(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`23 January 2014 (23.01.2014)
`
`WIPO!) PCT
`
`\SS
`
`(10) International Publication Number
`WO 2014/015183 Al
`
`GD)
`
`International Patent Classification:
`A61K 45/06 (2006.01)
`AGIK 31/4168 (2006.01)
`A61P 27/10 (2006.01)
`A6L1K 31/4174 (2006.01)
`A61K 9/00 (2006.01)
`AGIK 31/4178 (2006.01)
`A6LK 31/137 (2006.01)
`AG6LK 31/4402 (2006.01)
`A61K 31/167 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2013/051153
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(7)
`
`(72)
`(7)
`
`(74)
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`(81)
`
`Filing Language:
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`Publication Language:
`
`18 July 2013 (18.07.2013)
`
`English
`
`English
`
`Priority Data:
`13/553,615
`
`19 July 2012 (19.07.2012)
`
`US
`
`Applicant (for MN only): JUANG, Agnes [US/US]; 2040
`MainStreet, 14th Floor, Irvine, CA 92614 CUS).
`
`Inventor; and
`Applicant
`: VEJARANO RESTREPO, Luis Felipe
`[CO/CO}]; Carrera: 5 No. 2 -23, Popayan (CO).
`
`Agent: ALTMAN, Daniel E.; KNOBBE MARTENS
`OLSON & BEAR, LLP, 2040 Main Street, 14th Floor,
`Irvine, CA 92614 (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, CII, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,GT,
`IIN, IIR, IU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, 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,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, 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, SIL 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:
`
`as to applicant's entitlement to apply for and be granted a
`patent (Rule 4.17(ii))
`
`as to the applicant's entitlement to claim the priority of the
`earlier application (Rule 4.17(iii))
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: OPHTHALMIC FORMULATION AND METHOD FOR AMELIORATING PRESBYOPIA
`
`(57) Abstract: An ophthalmic formulation having an effective amount ofa parasympathomimetic agent comprising pilocarpine, or a
`pharmaceutically acceptable salt thereof, and one or moreal adrenergic agonists or antagonists is disclosed. The ophthalmic formula-
`tion may enable treatment of conditions adversely affecting the visual acuity of a patient, including presbyopia, A method of using
`the disclosed ophthalmic formulation to treat or ameliorate symptoms of presbyopia is also disclosed.
`
`
`
`wo2014/015183A1IIITINMIIMTAIMIMTAMTTARTANALTTA
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`

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`WO 2014/015183
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`PCT/US2013/051153
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`OPHTHALMIC FORMULATION AND METHOD FOR AMELIORATING
`
`PRESBYOPIA
`
`BACKGROUNDOF THE INVENTION
`
`HieldoftheInvention
`
`8007]
`
`This application relates to a pharmaceutical preparation comprising a
`
`parasympathomimetic drag and an ai
`
`falphal) adrenergic agonist or antagonist
`
`for
`
`amelorating, reducing or treating presbyopia.
`
`Description of the Related Art
`
`18662]
`
`Presbyopia is an age-related rechiction in visual acuity due to a decline im
`
`near focusing ability, commonly associated with blurred appearance of objects at nearby
`
`distances. Symptoms of presbyopta often become noticeable by around age 40 to around age
`
`45. Presiyopia is typically associated with the reduced accommodative ability of the eye.
`
`For example, flexibility or clasticity of the crystalline lens and strength of the cithary muscles
`
`often decrease with age. A deerease in the flexibility or elasticity of the crystalline lens or
`
`the strength of ciliary muscles can be associated with a decrease in the ability of the eye im
`
`adpusting the curvature of the crystalline lens to focus on objects at nearby distances,
`
`including objects at around a normal reading distance.
`
`(O003 |
`
`Common treatments of presbyopia include use of eye glasses, such as
`
`reading glasses tyjically worn for near distance vision, and bi-focals or muilti-focals to
`
`provide both improved near and distance vision for patients who already use correction for
`
`distance vision. Corrective contact lenses can also be used to treat presbyopia, including bi-
`
`foeal, multi-focal or monovision contact lenses. Monovision contact lenses typically include
`
`a lens for distance vision in one cye, for example a dominant eye, and a lens for near distance
`
`vision in the other eye, for example a non-dominant eye. Sargical options are also available
`
`for treating presbyopia,
`
`imcluding corrective eye surgery.
