(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`\a
`
`(43) International Publication Date
`21 September 2017 (21.09.2017)
`
`WIPO!) PCT
`
`GD)
`
`International Patent Classification:
`A61K 31/439 (2006.01)
`AGIK 47/38 (2006.01)
`A61K 31/4409 (2006.01)
`
`QD
`
`International Application Number:
`
`PCT/US2017/021244
`
`(74)
`
`(81)
`
`(22)
`
`International Filing Date:
`
`8 March 2017 (08.03.2017)
`
`(10) International Publication Number
`WO 2017/160548 Al
`
`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, DJ, 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, 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, SM, ST, SV, SY,
`TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA, ZM, ZW.
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`15/073,089
`15/073,139
`15/235,431
`
`17 March 2016 (17.03.2016)
`17 March 2016 (17.03.2016)
`12 August 2016 (12.08.2016)
`
`English
`
`English
`
`US
`US
`US
`
`Applicant: PRESBYOPIA THERAPIES, LLC [US/US];
`915 Ocean Blvd., Coronado, CA 92118 (US).
`
`Inventors: HORN, Gerald; 1150 Heather Road, Deer-
`field, IL 60015 (US). NORDAN,Lee; 26933 Camino De
`Estrella, 2nd Floor, Dana Point, CA 92624 (US).
`
`(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,
`
`[Continued on next page]
`
`(54) Title: COMPOSITIONS AND METHODS FOR THE TREATMENT OF PRESBYOPIA
`
`Vase
`
`20,800
`
`20.400
`20,200
`
`Baseline
`Near ee 20.100
`20.80
`
`ROTO
`
`20.80
`20.50
`
`20,40
`20.30
`
`20.25
`
`Baseline
`DEANE, ne POE
`
`20.13
`
`FIG,
`
`|
`
`MIOTIC +/- TROPICAMIDE
`
`(57) Abstract: The invention provides
`compositions and methods for the treat-
`ment of presbyopia and other vision de-
`fects. The
`compositions
`preferably
`comprise aceclidine and a polyol and/or
`a cycloplegic agent. The compositions
`optionally contain a surfactant, a vis-
`cosity enhancer, an osmolarity modifier
`
`>
`
`and a preservative.
`
`3.0
`Time (hrs)
`
`6.0
`
`70
`
`
`
`wo2017/160548A1TIMINNANTINYTNIIMTINATAMUUMTAIAAT
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`
`
`
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`

`

`SM, TR), OAPI (BF, BJ, CF, CG, CL CM, GA, GN, GQ, Published:
`
`GW, KM, ML, MR, NE, SN, TD, TG). —_with international search report (Art. 21(3))
`
`WO 2017/160548 A1 fTNUIT INTEM TATA TAME TEAAMA
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`WO2017/160548
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`COMPOSITIONS AND METHODS FOR THE TREATMENT OF PRESBYOPIA
`
`BACKGROUND OF THE INVENTION
`
`[001] Asa 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) from their eye
`
`while still 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 presbyopia, loosely
`
`translated as “old-man eye”.
`
`[002] Excellent unaided distance vision is also known as emmetropia. The inability to focus on
`
`distant focal points is known as myopia andthe inability to focus on near focal points is known
`
`as hyperopia. Specifically, “distance” vision is considered any focal point 1 meter or more from
`
`the eye and near vision is any focal point less than 1 meter from the eye. The minimum focal
`
`length at which an object will come into focus is knownas the “near point”. The changein focus
`
`from distance to the near point and any focal point in between is called accommodation.
`
`Accommodation is often 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
`
`eye to a 60 year-old eye is about 13 diopters (1 + 0.072 meters = 13.89 diopters; 1 + 1 meter = 1
`
`diopter).
`
`[003] The highest incidence of first complaint of presbyopia occurs in people ages 42-44.
