high degrees of astigrnatism may now
`
`require no correction or reduced astigmatic correction. Patients with small to moderate degrees
`
`of nearsightedness may require less correction or no longer require correction, Patients with
`
`small to moderate degrees of hyperopia Carsightedness) may require no correction or reduced
`
`correction.
`
`[O79] The present invention is directed to methods and ophthalmological compositions for
`
`improving eye sight.
`
`In a preferred embodiment the present invention is directed to methods and
`
`ophthalmological cornpositions for the treatment of presbyopia. In a more preferred embodiment
`
`the present invention is directed to ophthalmological compositions cornprising aceclidine.
`
`In a
`
`yet more preferred embodiment present invention is directed to ophthalmological compositions
`
`comprising aceclidine and a low-dase cycloplegic agent.
`
`In a most preferred embodiment the
`
`present imvention is directed to ophthalmological compositions comprising aceclidine, a low-
`
`dose cycloplegic agent and a combination of inactive ingredients that make effective and/or
`
`enhance aceclidine.
`
`[880] The present invention is further directed to a method for stabilizing the composition of
`
`claim 1 comprising maintaining the composition at 4 ternperature from about 2 to about § °C.
`
`[681] The present invention is further directed to a method for stabilizing an aqueous aceciidine
`
`composition comprising the steps off
`
`MD
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`adding a
`
`surfactant
`
`selected from polyoxy!
`
`40
`
`stearate,
`
`a gamma
`
`cyclodextrin,
`
`sulfobutylether P-cyclodextrin, 2-hydroxypropy! cyclodextrin, sodiumlauryl sulfate, sodium
`
`ester
`
`jauryl
`
`sulfate,
`
`a poloxamer,
`
`a polysorbate,
`
`sorbitan monclaurate,
`
`sorbitan
`
`rmonopalmitate, sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, a cyclodextrin
`
`and combinations thereof to the composition, preferably polyonyi 40 stearate;
`
`adding a tonicity adjustor selected frorn mannitel, sodium chloride, potassiurn chloride,
`
`glycerin and combinations thereof, preferably mannitoh
`
`optionally adding a viscosity enhancer selected from the group consisting of guar gum,
`
`bydroxypropyl-guar, xanthan gum, alginate, chitosan, gelrite, hyauluronic acid, dextran, a
`
`carbomer and combinations thereof to the composition, preferably carbomer 940,
`
`buffering the pH of the composition to from about 4.0 te about 6.0, preferably 4.75; and
`
`maintaining the composition at a ternperature from about 2 to about 8 °C.
`
`{@82] The present invention is further directed to a method for stabilizing an aqueous aceclidine
`
`composition comprising the steps of
`
`adding polyoxyl 40 stearate,
`
`adding mannitol:
`
`adding carbomer 940,
`
`buffering the pHofthe composition to 4.73; and
`
`maintaining the composition at a temperature from about 2 to about 8 PC.
`
`ioftheFigures
`
`[883] Figure i is a graphical representation of the effects of pilocarpine and aceclidine with or
`
`without tropicamide and with or without a carrier on near and distance vision in a patient over
`
`the age of 45.
`
` iptionoftheInvention
`
`[084] The present invention is directed to composrtions and methods of treating presbyopia,
`imregular astigmatism, and/or refractive error, comprising administering to a patient in need
`
`thereof a pharmaceutical composition comprising a muscarinic agonist
`
`that preferentially
`
`activates Mi and M3 muscarinic acetylcholine receptors, preferably activate Mi more than M3
`
`and most preferably aceclidine or
`
`its derivatives. Aceclidine has been surprisingly and
`
`unexpectedly discovered to provide enhanced presbyopic reversal with negligible side effects
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`day or night (when viewing includes one or more direct or reflected light sources) using
`
`compositions of the present invention.