`
`For example, retractive eye
`
`surgery generally involves reshaping of the cornea. Refractive surgery can allowreshaping
`
`of the cornea in one eye while feaving the other eye umtreated, for example correcting vision
`
`only in a non-dominant eye for improved near vision while allowing the dommant eye to
`
`maintain distance vision.
`
`Implantation of mtraocular lenses GOL) can be another surgical
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`

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`WO 2014/015183
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`option in treating presbyopia, generally mevolving replacernent of the natural
`
`lens with a
`
`synthetic one. However, eye glasses or corrective lenses ray be cumbersome or provide
`
`inadequate treatment, while surgical correction can be mvasive and are not without risks.
`
`Because these techniques merely compensate for the loss of accommodation by changing the
`
`waylight enters the eye, patients would have to put on the glasses for near vision and remove
`
`the glasses for distance vision, or have only one eye corrected for near vision while the other
`
`eye remains uncorrected in order to maintain distance vision. Thus, a way to ameliorate or
`
`reduce the symptoms of presbyopia while allowing accommodation is needed.
`
`SUMMARY OF THE INVENTION
`
`[084
`
`In somc cmbodimnents, an ophthalmic formulation compriscs an cffcoctive
`
`amount of pilocarpinc, or a pharmaccutically acceptable salt thercof, and enc or more ai
`
`adrenergic agonists or antagonists. The onc or more al adrenergic agonists or antagonists
`
`may be sclected from a group consisting of phenylephrine, phenylpropanolaminc, ctylefrinc,
`
`oxyimetazoline, xilometazoline, tramazoline, and a pharmaceutically acceptable salt thereof,
`
`(O8GS}
`
`In some embodiments, a method of ameliorating, reducing or treating
`
`presbyopia comprises administering an effective amount of an ophthalmic formulation to an
`
`eye of a patient.
`
`The ophthalmic formulation may incinde an effective amount of
`
`pilocarpine, or a pharmaceutically acceptable salt thereof, and one or more al adrenergic
`
`agonists or antagonists. The al adrenergic agonist may comprise phenylephrine, or a
`
`pharmaceutically acceptable salt thereof.
`
`DETAILED DESCRIPTION OF SOME EMBODIMENTS
`
`(6666
`
`The embodiments described in this application relate to a pharmaceutical
`
`preparation Comprising a parasympathomimetic diig and one or more al (alphal) adrenergic
`
`agonists or antagonists.
`
`In some embodiment,
`
`the pharmaceutical preparation described
`
`herein is useful for ameliorating, reducing and/or treating presbyopia or symptoms thereof,
`
`The pharmaceutical preparation may reduce or eliminate the symptoms of presbyopia while
`
`maintaining the accommodative function of the eyes, and allow pationts suffering from
`
`presbyopia the ability to focus both far and near.
`
`In some embodiments, the pharmaceutical
`
`preparation can improve near vision of a patient suffering from presbyopia without affecting
`
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`WO 2014/015183
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`the distance vision.
`
`in some embodiments,
`
`the pharmaceutical preparation may be
`
`formulated into an ophthalmic formulation that can be applied to the eye of a patient
`
`sutfering from conditions relating to presbyopia.
`
`18607]
`
`As used herein, the terms ameliorate, treat or treatment refer to a reduction
`
`in the severity of symptoms of an eye condition adversely affecting visual acuity.
`
`In sore
`
`embodiments, an ophthalmic formulation as described herein is suitable for treating, or
`
`reducing the severity of the symptoms of, presbyopia.
`
`For example, an ophthalmic
`
`formulation as described herein may be suitable for the treatment of presbyopia by enabling
`
`the patient to visually focus on objects at a nearby distance, including objects at around 4
`
`normal reading distance.
`
`(0068)
`
`As used herein, the terms effective amount include quantities of one or
`
`more active ingredients described herein sufficient for the treatment of a condition ofthe eye
`
`adversely affecting visual acnity,
`
`including achieving temporary improvement
`
`in the
`
`symptoms of presbyopia. For example, effective amounts of an active ingredient when
`
`applied te one or both eyes of a patient may enable the patient to visually focus on objects at
`
`a nearby distance, inchiding objects at a distance around a normal reading distance,
`
`[NNO]
`
`Some embodiments describe a pharmaceutical preparation comprising an
`
`effective amount of a parasympathomimetic drug and one or more al adrenergic agonist or
`
`antagonist.