`
`Presbyopia occurs because as a person ages the eye’s accommodative ability which uses near
`
`reflex-pupil constriction, convergence of the eyes and particularly ciliary muscle contraction,
`
`decreases. This reduction in accommodationresults in an inadequate change in the normal
`
`thickening and increased curvature of the anterior surface of the lens that is necessary for the
`
`shift in focus from distant objects to near objects. Important near focus tasks affected by
`
`presbyopia include viewing computer screens (21 inches) and reading print (16 inches).
`
`[004] Presbyopia is a normal and inevitable effect of ageing andis the first unmistakable sign
`
`for many in their forties that they are getting older. One study found that more than 1 billion
`
`people worldwide were presbyopic in 2005. This same study predicted that number to almost
`
`double by the year 2050. If everyoneover the age of 45 is considered to be presbyopic, then an
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`estimated 122 million people in the United States alone had presbyopia in 2010. As baby
`
`boomersreachthe critical age, this numberis only going to increase.
`
`[005] Presbyopia carries with it a stigma resulting 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
`
`eyeglasses, 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 byloss of depth
`
`perception and distance vision particularly in dim light (e.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
`
`cornea (PresbyLASIK and conductive keratoplasty); (3) scleral band expansion; and (4)
`implantation of corneal inlays (Flexivue Microlens®: registered trademark of PresbiBio LLC,
`Kamra®; registered trademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlays
`
`manufactured by AcuFocus work by inlaying a pinhole on the cornea to increase the depth of
`
`focus.
`
`[006] A similar effect can be achieved with general miotic agents, such as pilocarpine (a non-
`
`selective muscarinic acetylcholine receptor agonist), carbachol (a non-selective muscarinic
`
`acetylcholine receptor agonist), and phospholine iodide (an acetylcholinesterase inhibitor).
`
`These general miotics can induce a pinhole pupil at sufficient concentrations to achieve pupils
`
`below 2.0 mm andpotentially extend depth of focus muchlike an inlay, but at concentrations
`
`sufficient to cause pinhole pupil diamters of 2.0 mm orless these agents trigger increased ciliary
`
`muscle contraction and induce accommodation of any remaining reserves, improving near vision
`
`at the expense of distance vision in individuals whostill retain some accommodativefunction.
`
`The side effects of ciliary spasm induced migraine like brow pain andblurred distance vision
`
`from induced myopia beyond the ability of a pinhole pupil to correct then necessitate using
`
`weaker concentrations with much shorter acting and more marginal effect, such as found with
`
`pilocarpine. In such cases evenslight hyperopia helps offset the induced myopia while even
`
`very small increments of myopia, which is very common, exacerbate it.
`
`In extreme cases, such
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`ciliary muscle spasms may possibly be associated with anterior chamber shallowing and pull on
`
`the ora serrata of the retina, resulting in a retinal tear and or retinal detachment.
`
`[007] 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 describe the use of
`
`pilocarpine to regulate the contraction of ciliary muscles to restore the eyeto its resting state and
`
`potentially restore its accommodative abilities.
`
`[008] US Patent No. 8,524,758 describes the use of pilocarpine 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 regulated. International PCT Application Publication
`
`WO/2013/041967 describes the use of pilocarpine with oxymetazoline or meloxicam to
`
`temporarily overcome ocular conditions such as presbyopia.
`
`[009] US Patent No. 8,299,079 (HEK Development LLC) describes the use of direct acting
`
`general miotic agents such as pilocarpine, carbachol and phospholineiodide with the alpha 2
`
`selective vasoconstrictor brimonidine at a concentration from 0.05% to 3.0% w/v. However, the
`
`use of brimonidine concentrations of about 0.20% (or any at or above 0.05%) w/v inducesciliary
`
`spasm with often migraine intensity brow and/or head aches, and frequently 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.
`
`[010] US Patent Application Publication No. 2014/0113946 describes the use of pilocarpine
`
`with the alpha 1 and mild alpha 2 agonist vasoconstrictor oxymetazoline, demonstrating
`
`limitations in distance sharpness and duration, whereby a cohort largely restricted to mild
`
`hyperopesis required to neutralize the induced myopia (Table 1). Of the 16 eyes treated only
`
`three were -0.25 to -0.50 diopters, and eight were mildly hyperopic. Of the -0.50 diopter eyes
`
`two were reduced to 20.40 distance. Further, duration was limited as full effect became
`
`diminished in about four hours. Pupil size range was from 2.0 mm to 2.7 mm, where enhanced
`
`near effect and distance sharpness from depth of focus was minimal to absent.
