(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`\=
`
`(43) International Publication Date
`30 December 2015 (30.12.2015)
`
`WIPO!IPCT
`
`GD)
`
`International Patent Classification:
`A61K 31/46 (2006.01)
`A61K 9/08 (2006.01)
`A61K 31/245 (2006.01)
`A61P 27/02 (2006.01)
`
`(81)
`
`QD
`
`International Application Number:
`
`PCT/US2015/037249
`
`(22)
`
`International Filing Date:
`
`23 June 2015 (23.06.2015)
`
`(10) International Publication Number
`WO 2015/200361 Al
`
`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.
`
`(25)
`
`(26)
`
`(30)
`
`(7D)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`Priority Data:
`62/016,502
`62/096,433
`62/151,926
`14/726,139
`
`24 June 2014 (24.06.2014)
`23 December 2014 (23.12.2014)
`23 April 2015 (23.04.2015)
`29 May 2015 (29.05.2015)
`
`English
`
`English
`
`US
`US
`US
`US
`
`Applicant: SYDNEXIS, INC. [US/US]; 14051 Caminito
`Vistana, San Diego, CA 92130 (US).
`
`14051 Caminito
`I.;
`Inventors: OSTROW, Gregory,
`Vistana, San Diego, CA 92130 (US). WIDDER, Kenneth,
`J.; P.O. Box 676250, Rancho Santa Fe, CA 92067 (US).
`BAKER, David, S.; 7205 Aviara Drive, Carlsbad, CA
`92011 (US).
`
`(74)
`
`J.; Wilson Sonsini
`Agent: HOSTETLER, Michael,
`Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA
`94304 (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,
`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))
`
`(34)
`
`Title: OPHTHALMIC COMPOSITION
`
`Fig. 10
`Shelf Life for D20 versus H20 Formulations
`
`lifefmo 206 +
`
`_._ § Shelf life/me Total relatedsubstances
`% imit=8%} SC
`~ a Shelf life/mo Total related substances
`% {limit=B%}.25C
`@ Shelf fife/me Tropic acid’
`(limit=5%) BC
`@ Shelf ifefmo Tropic acid%
`{limit=594).25C.
`
`
`0.01% Atr
`0.9% wify NaCl
`pHS.9HLC
`extemporaneous
`preparation
`
`O.OL% wsfy Att
`0.04% w/w Citrate
`0.9% wis Mach
`G.OL% w/v BAK
`pH5.S H,0
`
`Z
`TLL.
`0.01% vefe Ate
`8.04% wv Citrate
`
`2600 +
`2400 +
`1200
`+
`2000
`soo +
`
`600 /
`400 +
`
`Shelf
`
`“lle.
`0!
`0.01%w/v Atr
`
`2
`wiv Acetate
`0.9% wey Nach
`0.0196 wiv BAK
`pD5.2D.0
`
`
`W..
`O.G1% wfAtr
`0.01% w/v Acetate
`0.9%wi Natt
`6.64% w/e BAK
`pH4SHO
`
`
`
`
`
`(57) Abstract: Provided herein is an ophthalmic composition. In some embodiments, the ophthalmic composition includes a low
`concentration ofan ophthalmic agent for treatment of an ophthalmic disorder or condition; and an ophthalmically acceptable carrier,
`wherein the ophthalmic agentis distributed with substantial unitormity throughout the ophthalmically acceptable carrier. Further dis -
`closed herein include an ophthalmic composition including a low concentration of an ophthalmic agent and deuterated water. Also
`disclosed herein are methods of arresting or preventing myopia development by administering to an eye of an individual in need
`thereof an effective amount of an ophthalmic composition as described herein.
`
`
`
`wo2015/200361A1|IMTIMNNINNIIMTAIMIANITTTATANETAINATA
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`

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`WO 2015/200361
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`PCT/US2015/037249
`
`1
`
`OPHTHALMIC COMPOSITION
`
`CROSS-REFERENCE
`
`[0001]
`
`This application claims the benefit of U.S. Provisional Application Nos. 62/016,502,
`
`filed June 24, 2014; 62/096,433, filed December 23, 2014; and 62/151,926, filed April 23, 2015; and is a
`
`continuation in part of U.S. Application No. 14/726,139, filed May 29, 2015, which are incorporated.