`
`In some embodiments,
`
`the pharmaceutical preparation is an ophthalmic
`
`formulation,
`
`in some embodiments, the ophthalmic formulation comprising an effective
`
`amount of a parasynipathomimetic drug and one or more ol adrenergic agonist or antagonist
`
`may further comprise one or more of ingredients selected from the group consisting ofa
`
`vasoconstricting agent, an anti-histarnine agent, a non-steroid anti-inflaramatory drug, and an
`
`lubricant.
`
`8010)
`
`In some embodiments, the parasympathomimetic drug is pilocarpine or a
`
`pharmaceutically acceptable salt thereof. Pilocarpine is a direct acting parasympathornimetic
`
`agent that acts on M3 mmscarinic receptor,
`
`It can cause the ciliary nmscie im the cye to
`
`contract and provide near focus. However, it may also cause contraction of the pupil or
`
`MOSIs,
`
`fOG1E]
`
`In some embodiments,
`
`the one or more a!
`
`adrenergic agonists or
`
`antagonisis may independently be selected from phenylephrine, phenylpropanolamime,
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`

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`etylefrine, oxymetazoline, xilometazoline, or tramazoline, or a pharrmaccutically acceptable
`
`salt thereof
`
`In some ernbodiments,
`
`the al adrenergic agonists or antagonists may be
`
`phenylephrine. Phenylephrine may dilate the pupil, and mayreduce pupil contraction due to
`
`pilccarpine.
`
`In some embodiments, phenylephrine may contribute to the normal movernent
`
`of pupil
`
`in any light situation, and/or reduces miosis. With proper concentrations of
`
`qilocarpine and phenylephrine, voluntary accommodation of the eyes can be maintaimed or
`
`restored while the presbyopia symptoms are ameliorated or treated,
`
`B012]
`
`In some embodiments of the ophthalmic formulation, pilocarpine or a
`
`pharmaceutically acceptable salt thereof, may be present m the amount of fromabout 0.1%
`
`to about 2.0%, from about 0.1% to about 1.9%, from about 0.2% to about 1.9%, including
`
`from about 0.3%to about 1.9%, from about 0.4%to about 1.9%, from about 6.2%to about
`
`1.8%, from about 0.3%to about 1.79, from abont 0.1%to about 1.8%, from about 6.1%to
`
`about 1.5%, from about 0.1% to about 1.2%, from about 0.1% toe about 1.2% from about
`
`0.1%to about 0.9%, fram about 0.1%to about 0.7%, from about 0.4%to about 1.6%, from
`
`about 0.5%to about 1.3%, or at about 0.4%, about 0.5%, about 0.6%, about 0.7%, about
`
`0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, by weight.
`
`{0013]
`
`In some embodiments of the ophthalmic formulation, the phenylephrine or
`
`a pharmaceutically acceptable salt thereof, may be present in the amount of from about 0.1%
`
`to about 7%, from about 0.1%to about 6%, from about 0.1% to about $.5%, from about
`
`0.1% to about 4.5%, from about 0.1% to about 3%, from about 0.2%to about 3.5%, from
`
`about 0.2%to about 4.5%, from about 0.2%to about 5.5%, from about 0.2% to about 6%,
`
`from about 0.3%to about 5%, from about 0.4%to about 4%, from about 0.5%to about 3%,
`
`fromabout 0.6% to about 3%, from about 0.6% to about 2.5%, fromm about 0.7% to about
`
`2.5%, from about 0.7%to about 2.0%,
`
`or about 0.5%, about 1°, about 1.5%, about 2%,
`
`about 2.5%, about 3, about 3.5%, about 4%, about 3%by weight.
`
`(0014)
`
`In some embodiments, an ophthalmic formulation may further comprise a
`
`vasoconstricting agent.
`
`In some embodiments, a suitable vasoconstricting agent or drug
`
`comprises naphazolinc, or a pharmaccutically acceptable salt
`
`thercof. An ophthalmic
`
`formufation suitable for the treating a condition of the eye adversely affecting the visual
`
`acuity of a patient, for example presbyopia, may comprise effective armounts of one or more
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`vasoconsiricting agents. Alternatively, an ophthalmic formulation may not comrprise ¢ 4
`
`vasoconstricting agent.