`
`[011] These attempts at miotic treatment for presbyopiaall 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. This myopic effect
`
`is amplified by the exponential drop off in distance acuity with even small increments of nominal
`
`myopia in terms of unaided untreated vision. For example, a person having mild myopia (e.g.
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`spherical equivalents of -0.25 D, -0.50 D) that is usually associated with glasses free distance
`
`vision, typically will have several lines of distance vision loss after instillation of pilocarpine 1%
`
`(i.e. spherical equivalent of -0.75 D.).
`
`[012] Miotics historically used to treat glaucoma, other than pilocarpine, particularly
`
`aceclidine, are also associated with ciliary spasm, brow and/or headache, and myopic blur.
`
`Further, aceclidine is unstable in solution. Normally, aceclidine is 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. However, the
`
`primary issue with its use as a presbyopic miotic is the attendant pain and in some cases distance
`
`blur that may be induced.
`
`[013] U.S. Patent No. 9,089,562 describes a composition containing aceclidine combined with
`
`a cycloplegic agent, such that in preferred embodiments aceclidine 1.45% is combined with
`
`tropicamide 0.042%. The addition of the cycloplegic agent at extremely low concentratnos (less
`
`than 0.10%) surprisingly still results in pupil miosis and allows for useful distance and improved
`
`near vision without ciliary spasm (often a migraine like brow ache that can be extremely painful
`
`and disabling), which is induced by the use of aceclidine alone. Further, aceclidine and the
`
`cycloplegic agent require particular narrowly defined ratios and ranges of concentrations relative
`
`to each other such that complications in the manufacturing and regulatory process, particularly
`
`the need for lyophilization of aceclidine to allow its stable storage, and attendanteffects of
`
`cryoprecipitant required, where it is a discovery of the present invention the addition of a
`
`cryoprecipitate such as a polyol, in a preferred embodiment mannitol, results in reduced efficacy
`
`of the defined ranges and ratios of concentrations of US 9,089,562. Due to these medical and
`
`practical inefficiencies, it is discovered an aceclidine composition requiring same orslightly
`
`higher concentrations of aceclidine and much lower concentrations than US 9,089,562 or in
`
`some cases no cycloplegic agent, while allowing for formulation modifications to lyophilize
`
`aceclidine would be preferred for the treatment of presbyopia with necessary commercially
`
`stable formulations. However, to date, no aceclidine composition with amounts of cycloplegic
`
`agent lower than that claimed in US 9,089,562 has been effective to treat presbyopia because, as
`
`mentioned above, aceclidine alone, particularly young and middle-aged presbyopes(ages 45 to
`
`58), severe ciliary spasms and may cause accommodative induced distance blur in somesubjects.
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`[014] Thus, there is a need in the art for a treatment of presbyopia that is non-invasive 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 on near objects without
`
`significant side effects such as diminished distancevision, 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 a reduction or elimination of the need for a
`
`cycloplegic agent to be used with aceclidine potentially enhancing duration andefficacy, as well
`
`as for means of storage of stable aceclidine compositions, where such compositions preferably
`
`enhance both distance and near depth of focus allowing pupil miosis to a 1.50 to 2.0 mm range
`
`without clinically significant side effects.
`
`SUMMARYOF THE INVENTION
`
`[015]
`
`In certain embodiments, the present invention is directed to compositions and methods
`
`for the treatment of presbyopia.
`
`[016]
`
`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 M1 and M3 muscarinic acetylcholine receptors. In still more preferred
`
`embodiments the muscarinic agonist is more highly selective for M1 than M3.
`
`In certain
`
`embodiments, the present invention is directed to compositions and methodsfor the treatment of
`
`presbyopia comprising a muscarinic agonist that preferentially activates M1 and M3 muscarinic
`
`acetylcholine receptors.