`
`herein by reference in their entirety.
`
`[0002]
`
`BACKGROUND OF THE DISCLOSURE
`Pharmaceutical formulations have an expiration date which is based on the degradation
`
`of the active ingredient.
`
`SUMMARYOF THE DISCLOSURE
`
`[0003]
`
`Provided herein are ophthalmic compositions. In some embodiments, disclosed herein is
`
`an ophthalmic composition, comprising from about 0.001 wt% to about 0.05 wt% of a muscarinic
`
`antagonist and deuterated water, at a pD of from about 4.2 to about 7.9.
`
`[0004]
`
`In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate,
`
`noratropine, atropine-N-oxide, tropine, tropic acid, hyoscine, scopolomine, tropicamide, cyclopentolate,
`
`pirenzapine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is
`
`atropine. In some embodiments, the muscarinic antagonist is atropine sulfate.
`
`[0005]
`
`Tn some embodiments, the ophthalmic composition has a pD of one of: less than about
`
`7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less
`
`than about 6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about6, less than
`
`about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8 after extended period of time
`
`understorage condition.
`
`[0006]
`
`In some embodiments, the ophthalmic composition comprises one of: at least about 80%,
`
`at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least
`
`about 98%, or at least about 99% of the muscarinic antagonist based on initial concentration after
`
`extended period of time under storage condition. As described in this disclosure, the percentage of the
`
`ophthalmic agent in the composition after storage is based on the amount of ophthalmic agent that is
`
`initially present in the composition (i.e. prior to the storage condition).
`
`[0007]
`
`In some embodiments, the ophthalmic composition further has a potency of oneof: at
`
`least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least
`
`99% after extended period of time understorage condition. As described in this disclosure, the potency of
`
`the ophthalmic agent in the composition after storage is based on the potency of ophthalmic agentthatis
`
`initially present in the composition(i.¢. prior to the storage condition).
`
`[0008]
`
`In some embodiments, the extended period of time is one of: about | week, about 2
`
`weeks, about 3 weeks, about | month, about 2 months, about 3 months, about 4 months, about 5 months,
`
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`
`about 6 months, about 8 months, about 10 months, about 12 months, about 18 months, about 24 months,
`
`about 36 months, about 4 years, or about 5 years.
`
`[0009]
`
`In some embodiments, the storage condition has a storage temperature of from about 2°C
`
`to about 10°C or from about 16°C to about 26°C. In some embodiments, the storage condition has a
`
`storage temperature of about 25°C. In some embodiments, the storage condition has a storage
`
`temperature of about 40°C. In some embodiments, the storage condition has a storage temperature of
`
`about 60°C.
`
`[0010]
`
`In some embodiments, the storage condition has a relative humidity of about 60%. In
`
`some embodiments, the storage condition has a relative humidity of about 75%.
`
`[0011]
`
`In some embodiments, the muscarinic antagonist is present in the composition at a
`
`concentration of one of: from about 0.001 wt% to about 0.04 wt%, from about 0.001 wt% to about 0.03
`
`wt%, from about 0.001 wt% to about 0.025 wt%, from about 0.001 wt% to about 0.02 wt%, from about
`
`0.001 wt% to about 0.01 wt%, from about 0.001 wt% to about 0.008 wt%, or from about 0.001 wt% to
`
`about 0.005 wt%.
`
`[0012]
`
`In some embodiments, the composition comprises less than 20% of major degradant
`
`based on the concentration of the ophthalmic agent after extended period of time under storage condition.
`
`In some embodiments, the composition comprises less than 15% of major degradant based on the
`
`concentration of the ophthalmic agent after extended period of time under storage condition.
`
`[0013]
`
`In some embodiments, the composition comprises less than 10% of major degradant
`
`based on the concentration of the ophthalmic agent after extended period of time under storage condition.