`
`{0015}
`
`For example, an ophthalmic formulation may include by weight from
`
`about 0.001% to about 0.020%, inchiding from about 0.002% to about 0.018%, inchiding
`
`from about 0.004% to about 0.016%,
`
`inchiding from about 0.006% fo about 0.01%2,
`
`including from about 0.001% to about 0.015%,
`
`including from about 0.001% to about
`
`0.012%, including from about 0.001%to about 0.011%, inchiding from about 0.661% to
`
`about 0.616%, inchuding from about G.O01%to about 0.009%, inchiding from about 6.001%
`
`to about 0.008%,
`
`including from about 0.002% to about 0.008%,
`
`inchiding from about
`
`0.003% to about 0.609%,
`
`including about 0.002%, about 6.003%, about 0.004%, about
`
`0.005%, about 0.006%, about 0.007%, about 0.608%, about 0.009%, about 0.010%, or about
`
`0.012%, of naphazoline, or a pharmaceutically acceptable salt thereof.
`
`{0816}
`
`In some
`
`embodiments,
`
`an ophthaimic
`
`formulation also optionally
`
`comprises one or more anti-histamine agents. A suitable anti-histamine agent or drug may be
`
`independently
`
`selected
`
`from pheniramine,
`
`chlorpheniramine,
`
`dexchlorphentramine,
`
`dexbrompheniramine,
`
`deschlorphenirarnine,
`
`triprolidine,
`
`brompheniramine,
`
`iodopheniramine, fluorphenirarmine, or a pharmaceutically acceptabie salt thereof
`
`In some
`
`embodiments, the anti-histamine agent is pheniramine, or a pharmaceutically acceptable salt
`
`thereof. Phentramine may serve to avoid conjunctival injection or congestion and reduce red
`
`eye. Ht also has a minimal effect on the ciliary muscle, and may improve accommodation.
`
`Pheniramine or a pharmaceutically acceptable salt thereof, may be present in an amount of
`
`from about 0.01%to about 0.20%, frorn about 0.05%to about 0.15%, from about 0.02% to
`
`about 0.10%, from about 0.03%to about 0.09%, from about 6.04% to about 0.08%, from
`
`about 0.02% to about 0.20%, from about 0.04% to about 0.15%, from about 0.04%to about
`
`0.15%, at about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%,
`
`about 0.07%, about 0.08%, about 0.09%, or about 0.10% by weight in the ophthalmic
`
`formulation, AHcrnatively, an ophthalmic formulation may not comprise an anti-histamime
`
`agent.
`
`(6617)
`
`in some embodiments, an ophthalmic formulation may further comprise a
`
`non-steroid anti-inflammatory drugs (NSAID). The NSATD mayreduceor clurumate anterior
`
`segment inflammation.
`
`In some embodiments, a suitable NSAID is independently selected
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`from the group consisting of nepafenac, meloxicarn, diclofenac, bendazac, ketorolac,
`
`oxyphenbutazone, bromfenac, flurbiprofen, pranoprofen, surprofen, orindomethacin, and a
`
`pharmaceutically acceptable salt thereof,
`
`In some embodiments, an ophthalmic formulation
`
`comprises at least one of nepafenac or meloxicam. Alternatively, an ophthalmic formulation
`
`may not comprise a non-steroid anti-inflammatorydrug.
`
`[8013}
`
`In some embodiments, an ophthalmic formulation may be formulated to
`
`further cormprise an effective amount of a NSAID nepatenac.
`
`For example, an ophthalmic
`
`formulation formulated to comprise nepafenac may inclide by weight from about 0.01% to
`
`about 0.10%,
`
`incloding from
`
`about 0.02%to
`
`about 0,09%,
`
`incloding from
`
`about 0.03%to
`
`about 0.08%,
`
`including from
`
`about 0.04% to
`
`about 0.07%,
`
`inchiding from
`
`about 0.01%to
`
`about 0.09%,
`
`including from
`
`about 0.01%to
`
`about 0.08%,
`
`including from
`
`about 0.01%to
`
`about 0.07%,
`
`including from
`
`about 0.01%to
`
`about 6.06%,
`
`inclading from
`
`about 0.01% to
`
`about 0.05%,
`
`inchiding from
`
`about 0.01% to
`
`about 0.04%,
`
`inchiding from
`
`about 0.01% to
`
`about 0.03%,
`
`including from
`
`about 0.02%to
`
`about 0.08%,
`
`including from
`
`about 0.02%to
`
`about 0.07%,
`
`including from
`
`about 0.02% to
`
`about 0.06%,
`
`inchiding from
`
`about 0.02% to
`
`about 0.05%, including about 0.02%, abont 0.04%, about 0.03%, about 0.04%, or about
`
`0.05%of nepafenac, or a pharmaceutically acceptable salt thereof.