`
`[017]
`
`In certain embodiments, the present invention is directed to compositions 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.
`
`[018]
`
`In certain embodiments, the present invention is directed to compositions and methods
`
`for the treatment of presbyopia comprising a muscarinic agonist that activates only M1
`
`muscarinic acetylcholine receptors.
`
`[019]
`
`In certain other embodiments, the present invention is directed to an ophthalmological
`
`composition for the treatment of presbyopia comprising aceclidine.
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`[020]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
`
`from about 0.25% to about 2.0% w/v, and a cycloplegic agent at a concentration from about
`
`0.004% to about 0.025% w/v, preferably from about 0.004% to about 0.02% w/v and more
`
`preferably the cycloplegic agent is tropicamide.
`
`[021]
`
`In certain preferred embodiments, the present invention is directed ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
`
`from about 0.25% to about 2.0% w/v and a polyol, preferably at a concentration from about 1.0%
`
`to about 10.0% w/v, more preferably mannitol at a concentration from about 2.0% to about 3.0%
`
`w/v, wherein the composition is free of a cycloplegic agent.
`
`[022]
`
`In certain preferred embodiments, the present invention is directed ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
`
`from about 0.25% to about 2.0% w/v and a polyol, preferably mannitol at a concentration from
`
`about 1.0% to about 10.0% w/v, more preferably 2.5% w/v and from about 0.004% to about
`
`0.025% of a cycloplegic agent, preferably from about 0.004% to about 0.02% w/v and more
`
`preferably the cycloplegic agent is tropicamide.
`
`[023]
`
`In certain more preferred embodiments, the present invention is directed to
`
`ophthalmological compositions for the treatment of presbyopia comprising about 1.65% to about
`
`1.8% aceclidine and about 2.0% to about 3.0% w/v polyol and from about 0.004% to about
`
`0.025% w/v of a cycloplegic agent, preferably from about 0.004% to about 0.008% w/v and
`
`more preferably the cycloplegic agent is tropicamide, preferably at 0.01% w/v.
`
`[024]
`
`In certain other more preferred embodiments the present invention is directed to
`
`ophthalmological compositions for the treatment of presbyopia that further comprise about 1.0%
`
`to about 6.0% w/v nonionic surfactant and/or about 0.1% to about 2.25% w/v viscosity enhancer.
`
`[025]
`
`In certain more preferred embodiments, the present invention is directed to
`
`ophthalmological compositions for the treatment of presbyopia comprising about 1.75% w/v
`
`aceclidine, about 2.5% w/v polyol, about 2.75% w/v polysorbate 80, and about 1.80% w/v
`
`hydroxypropylmethyl cellulose, and where hydroxypropylmethyl cellulose mayin all
`
`formulations be substituted for about 1.25% to about 1.45% high molecular weight
`
`carboxymethyl cellulose.
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`[026]
`
`In certain more preferred embodiments, the present invention is directed to
`
`ophthalmological compositions for the treatment of presbyopia comprising about 1.75% w/v
`
`aceclidine, about 0.004% to about 0.007% w/v tropicamide, about 2.75% w/v polyol, about 2.5%
`
`w/v polysorbate 80, and about 1.25% to 1.45% w/v carboxymethyl cellulose, or 1.80% w/v
`
`hydroxypropylmethyl] cellulose.
`
`[027]
`
`In certain other embodiments, the present invention is directed to a method oftreating
`
`presbyopia comprising administering to a subject in need thereof a composition of the present
`
`invention.
`
`[028]
`
`In certain other embodiments, the present invention is directed to a method oftreating
`
`presbyopia comprising administering to a subject in need thereof an ophthalmological
`
`composition of the present invention, wherein near vision acuity of the subject is improved by
`
`about 3 lines of resolution or more for at least 6 hours.
`
`[029] A methodof treating a refractive error of the eye in a subject in need thereof comprising
`
`administering to a subject in need thereof a pharmaceutically acceptable amount of a
`
`composition of the present invention wherein the refractive error of the eye is selected from
`
`presbyopia, myopia, hyperopia, astigmatism or a combination thereof.