`
`In some embodiments, the composition comprises less than 5% of major degradant based on the
`
`concentration of the ophthalmic agent after extended period of time understorage condition.
`
`In some
`
`embodiments, the composition comprises less than 2.5% of major degradant based on the concentration
`
`of the ophthalmic agent after extended period of time understorage condition. In some embodiments, the
`
`composition comprises less than 2.0% of major degradant based on the concentration of the ophthalmic
`
`agent after extended period of time under storage condition. In some embodiments, the composition
`
`comprises less than 1.5% of major degradant based on the concentration of the ophthalmic agent after
`
`extended period of time understorage condition. In some embodiments, the composition comprises less
`
`than 1.0% of major degradant based on the concentration of the ophthalmic agent after extended period
`
`of time under storage condition. In some embodiments, the composition comprises less than 0.5% of
`
`major dcegradant based on the concentration of the ophthalmic agent after extended period of time under
`
`storage condition. In some embodiments, the composition comprises less than 0.4% of major degradant
`
`based on the concentration of the ophthalmic agent after extended period of time under storage condition.
`
`In some embodiments, the composition comprises less than 0.3% of major degradant based on the
`
`concentration of the ophthalmic agent after extended period of time under storage condition. In some
`
`embodiments, the composition comprises less than 0.2% of major degradant based on the concentration
`
`of the ophthalmic agent after extended period of time under storage condition. In some embodiments, the
`
`

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`3
`
`composition comprises less than 0.1% of major degradant based on the concentration of the ophthalmic
`
`agent after extended period of time understorage condition. In some embodiments, the major degradant
`
`is tropic acid. As described in this disclosure, the percentage of the primary degradant in the composition
`
`after storage is based on the amount of ophthalmic agentthatis initially present in the composition(i.e.
`
`prior to the storage condition).
`
`[0014]
`
`[0015]
`
`In some embodiments, the composition is in a form of an aqueoussolution.
`
`In some embodiments, the composition further comprises an osmolarity adjusting agent.
`
`In some embodiments, the osmolarity adjusting agent is sodium chloride.
`
`[0016]
`
`In some embodiments, the ophthalmic composition further comprises a preservative. In
`
`some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium
`
`perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium,
`
`polyhexamethylene biguanide, or combinations thereof.
`
`[0017]
`
`In some embodiments, the ophthalmic composition further comprises a buffer agent. In
`
`some embodiments, the buffer agent is selected from borates, borate-polyol complexes, phosphate
`
`buffering agents, citrate buffering agents, acetate buffering agents, carbonate buffering agents, organic
`
`buffering agents, amino acid buffering agents, or combinationsthereof.
`
`[0018]
`
`In some embodiments, the ophthalmic composition further comprises a tonicity adjusting
`
`agent. In some embodiments, the tonicity adjusting agent is selected from sodium chloride, sodium
`
`nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc
`
`chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate,
`
`magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen
`
`phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or a
`
`combination thereof.
`
`[0019]
`
`In some embodiments, the composition is stored in a plastic container. In some
`
`embodiments, the material of the plastic container comprises low-density polyethylene (LDPE).
`
`[0020]
`
`In some embodiments, the ophthalmic composition is essentially free of procaine and
`
`benactyzine, or pharmaceutically acceptable salts thereof.
`
`[0021]
`
`In some embodiments, the composition has a dose-to-dose ophthalmic agent
`
`concentration variation of less than 50%. In some embodiments, the composition has a dose-to-dose
`
`ophthalmic agent concentration variation of less than 40%. In some embodiments, the composition has a
`
`dose-to-dose ophthalmic agent concentration variation of less than 30%. In some embodiments, the
`
`composition has a dose-to-dose ophthalmic agent concentration variation of less than 20%. In some
`
`embodiments, the composition has a dose-to-dose ophthalmic agent concentration variation of less than
`
`10%. In some embodiments, the composition has a dose-to-dose ophthalmic agent concentration
`
`variation of less than 5%. In some embodiments, the dose-to-dose ophthalmic agent concentration
`
`variation is based on 10 consecutive doses. In some embodiments, the dose-to-dose ophthalmic agent
`
`concentration variation is based on 8 consecutive doses. In some embodiments, the dose-to-dose
`
`

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`4
`
`ophthalmic agent concentration variation is based on 5 consecutive doses. In some embodiments, the
`
`dose-to-dose ophthalmic agent concentration variation is based on 3 consecutive doses. In some
`
`embodiments, the dose-to-dose ophthalmic agent concentration variation is based on 2 consecutive doses.