`
`0019}
`
`Ly
`Alternatively,
`
`the NSAID
`
`may be meloxicam.
`
`For example,
`
`the
`
`ophthalmic formulation may imclude by weight from about 0.001% to about 0.015%,
`
`including from about 0.001%to about 0.014%, including from about 0.001%to about 0.013,
`
`including from about G.001% to about 0.014%, mcluding from about 0.001% to about
`AD
`25%,
`
`0.014%, including from about 0.001%to about 0.01
`
`inchiding from about 0.01%to about
`
`0.009%, mehiding from about 0.001% to about 0.008%,
`
`imebiding from about 0.002% to
`
`about 6.007%, inchiding from about 0.002% to about 0.006%, including from about 0.003%
`re
`to about 0.012%, including from about 6.003% to about 0.01%, including from about 6.003%
`
`to about 0.009%, mecluding from about 6.004%to about 0.012%, inchiding about @.003%,
`
`about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.008%,
`
`about 0.010%, or about 0.011% of meloxicam, or a pharmaceutically acceptable salt thereof.
`
`(0020)
`
`An ophthalmic formulation, as described hherem, may also forther
`
`comprise a lubricant or lubricating agent.
`
`In some embodiments, the lubricant or lubricating
`
`agent mayfacilitate administration of the ophthalmic formulation. Suitable hibricants can be
`
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`independently selected from polyethyleneglycol 400 or propyleneglycol.
`
`In some
`
`embodiments,
`
`the ophthalmic formulation comyprises one or more suitable lubricants or
`
`lubricating agents. Alternatively, an ophthalmic formulation maynot comprise a lubricant or
`
`lubricating agent.
`
`LP ag|
`
`In some embodiments, where polyethyleneglycol 400 is selected as the
`
`lubricant for the ophthalmic fornnilation,
`
`the ophthaimic formulation may comprise by
`
`weight of from about 0.01%to about 0.30%, inchiding from about 0.02%to about 0.25%,
`
`0.03%to about 0.20%, 0.64%to about 6.15%, 0.05%to about 0.15%, 6.05%to about 0.10%,
`
`0.10% to about 6.30%, 6.10%to about 0.20%, 0.06% to about 0.20%, 0.05%to about 0.20%,
`
`including about 0.05%, about 0.10%, or about 0.15% of polyethyleneglycol 400 or a
`
`pharmaceutically acceptable salt thereof.
`
`[0022]
`
`in some embodiments,
`
`the lubricant may be propyleneglycol.
`
`For
`
`example, an ophthalmic formulation may inchide by weight of from about 0.01% to about
`
`0.20%, inciiding from abont 0.02%to about 6.10%, inchidme from about 0.04% ta about
`
`9.09%,
`
`inclidine from about 0.04%to about 0.08%,
`
`inchiding from about 0.04%% to about
`
`0.06%,
`
`including from about 0.02% to about 0.10%,
`
`including from about 6.02%to about
`
`0.12%,
`
`inchiding from about 0.02%to about 0.14%,
`
`inchiding from about 0.05%to about
`
`0.20%,
`
`inchiding from about 0.05%to about 0.15%,
`
`incinding about 0.01%, about 0.02%,
`
`about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
`
`0.09%, or about 0.10% of propyiencglycal or a pharmaceutically acceptable salt thereof,
`
`10023]
`
`in some embodiments, the ophthalmic formulation comprises one or more
`
`components to facilitate application of the ophthalmic formmiation.
`
`For example,
`
`the
`
`ophthalmic formulation may also optionally comprise a pharmaceutically acceptable carrier,
`
`antibactcrial agent, or a prescrvative.
`
`In some embodiments, a pharmaccutically acccptabic
`
`carrier comprises purified water.