`
`[030] The present invention is further directed to a methodfor treating presbyopia comprising
`
`administering to a patient in need thereof a composition of the present invention.
`
`[031]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol; and
`
`optionally about 0.004% to 0.015% w/v tropicamide.
`
`[032]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol;
`
`about 1.0% to about 6.0% w/v of a nonionic surfactant;
`
`about 0.1% to about 2.25% w/v hydroxypropylmethyl cellulose; and
`
`optionally about 0.004% to 0.015% w/v tropicamide.
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`[033]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol,
`
`about 1.0% to about 6.0% w/v of a nonionic surfactant, preferably the nonionic surfactant
`
`is selected from a polysorbate, tyloxapol, a poloxamer, a cyclodextrin, vitamin E TPGS
`
`and a polyoxyl, more preferably polysorbate 80, even more preferably from about 1.0% to
`
`about 5.0% w/v polysorbate 80 and most preferably from about 2.0% to about 4.0% w/v
`
`polysorbate 80;
`
`about 0.1% to about 2.25% w/v hydroxypropylmethyl cellulose, more preferably from
`
`about 0.75% to about 1.5% w/v hydroxypropylmethyl cellulose and most preferably from
`
`about 1.0% to about 1.25% w/v hydroxypropylmethy] cellulose;
`
`about 0.10% to about 0.12% w/v sorbic acid;
`
`about 0.005% to about 0.02% w/v benzalkonium chloride; and
`
`optionally about 0.004% to 0.015% w/v tropicamide.
`
`[034]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol;
`
`about 1.0% to about 6.0% w/v of a nonionic surfactant, preferably the nonionic surfactant
`
`is selected from a polysorbate, tyloxapol, a poloxamer, a cyclodextrin, vitamin E TPGS
`
`and a polyoxyl, more preferably polysorbate 80, even more preferably from about 1.0% to
`
`about 5.0% w/v polysorbate 80 and most preferably from about 2.0% to about 4.0% w/v
`
`polysorbate 80;
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`about 0.1% to about 2.25% w/v hydroxypropylmethyl cellulose, more preferably from
`
`about 0.75% to about 1.5% w/v hydroxypropylmethyl cellulose and most preferably from
`
`about 1.0% to about 1.25% w/v hydroxypropylmethyl cellulose;
`
`about 0.10% to about 0.12% w/v sorbic acid;
`
`about 0.005% to about 0.02% w/v benzalkonium chloride;
`
`one or more antioxidants selected from the group consisting of ethylenediaminetetraacetic
`
`acid (EDTA), ethylenediaminetetraacetic acid dihydrate, sodium citrate and citrate buffer,
`
`preferably selected from the group consisting of ethylenediaminetetraacetic acid dihydrate
`
`and sodium citrate or citrate buffer; and
`
`optionally about 0.004% to 0.015% w/v tropicamide.
`
`[035]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`optionally, about 0.004% to 0.015% w/v tropicamide;
`
`about 1.0% to about 6.0% w/v of a nonionic surfactant;
`
`about 0.1% to about 2.25% w/v hydroxypropylmethyl cellulose;
`
`about 0.10% to about 0.12% w/v sorbic acid; and
`
`about 0.005% to about 0.02% w/v benzalkonium chloride,
`
`wherein the composition is maintained at a temperature from about 2 to about 8 degrees celsius.
`
`[036]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol;
`
`about 4.0% w/v polysorbate 80;
`
`about 1.25% w/v hydroxypropylmethyl cellulose;
`
`about 0.12% w/v sorbic acid;
`
`about 0.1% w/v ethylenediaminetetraacetic acid dihydrate;
`
`about 0.02% w/v benzalkonium chloride; and
`
`about 0.1% w/v sodium citrate or citrate buffer.