`
`[0022]
`
`In some embodiments, the composition further comprises a pD adjusting agent. In some
`
`embodiments, the pD adjusting agent comprises DCI, NaOD, CD3;COOD,or CsDgQv>.
`
`[0023]
`
`In some embodiments, the composition further comprises a pharmaccutically acceptable
`
`carrier. In some embodiments, the ophthalmically acceptable carrier further comprises at least one
`
`viscosity-enhancing agent. In some embodiments, the viscosity-enhancing agent is selected from
`
`cellulose-based polymers, polyoxyethylene-polyoxypropylene triblock copolymers, dextran-based
`
`polymers, polyvinyl alcohol, dextrin, polyvinylpyrrolidone, polyalkylene glycols, chitosan, collagen,
`
`gelatin, hyaluronic acid, or combinationsthereof.
`
`[0024]
`
`In some embodiments, the ophthalmic composition comprises one of: less than 60% of
`
`H.O,less than 55% of H2O, less than 50% of H,0,less than 45% of H2O,less than 40% of H2O,less than
`
`35% of H,O, less than 30% of H,O, less than 25% of H,O, less than 20% of H;O, less than 15% of HO,
`
`or less than 10% of H,O.
`
`[0025]
`
`In some embodiments, the ophthalmic composition comprises one of: less than 5% of
`
`H20O,less than 4% of H.O, less than 3% of HO, less than 2% of H2O,less than 1% of H2O, less than
`
`0.5% of HO, less than 0.1% of H;O, or 0% of H.O.
`
`[0026]
`
`In some embodiments, the ophthalmic composition is stored below room temperature
`
`prior to first use. In some embodiments, the ophthalmic composition is stored at between about 2 °C to
`
`about 10 °C priorto first use. In some embodiments, the ophthalmic composition is stored at between
`
`about4 °C to about 8 °C priorto first use.
`
`[0027]
`
`In some embodiments, the ophthalmic composition is stored at room temperatureafter
`
`first use. In some embodiments, the ophthalmic composition is stored at between about 16 °C to about 26
`
`°C after first use.
`
`[0028]
`
`In some embodiments, the ophthalmic composition is not formulated as an injectable
`
`formulation.
`
`[0029]
`
`In some embodiments, the ophthalmic composition is formulated as an ophthalmic
`
`solution for the treatment of an ophthalmic disorder. In some embodiments, the ophthalmic disorder or
`
`condition is pre-myopia, myopia, or progression of myopia. In some embodiments, the ophthalmic
`
`composition is formulated as an ophthalmic solution for the treatment of pre-myopia, myopia, or
`
`progression of myopia.
`
`[0030]
`
`[0031]
`
`In some embodiments, the ophthalmic composition is a solution.
`
`In some embodiments, disclosed herein is a method of arresting myopia development
`
`that compriscs administcring to an cyc of an individual in need thercof an cffective amount of an
`
`ophthalmic composition described herein. Also described herein is a method of preventing myopia
`
`development that comprises administering to an eye of an individual in need thereof an effective amount
`
`

`

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`PCT/US2015/037249
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`5
`
`of an ophthalmic composition described herein. In some embodiments, described herein is a method of
`
`arresting or preventing myopia development, comprising administering to an eye of an individual in need
`
`thereof an effective amount of an ophthalmic composition comprising from about 0.001 wt% to about
`
`0.05 wt% ofa muscarinic antagonist and deuterated water, at a pD of from about 4.2 to about 7.9.