`
`[0024]
`
`Some embodiments described herein relate to a method of treating a
`
`condition of the cye adversely affecting near distance visual acuity of a patient, including
`
`ameliorating symptoms of presbyopia. A method of treating the symptoms of presbyopia
`
`mayinclude applying to one or both eyes of a patient an ophthalmic formulation as descrihed
`
`herem. The ophthalmic formulation may be applied to the eve of a patient as a liquid, a gel,
`
`a schition, a suspension, or any combmation thereof.
`
`In some embodiments, the ophthalmic
`
`Je
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`formulation is administered to the oye via an ocular route, inchiding topical application to the
`
`conjunctiva.
`
`{0025}
`
`An ophthalmic formulation may cormprise one or more components, each
`
`component may be administered sequentially or simultaneously to the one or both eyes of a
`
`patient for improved visnal acuity, including for the treatment of the symptoms of presbyopia.
`
`For example, application of an ophthalmic formulation comprising an effective amount of a
`
`parasympathomimetic agent and an effective amount of an al adrenergic agonist or
`
`antagonist may
`
`ameliorate
`
`symptoms
`
`of
`
`presbyopia while
`
`allowing
`
`voluntary
`
`accommodation,
`
`10625)
`
`in some embodiments, an ophthalmic formulation as described herein is
`
`applied to one or both eyes of a patient showing symptoms of presbyopia to improve the
`
`ability of the patient to focus on objects at a nearby distance, including objects at around a
`
`normal reading distance.
`
`In some embodiments, application of an ophthalmic formulation as
`
`described herein may sufficiently improve the near distance visual acuity of a patient
`
`independent of other methods oftreatment. For example, admimistration of an ophthalmic
`
`formulation as described herem may enable a patient to focus on objects at a distance around
`
`a normal reading distance without use of corrective lenses or corrective eye surgery.
`
`Administration of the ophthalmic fornnilation mayrelieve symptoms for a patient in the carly
`
`stages of presbyopia, including enabling near distance visual acuity without use of corrective
`
`lonses or glasses.
`
`10027)
`
`in some embodiments, an ophthalmic formulation as described herein is
`
`administered to a patient having symptoms of presbyopia,
`
`in addition to symptoms from
`
`myopia or hyperopia to facilitate near distance visual acuity such that the patient may not
`
`need to depend on the corrective treatment
`
`such as bifocals/multi-focais
`
`lenses or
`
`monovision contact lenses or to remove the glasses to read in myopes,
`
`(0828)
`
`in some embodiments, an ophthalrnic fornmilation as described herein is
`
`administered to one or both cyes of a patient to provide treatment for presbyopia as an
`
`alternative to corrective eye surgery. For example, an ophthalmic formulation as described
`
`herein may be administered to a patient having symptoms of presbyopia where the patient
`
`either prefers not to or cannot reccive corrective eve surgery to treat presbyoria. The
`
`ophthalmic formulation as described herein may also be administered to a nryopic or
`
`8-
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`PCT/US2013/051153
`
`hyperupic patient (with or without astizmatism) having symptoms of presbyopia, but prefers
`
`io receive treatment only for the far vision defect. Altematively, an ophthalmic formulation
`
`as described herein may be administered to a patient who continues to have symptoms of
`
`presbyopia after the patient has undergone corrective eye surgery for presbyopia. The
`
`ophthalmic formulation may be used in conpumetion with corrective eye surgery for
`
`presbyopia to further reduce the symptoms of presbyopia.
`
`In some embodiments,
`
`the
`
`ophthalmic formulation as described hereimis applied to one or both eyes of a patient to
`
`reduce a decline in near distance visual acuity after undergoing a corrective cye surgery for
`
`far vision at a younger age.
`
`10029)
`
`In some embodiments, administration of an ophthalmic formmiation as
`
`described herein facilitates improvement in the symptoms of presbyopia for a patient wha
`
`has reversed a previously received corrective eye surgery for presbyopia. For example,
`
`administration of the ophthalmic formulation may enable reestablishment of binocularity for
`
`a patient after a reversal or regression of a previously received monovision laser surgery for
`
`treating presbyopia.