`
`[O85] Aceclidine is traditionally used as a treatment for glancoma. Whenaceclidine is used to
`
`treat glaucoma if is normally stored in a two-bottle system; one bottle containing the lyophilized
`
`aceclidine and the second bottle containing the diluent necessary to reconstitute the lyophilized
`
`aceclidine before topical instillation. Romano J.H., Double-blind cross-over comparison of
`
`aceclidine and pilocarpine in open-angle glaucoma, Brit / Ophthal, Aug 1976, 54(8), S1O-521. Tt
`
`is a further aspect of the present invention to provide an aqueous aceclidine composition that is
`
`stable in combination with cold chain storage.
`
`It is yet a further aspect of the present invention
`
`to provide a method of stabilizing aqueous aceclidine by combining effective excipients, pH
`
`ranges and temperature ranges.
`
`[986] The compositions and methods of the present invention treat presbyopia by improving
`
`depth of focus in patients with presbyopia by administering an ophthalmological composition to
`
`the eye that reduces pupil dilation in the dark or in dim light, produces a particular degree and
`
`duration of miosis without accommodation, provides cosmetic whitening and/or induce redness
`
`prophylaxis.
`
`The compositions and methods of the present
`
`invention also do not cause
`
`significant pupil rebound, tachyphylaxis, ciliary spasms, induction of myopia or reduction im
`
`distance vision. Additionally, the compositions and methads of the present invention allowfor
`
`the further improvement in visual acuity and depth perception of binocular (both eyes) treatment.
`
`The ophthalmological composition of the present invention surprismgly creates a pupil of from
`
`about 1.5 to about 2.4 mumat the anterior iris plane and about 2.0 mmat the corneal surface with
`
`negligible increase in accommodative tone and with a reduction or ablation of the redness that is
`
`otherwise a hallmark of the use of miotic agents. This pupil miosis with greatly diminished or
`
`absent accommodative tone is superior to the pinhole effect of the Kama
`
`® and Flexivue
`
`Microlens® corneal inlays. Pupil miosis is superior because the constriction of the actual pupil
`
`does not result in the attendant severe night vision disturbance caused by the light scattering
`
`borders of the pre-corneal pinholes created by the inlays. Further pupil miosis provides a greater
`
`field of vision and tranemission of more focused light. The use of aceclidine has a minimal
`
`effect on the longitudinal ciliary muscle, thus reducing risk of retinal detachment when compared
`
`to the use of general muscarinic agonists such as pilocarpine and carbachol. The further
`
`inclusion of a cycloplegic agent resulted in only 0.04 mm of anterior chamber shallowing.
`
`il
`
`

`

`WO 2016/205068
`
`PCT/US2016/036687
`
`Aceclidine particularly es enhanced for the present
`
`invention also has greater magnitude,
`
`duration, and control of minimum pupil diameter.
`
`Compositions of the present invention
`
`achieve these advantages while having negligible effects on accornmodation, thus avoiding the
`
`distance blur typically seen in patients as a response to pilocarpine and/or carbachol induced
`
`miosis. Any effects on accormmodation may be further reduced or totally eliminated in preferred
`
`embodiments with a cycloplegic agent. Aceclidine is capable of producing the increased depth
`
`of focus by pupil miosis described in the present invention without the need of a selective a-2
`adrenergic receptor agonist (“a-? agonist”). Particularly enhanced miosis occurs with use of
`
`compositions of the present invention, thus making i possible to use an a-2 agonist al low
`
`concentrations to reduce eye redness. Further, due to the apparent and surprisingly selective
`
`nature of aceclidine, administration io the eve almost exclusively affects pupil miosis rather than
`
`ciliary muscle contraction. Thus, the administration of aceclidine results in pupil miosis without
`
`accommodation and attendant distance blur. However, aceclidine may cause some redness and
`
`browache, and without formulation enhancement ofthe present invention may produce less than
`
`optimal pupil miosis or at extremely high concentration more than desired peak miosis with
`
`added dimuming of vision in dim or absent lighting.
`
`iO87] Certain embodiments of the present invention enhance the discovered preferred degree of
`
`pupillary miosis by providing a consistent range of effect of about 1.50 — 2.20 mm for most
`
`patients using a preferred embodiment of a nonionic serfactant and viscosity enhancer. Sunilar
`henefit may be achieved using other permeation enhancers, particularly Carbop