`
`In
`
`some embodiments, the ophthalmic composition is administered at predetermined time intervals over an
`
`extended period of time. In some embodiments, the ophthalmic composition is administered once every
`
`day. In some embodiments, the ophthalmic composition is administered every other day. In some
`
`embodiments, the ophthalmic composition is administered over 1 week, 2 weeks, | month, 2 months, 3
`
`months, 6 months, | year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years,
`
`11 years, or 12-15 years. In some embodimemts, the ophthalmic composition is stored below room
`
`tempcrature priorto first usc. In some cmbodiments, the ophthalmic composition is stored at between
`
`about 2 °C to about 10 °C priorto first use. In some embodiments, the ophthalmic composition is stored
`
`at between about 4 °C to about 8 °C prior to first use. In some embodiments, the ophthalmic composition
`
`is stored at room temperatureafter first use. In some embodiments, the ophthalmic composition is stored
`
`at between about 16 °C to about 26 °C after first use.
`
`[0032]
`
`In some embodiments, disclosed herein is an ophthalmic solution that comprises from
`
`about 0.001 wt% to about 0.05 wt% ofa muscarinic antagonist and deuterated water, at a pD of from
`
`about 4.2 to about 7.9. In some embodiments, the ophthalmic solution has a pD of oneof: less than about
`
`7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less
`
`than about 6.4, less than about 6.3, less than about6.2, less than about 6.1, less than about6, less than
`
`about 5.9, less than about 5.8, less than about 5.2, or less than about 4.8 after extended period of time
`
`under storage condition. In some embodiments, the muscarinic antagonist comprises atropine, atropine
`
`sulfate, noratropine, atropine-N-oxide, tropine, tropic acid, hyoscine, scopolomine, tropicamide,
`
`cyclopentolate, pirenzapine, homatropine, or a combination thereof. In some embodiments, the
`
`ophthalmic solution comprises oneof: less than 5% of H2O,less than 4% of H2O,less than 3% of H.O,
`
`less than 2% of H,O,less than 1% of H,O,less than 0.5% of H,O,less than 0.1% of H,O, or 0% of HO.
`
`In some embodiments, the ophthalmic composition comprises one of: at least about 80%, at least about
`
`85%, at least about 90%, at lcast about 93%, at Icast about 95%, at lcast about 97%, at lcast about 98%,
`
`or at least about 99% of the muscarinic antagonist based on initial concentration after extended period of
`
`time under storage condition. In some embodiments, the ophthalmic composition further has a potency of
`
`one of: at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or
`
`at least 99% after extended period of time understorage condition. In some embodiments, the extended
`
`period of time is one of: about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months,
`
`about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 10 months,
`
`about 12 months, about 18 months, about 24 months, about 36 months, about 4 years, or about 5 years. In
`
`some embodiments, the muscarinic antagonist is present in the composition at a concentration of oneof:
`
`from about 0.001 wt% to about 0.04 wt%, from about 0.001 wt% to about 0.03 wt%, from about 0.001
`
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`6
`
`wt% to about 0.025 wt%, from about 0.001 wt% to about 0.02 wt%, from about 0.001 wt% to about 0.01
`
`wt%, from about 0.001 wt% to about 0.008 wt%, or from about 0.001 wt% to about 0.005 wt%. In some
`
`embodiments, the storage condition has a storage temperature of from about 2°C to about 10°C or from
`
`about 16°C to about 26°C. In some embodiments, the ophthalmic composition has a dose-to-dose
`
`muscarinic antagonist concentration variation of one of: less than 50%,less than 40%, less than 30%, less
`
`than 20%,less than 10%, or less than 5%. In some embodiments, the dose-to-dose muscarinic antagonist
`
`concentration variation is based on one of: 10 consecutive doses, 8 consecutive doses, 5 consecutive
`
`doses, 3 consecutive doses, or 2 consecutive doses.
`
`[0033]
`
`In some embodiments, disclosed herein is an ophthalmic composition, comprising from
`
`about 0.001 wt% to about 0.05 wt% of a muscarinic antagonist and water, at a pH of from about 3.8 to
`
`about 7.5.