`
`(0039)
`
`In some embodiments, an ophthalmic formulation as described herein is
`
`administered to a patient to improve the ability of the patient to focus on nearby objects atter
`
`the patient has undergone corrective surgery for treatment of ocular conditions other than
`
`presbyopia, mcluding for example a corrective eye surgery for the treatment of a cataract,
`
`0031]
`
`In some embodiments, an ophthalmic formulation as described herein is
`
`used in conjunction with other treatments for eye conditions, inchiding treatments for the
`
`symptoms of presbyopia. For example, an ophthaimic formulation as described herein may
`
`be adimunistered to a patient in conjunction with use of mono-focal urtraocular fenses, multi-
`
`focal intraocular icnscs, or accommodative intraocular icnses to improve the near focusing
`
`ability of the patient,
`
`10032)
`
`In some embodiments, apphcation of an ophthalmic formulation as
`
`described herem is suitable for reducmg the symptoms of ocular hypertension.
`
`The
`
`ophthalmic formulation may be administered to an eye of a patient to improve symptoms of
`
`ocular hypertension through a reduction in intraocular pressure.
`
`10033]
`
`Although this invention has been disclosed in the context of certain
`
`embodiments and examples, it will be understood by those skilled inthe art that the mvention
`
`9.
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`WO 2014/015183
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`PCT/US2013/051153
`
`extends beyond the specifically disclosed embodiments to other alternative crabodiments
`
`and/or uses of the invention and obvious madifications and equivalents thereof In addition,
`
`while several variations of the embodiments of the invention have been shown and deseribed
`
`in detail, other modifications, which are within the scope of this invention, will be readily
`
`apparent to those of skill in the art based upon this disclosure.
`
`It is also contemplated that
`
`various combinations or sub-combinations of the specific features and aspects of the
`
`embodiments may be made and still fall within the scope of the invention.
`
`It should be
`
`understood that various features and aspects of the disclosed embodiments can be combined
`
`with, or substituted for, one another in order to form varying modes of the ermbodiments of
`
`the disclosed invention. Thus, it is intended that the scope of the invention herein disclosed
`
`should not be limited bythe particular embodiments described above.
`
`EXAMPLES
`
`8034]
`
`A Prospective study was performed under a clinical protocol approved by
`
`the Clinic’s Ethics Commities in Colombia, All subjects had signed an informed consent. A
`
`group of 20 presbvopia subjects with an average age of 49.65 (between 41 and 37 years old)
`
`participated in this study. Of the 20 presbyopia subjects, 9 were emmetropes, 5 were post-
`
`LASIK, and 6 were post-PresbV LASIS. The emmietropes are those who had perfect far
`
`vision but need glasses to correct the near vision. The post-LASIK subjects are those who
`
`received refractive surgery to correct their far visions before developing presbyopia. The
`
`post-PresbY¥ LASIKsubjects are those who previously received refractive surgery to correct
`
`presbyopia, and noticed a slight decrease in the near vision through time.
`
`POG3 5]
`
`Each subject was given one drop of the ophthalmic formulation A in cach
`
`eye. Various vision measurements were taken prior to the administration of the ophthalmic
`
`formulation A, and then 0.5 hour, | hour, 2 hours, 3 hours, 4 hours, 5 hours,
`
`| week and 1
`
`month post administration in cach cye and then bimocularly. Tho vision mcasuroments
`
`performed include uncorrected visual acuity in 20/20 format for distance and Jacgcr for near
`
`(UCVA), best corrected visual acuity G3CVA), Refraction for far and near, pupil size,
`
`Schirmer Test, Endothehal Cell Count, Intra Ocular Pressure GOP), Keratometry, and
`
`Anterior Chamber Depth (ACD).
`
`P36)
`
`The
`
`active
`
`imgredients of
`
`the ophthalmic
`
`formulation A include:
`
`qyalocarpine
`
`0.247% and Phenilephrinc
`
`0.78%.
`
`Additional
`
`ingredients
`
`include:
`
`-1iG-
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`

`

`WO 2014/015183
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`PCT/US2013/051153
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`Polyethyleneglycol as lubricant 6.09%, nepafenac 0.023%, and pheniramine 0.034%, and
`
`naphazoline 0.003%.