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`WO 2017/160548
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`PCT/US2017/021244
`
`[037]
`
`In certain preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising:
`
`about 1.75% w/v aceclidine;
`
`about 2.5% w/v mannitol,
`
`about 4.0% w/v polysorbate 80;
`
`about 1.25% w/v hydroxypropylmethyl cellulose;
`
`about 0.12% w/v sorbic acid;
`
`about 0.1% w/v ethylenediaminetetraacetic acid dihydrate;
`
`about 0.02% w/v benzalkonium chloride;
`
`about 0.1% w/v sodium citrate or citrate buffer; and
`
`about 0.01% w/v tropicamide.
`
`[038]
`
`Ina preferred embodiment the concentration of hydroxypropylmethyl cellulose is from
`
`about 0.1% to about 2.25% w/v, more preferably from about 0.75% to about 1.5% w/v and most
`
`preferably from about 1.0% to about 1.25% w/v. Preferably, the concentration of
`
`hydroxypropylmethyl cellulose is such that the viscosity is from about 1 to about 10,000 cps
`
`priorto instillation, more preferably from about 200 to about 500 cps and most preferably about
`
`400 cps.
`
`[039]
`
`In another preferred embodiment, opththalmological compositions of the present
`
`invention comprise one or more antioxidants selected from the group consisting of
`
`ethylenediaminetetraacetic acid (“EDTA”), ethylenediaminetetraacetic acid dihydrate, sodium
`
`citrate and citrate buffer, preferably 0.1% w/v ethylenediaminetetraacetic acid dihydrate; and
`
`0.1% w/v sodium citrate or citrate buffer.
`
`[040]
`
`In another preferred embodiment, the nonionic surfactant is selected from a polysorbate,
`
`tyloxapol, a poloxamer, a cyclodextrin, vitamin E TPGSand a polyoxyl, preferably polysorbate
`
`80, more preferably 4.0% w/v polysorbate 80.
`
`[041]
`
`In another preferred embodiment, opththalmological compositions of the present
`
`invention have a pH ofabout 4.0 to about 8.0 for tropicamide free compositions and from about
`
`4.0 to about 6.0 in compositions containing tropicamide and more preferably 5.0 in
`
`compositions, regardless of tropicamide content.
`
`[042]
`
`Incertain preferred embodiments, the present invention is directed ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
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`from about 0.25% to about 2.0% w/v, a polyol, preferably mannitol at a concentration from
`
`about 1.0% to about 10.0% w/v, more preferably 2.5% w/v, and a nonionic surfactant, preferably
`
`the nonionic surfactant is selected from the group consisting of a polysorbate, a polyoxyl castor
`
`oil, a polyoxyl stearate, a poloxamer, a polyethylene glycol, a polyoxyethylene glycol alkyl
`
`ether, tyloxapol and 2-[[10,13-dimethyl-17-(6-methylheptan-2-yl)-2,3,4,7,8,9,11,12,14,15,16,17-
`
`dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]ethanol, more preferably polysorbate 80 or
`
`polyoxyl 35 castor oil, more preferably at a concentration of about 0.5% to about 10.0% w/v,
`
`more preferably from about 1.0% to about 7.0% w/v, even more preferably about 2.5% or 3.5%
`
`w/v.
`
`[043]
`
`In certain preferred embodiments, the present invention is directed ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
`
`from about 0.25% to about 2.0% w/v, more preferably 1.75% w/v, a polyol, preferably mannitol
`
`at a concentration from about 1.0% to about 10.0% w/v, morepreferably 2.5% w/v, tropicamide,
`
`preferably at a concentration from about 0.004% to about 0.025% w/v, more preferably about
`
`0.005% to about 0.007%, a nonionic surfactant, preferably polysorbate 80, more preferably at a
`
`concentration of about 0.5% to about 10.0% w/v, more preferably from about 2.0% to about
`
`6.0% w/v, even more preferably about 2.5% to about 4.0% w/v and a viscosity enhancer,
`
`preferably selected from the group consisting of a cellulose derivative, hyaluronate, a carbomer
`
`and a gum, more preferably high molecular weight carboxymethyl cellulose or carbomer 940,
`
`preferably at a concentration from about 1.0% to about 2.0% w/v, and more preferably about
`
`1.35% to 1.45% w/v and even more preferably about 1.42% w/v, or other viscosity agent such as
`
`hydroxypropylmethyl cellulose, preferably at a concentration from about 1.0% to about 2.0%,
`
`and more preferably about about 0.50% to 1.95%, wherein initial viscosity of the composition
`
`prior to instillation in the eye may range from about 25 to about 10,000 centipoise, and more
`
`preferably about 100 to about 5,000 centipoise and may be non-Newtonian and or inducetear
`
`secretion resulting in minimalblur, and or with minimal blurat high shear (intrablink) vs. low
`
`shear (between blinks) after instillation.