`
`[0034]
`
`In some embodiments, the muscarinic antagonist comprises atropine, atropine sulfate,
`
`noratropine, atropine-N-oxide, tropine, tropic acid, hyoscine, scopolomine, tropicamide, cyclopentolate,
`
`pirenzapine, homatropine, or a combination thereof. In some embodiments, the muscarinic antagonist is
`
`atropine or atropine sulfate.
`
`[0035]
`
`Tn some embodiments, the ophthalmic composition comprises one of: at least about 80%,
`
`at least about 85%, at least about 90%, at least about 93%, at least about 95%, at least about 97%, at least
`
`about 98%, or at least about 99% of the muscarinic antagonist based on initial concentration after
`
`extended period of time under storage condition.
`
`[0036]
`
`In some embodiments, the ophthalmic composition has a pH ofoneof: less than about
`
`7.3, less than about 7.2, less than about 7.1, less than about 7, less than about 6.8, less than about 6.5, less
`
`than about6.4, less than about 6.3, less than about 6.2, less than about 6.1, less than about 6, less than
`
`about 5.9, less than about 5.8, less than about 5.2, less than about 4.8, or less than about 4.2 after
`
`extended period of time understorage condition.
`
`[0037]
`
`In some embodiments, the ophthalmic composition further has a potency of one of: at
`
`least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, at least 98%, or at least
`
`99% after extended period of time under storage condition.
`
`[0038]
`
`In some embodiments, the extended periodof time is one of: about 1 week, about 2
`
`weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months,
`
`about 6 months, about 8 months, about 10 months, about 12 months, about 18 months, about 24 months,
`
`about 36 months, about 4 years, or about 5 years.
`
`[0039]
`
`In some embodiments, the storage condition has a storage temperature of one of: about
`
`25°C, about 40°C, or about 60°C. In some embodiments, the storage condition has a storage temperature
`
`of from about 2°C to about 10°C or from about 16°C to about 26°C.
`
`[0040]
`
`In some embodiments, the storage condition has a relative humidity of about 60% or
`
`about 75%.
`
`

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`WO 2015/200361
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`PCT/US2015/037249
`
`[0041]
`
`In some embodiments, the muscarinic antagonist is present in the composition at a
`
`concentration of one of: from about 0.001 wt% to about 0.04 wt, from about 0.001 wt% to about 0.03
`
`wt, from about 0.001 wt% to about 0.025 wt%, from about 0.001 wt% to about 0.02 wt%, from about
`
`0.001 wt% to about 0.01 wt%, from about 0.001 wt% to about 0.008 wt%, or from about 0.001 wt% to
`
`about 0.005 wt%.
`
`[0042]
`
`In some cmbodiments, the ophthalmic composition further compriscs an osmolarity
`
`adjusting agent. In some embodiments, the osmolarity adjusting agent is sodium chloride.
`
`[0043]
`
`In some embodiments, the ophthalmic composition further comprises a preservative. In
`
`some embodiments, the preservative is selected from benzalkonitum chloride, cetrimonium, sodium
`
`perborate, stabilized oxychloro complex, SofZia, polyquaternium-1, chlorobutanol, edetate disodium,
`
`polyhexamethylene biguanide, or combinations thereof.
`
`[0044]
`
`In some embodiments, the ophthalmic composition further comprises a buffer agent. In
`
`some embodiments, the buffer agent is selected from borates, borate-polyol complexes, phosphate
`
`buffering agents, citrate buffering agents, acetate buffering agents, carbonate buffering agents, organic
`
`buffering agents, amino acid buffering agents, or combinations thereof.
`
`[0045]
`
`In some embodiments, the ophthalmic composition further comprises a tonicity adjusting
`
`agent. In some embodiments, the tonicity adjusting agent is selected from sodium chloride, sodium
`
`nitrate, sodium sulfate, sodium bisulfate, potassium chloride, calcium chloride, magnesium chloride, zinc
`
`chloride, potasstum acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate,
`
`magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen
`
`phosphate, dextrose, mannitol, sorbitol, dextrose, sucrose, urea, propylene glycol, glycerin, or a
`
`combination thereof.