`
`UCVA Measurements
`
`Table 1: BinocularUCVAresults for near vision in emumetropes, post-LASIK subjects, post-
`~bresbsubjects, andaverageofallsubjectsVacgerformat
`
`|UCVA Near Gaeger) Emmetropes|Post-LASIK|Past-PresbV|Overall
`
`
`
`
`LL hour
`| 2 hours
`|3hoursOFOBBFS
`
`i 4 hours
`| 5 hours
`3]
`i
`| week
`3.26
`I
`
`|
`L month
`3.34
`1.12
`1.83
`241
`
`37]
`
`The binocular UCVA results for near vision shows that the ophthalmic
`
`formulation is effective in correcting the near vision in the preshbyopia subjects, regardless of
`
`whether they had a perfect distance vision or previously had refractive surgerics to correct
`
`either the distance or near vision. The same results were also obtamed for measurements
`
`performed on cach cye separately, indicating that the ophthalmic fornmilation treatment is
`
`effective in treating both eyes, and is not a monovision treatment. The resulis mdicate
`
`improvement of the near vision by 2-3 lines in each eye and bmocularly. Surprisingly, with
`
`only | drop m each eye and administered once, the near vision improvement persisis even at
`
`| week and at 1 month later, past the acting period of the ophthalmic formulation. Although
`
`ihe near vision improvement fades a Little after the initial acting period, the potential long-
`
`term benefit of the ophthalmic formulation has been demonstrated with only 1 drop
`
`installation.
`
`Table 2: Binocular UCVA results for distance vision in emmetropes, post-LASIK subjects,
`
`
`
`nost-PresbV subiects, and average of all subjects (20/20 format).
`
`
`| UCVA Far (20/20)
`| Emmetropes
`| Post-LASIK | Post-PreshV_
`| Overall
`
`_Pre-eyedrop20/2361(20/245120/275120/25
`| 26/20.56
`| 6.5 hour post
`| 20/23
`1 20/21.67
`£ 20/215
`
`
`
`| 20/2441
`| 20/30
`|i hour
`| 20/23
`|2bours20/2056(20221 20/20.83(2621
`3 hours
`i 20/20
`i 20/20
`
`
`
`£ 20/20
`£ 20/20
`i 4 hours
`TLeneeeheedencreenaceenenennnnenenncnenel
`i S hours
`20/21
`1260.75
`
`
`
`

`

`WO 2014/015183
`
`PCT/US2013/051153
`
` a
`
`| 20/20.5
`| 20/20.83
`| 20/21
`| 20/20
`1 week
`|
`
`
`
`
`
`i month | 20/20 | 20/20 | 20/20.83| | 20/20.2CeeenneeteetaNnaetnaed
`
`G038)
`
`The binocular UCVA results for distance vision shows that the ophthalmic
`
`formulation does not adversely affect
`
`the visual acuity for the distance vision of the
`
`presbyopia subjects, regardless of whether they had a perfect distance vision or previously
`
`had refractive surgeries to correct either the distance or near vision. The same results were
`
`also obtained for measurements performed on each eye separately. Furthermore, the results
`
`also indicate improvement of the distance vision by between one and two lines binocularly
`
`and generally by one line in each eye. Thus,
`
`the results for binocular UCVA can be
`
`attributed to the improvements in both eyes. This also shows that, unlike other presbyopia
`
`eye drops,
`
`the ophthalmic formulation disclosed hercin is effective in unproving the near
`
`vision without compromising or adversclyaffecting the distance vision.
`
`Refraction Mcasurcments
`
`(8839)
`
`The refraction of the eye pre- and post-administration of | drop of
`
`ophthalmic formulation was measured. The changes in sphere and cylinder are calculated
`
`from the measurements and displayed in Table 3. The cylinder was not changed by the
`
`ophthalmic formulation, while a mild change in the sphere was observed. The change in the
`
`Sphere is most noticeable at
`
`| hour after the administration of the formulation, but the
`
`change is onlya half of diopter. Since the cylinder docs not change and only mild changeis
`
`observed in the sphere, it only caused a mild myopic shift, and thus no adverse effect on the
`
`distance vision. In comparison, other presbyopia drops cause a large myopic shift to improve
`
`the near vision, but that also decrease the distance vision.
`
`Table 3: Refractive change following the admimustration of 1 drop of ophthalmic formulation
`
`
`
`measure in Diopters}.
`
`
`
`
` 0.5h l week|1 mo| ih | 2h 3h 4h Sh
`
`
`
`
`
`
`
`P-O.5h
` § -O.36 23 -O.11
`~O.07-O.10 -O.0)
`
`
`
`
`
`
`
`
`Capacity of Accommeadation
`
`(6640)
`
`The optical quality of the eye was measured using an OQAS HD Analyzer
`
`prior fo the administration of the ophthalmic formulation and 2 hours after ad