`
`[044]
`
`In certain preferred embodiments, the present invention is directed ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine, preferably at a concentration
`
`from about 0.25% to about 2.0% w/v, more preferably 1.75% w/v, a polyol, preferably mannitol
`
`at a concentration from about 1.0% to about 10.0% w/v, more preferably 2.5% w/v,tropicamide,
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`preferably at a concentration from about 0.004% to about 0.025% w/v, more preferably about
`
`0.005% to about 0.007%, a nonionic surfactant, preferably polysorbate 80, more preferably at a
`
`concentration of about 0.5% to about 10.0% w/v, more preferably from about 2.0% to about
`
`6.0% w/v, even more preferably about 2.5% to about 4.0% w/v, a viscosity enhancer, preferably
`
`selected from the group consisting of a cellulose derivative, hyaluronate, carbomer 940 and a
`
`gum, more preferably high molecular weight carboxymethyl cellulose or carbomer 940,
`
`preferably at a concentration from about 1.0% to about 2.0% w/v, and more preferably about
`
`1.35% to 1.45% w/v and even more preferably about 1.42% w/v, or other viscosity agent such as
`
`hydroxypropylmethyl cellulose, preferably at a concentration from about 0.5% to about 1.75%,
`
`and morepreferably about 0.75% or 1.5%, most preferably from about 1.0% to about 1.5%, and
`
`most preferably at about 1.05% to 1.25%, wherein initial viscosity of the composition prior to
`
`instillation in the eye may range from about 25 to about 10,000 centipoise, and more preferably
`
`about 100 to about 5000 centipoise and may be non-Newtonian with minimal blur at high shear
`
`(intrablink) vs. low shear (between blinks) after instillation, and a preservative, preferably
`
`selected from the group consisting of benzalkonium chloride (“BAK’’), sorbic acid and
`
`oxychloro complex.
`
`[045]
`
`In preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine and tropicamide.
`
`[046]
`
`In other preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine at a concentration from
`
`about 0.25% to about 2.0% w/v and a cycloplegic agent.
`
`[047]
`
`In other preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine and from about 0.004% to
`
`about 0.08% w/v of a cycloplegic agent, preferably from about 0.004% to about 0.049% w/v and
`
`more preferably from about 0.004% to about 0.025% w/v.
`
`[048]
`
`In other preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine and from about 0.25% to
`
`about 2.0% w/v and from about 0.004% to about 0.08% w/v of a cycloplegic agent, preferably
`
`from about 0.004% to about 0.049% w/v and more preferably from about 0.004% to about
`
`0.025% wiv.
`
`12
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`WO 2017/160548
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`PCT/US2017/021244
`
`[049]
`
`In other preferred embodiments, the present invention is directed to ophthalmological
`
`compositions for the treatment of presbyopia comprising aceclidine and from about 0.25% to
`
`about 2.0% w/v and tropicamide at a concentration from about 0.004% to about 0.08% w/v,
`
`preferably from about 0.004% to about 0.049% w/v and more preferably from about 0.004% to
`
`about 0.025% w/v.
`
`[050]
`
`[051]
`
`In certain other embodiments, the present invention is directed to a method oftreating
`
`presbyopia comprising administering to a subject in need thereof a composition of the present
`
`invention.
`
`[052]
`
`In certain other embodiments, the prese