`
`[0046]
`
`In some embodiments, the ophthalmic composition is stored in a plastic container. In
`
`some embodiments, the material of the plastic container comprises low-density polyethylene (LDPE).
`
`[0047]
`
`In some embodiments, the ophthalmic composition has a dose-to-dose muscarinic
`
`antagonist concentration variation ofonc of: less than 50%, less than 40%, Icss than 30%,Iess than 20%,
`
`less than 10%, or less than 5%.
`
`[0048]
`
`In some embodiments, the dose-to-dose muscarinic antagonist concentration variation is
`
`based on one of: 10 consecutive doses, 8 consecutive doses, 5 consecutive doses, 3 consecutive doses, or
`
`2 consecutive doses.
`
`[0049]
`
`In some embodiments, the ophthalmic composition has a pH of one of: from about 3.8 to
`
`about 7.5, from about 4.2 to about 7.5, from about 4.8 to about 7.3, from about 5.2 to about 7.2, from
`
`about 5.8 to about 7.1, from about 6.0 to about 7.0, or from about 6.2 to about 6.8.
`
`[0050]
`
`In some embodiments, the ophthalmic composition further comprises a pH adjusting
`
`agent. In some cmbodiments, the pH adjusting agent compriscs HCl, NaOH, CH3COOH,or CeHgQ,.
`
`[0051]
`
`In some embodiments, the ophthalmic composition comprises oneof: less than 60% of
`
`D,O,less than 55% of DO, less than 50% of D,O,less than 45% of D,O,less than 40% of D,O,less than
`
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`PCT/US2015/037249
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`8
`
`35% of D2O,less than 30% of D2O,less than 25% of D2O, less than 20% of D.O,less than 15% of D2O,
`
`or less than 10% of D2O.
`
`[0052]
`
`In some embodiments, the ophthalmic composition comprises one of: less than 5% of
`
`DO,less than 4% of D.O, less than 3% of DO, less than 2% of D2O,less than 1% of DO, less than
`
`0.5% of D20O,less than 0.1% of D2O, or 0% of D20. In some embodiments, ophthalmic composition is
`
`essentially free of DO.
`
`[0053]
`
`carrier.
`
`[0054]
`
`In some embodiments, the composition further comprises a pharmaceutically acceptable
`
`In some embodiments, the ophthalmic composition is formulated as an ophthalmic
`
`solution for the treatment of an ophthalmic disorder. In some embodiments, the ophthalmic disorder or
`
`condition is pre-myopia, myopia, or progression of myopia.
`
`[0055]
`
`In some embodiments, the ophthalmic composition is not formulated as an injectable
`
`formulation.
`
`[0056]
`
`Other features and technical effects of the methods and compositions described herein
`
`will become apparent from the following detailed description. It should be understood, however, that the
`
`detailed description and the specific examples, while indicating specific embodiments, are given by way
`
`of illustration only.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0057]
`
`The novel features of the disclosu re are set forth with particularity in the appended claims.
`
`A better understanding of the features and advantages of the present disclosure will be obtained by
`
`reference to the following detailed description that sets forth illustrative embodiments, in which the
`
`principles of the disclosure are utilized, and the accompanying drawings of which:
`
`[0058]
`
`Fig. 1A-Fig. 1C show the shelf life prediction of 0.01% atropine sulfate solution with a
`
`primary degradant RRT 0.87-0.89, and a n.m.t. of 0.5% area, based on data obtained from samples stored
`
`at 25°C and 40°C. The pH range ofthe atropine sulfate solution is from 5.9-6.2.
`
`[0059]
`
`Fig. 2A-Fig. 2C show theshelf life prediction of 0.01% atropine sulfate solution with a
`
`primary degradant RRT 0.87-0.89, and a n.m.t. of 0.5% area, based on data obtained from samples stored
`
`at 25°C and 60°C. The pH range of the atropine sulfate solution is from 5.9-6.2.
`
`[0060]
`
`Fig. 3 illustrates mass balance at 4 weeks and at 60°C condition for atropine sulfate
`
`formulations disclosed in Example 9.
`
`[0061]
`
`Fig. 4 illustrates atropine sulfate (0.010%) formulation stability in acetic acid. The
`
`atropine sulfate formulation is formulated with acetic acid and either with H,O (top panel, Formulation 3)
`
`or D,O (bottom panel, Formulation 7). Formulation 3 has a pH of 4.8 and Formulation 7 has a pD of 5.2.
`
`Both formulations are stored at 60 °C for 4 weeks prior to analysis.
`
`[0062]
`
`Fig. 5 illustrates atropine sulfate (0.01%) formulation stability in citric acid. The atropine
`
`sulfate formulation is formulated with citric acid and either with H2O (top panel, Formulation 5) or D,O
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`PCT/US2015/037249
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`9
`
`(bottom panel, Formulation 8). Formulation 5 has a pH of 5.8 and Formulation 8 has a pD of 6.2. Both
`
`formulations are stored at 60 °C for 4 weeks prior to analysis.
`
`[0063]
`
`Fig. 6 illustrates comparison of total RS and tropic acid for atropine sulfate (0.025%)
`
`formulation (Formulation 4) at pH 4.8 in H20.
`
`[0064]
`
`Fig. 7 illustrates comparison of total RS and tropic acid for atropine sulfate (0.01%)
`
`formulation (Formulation 7) at pD 5.2 in D2O.
`
`[0065]
`
`Fig. 8 illustrates comparison of total RS and tropic acid for atropine sulfate (0.01%)
`
`formulation (Formulation 5) at pH 5.8 in H20.
`
`[0066]
`
`Fig. 9 illustrates comparison of total RS and tropic acid for atropine sulfate (0.025%)
`
`formulation (Formulation 6) at pH 5.8 in H20.
`
`[0067]
`
`Fig. 10 illustrates estimated shelf lifes for D2xO and H.O formulations disclosed in
`
`Examples 11 and 12.
`
`DETAILED DESCRIPTION OF THE DISCLOSURE
`
`[0068]
`
`Thepresent disclosure recognizes that there is a need for a stabilized ophthalmic
`
`composition with extended shelf life upon storage. The present disclosure also recognizes that there is a
`
`need for stabilizing an ophthalmic composition through arresting or reducing hydrolysis of at least some
`
`of its active agents. The present disclosure further recognizes that there is a need for an ophthalmic
`
`composition that provides convenient and effective delivery of a muscarinic antagonist such as atropine
`
`in the eye of a patient.
`
`[0069]
`
`Thepresent disclosure recognizes that muscarinic antagonist (e.g. atropine orits
`
`pharmaceutically acceptable salts) prevents or arrests the development of myopia in humans, for example
`
`as evidenced by reduction of the rate of increase of myopia in young people. The present disclosure also
`
`recognizes the cffects of muscarinic antagonist (c.g. atropine or its pharmaccutically acceptable salts) on
`
`reduction of axial elongation and myopia in visually impaired chick eyes, and on ocular growth and
`
`muscarinic cholinergic receptors in young rhesus monkeys.
`
`[0070]
`
`Tn addition, the present disclosure recognizes that systemic absorption of muscarinic
`
`antagonist (e.g. atropine) sometimes leads to undesirable side effect, and that localized delivery of
`
`muscarinic antagonist (e.g. atropine or its pharmaceutically acceptable salts) reduces or prevents the
`
`aforementioned systemic exposure.
`
`[0071]
`
`Further, the present disclosure recognizes that some liquid muscarinic antagonist(e.g.
`
`atropinc) compositions arc formulated at a rclativcly lower pH range (c.g. less than 4.5) for stability of
`
`muscarinic antagonist (e.g. atropine or its pharmaceutically acceptable salts). For some individuals, the
`
`lower pH range in some instances causes discomfort or other side effects such as pain or burning
`
`sensation in the eye, which is prevented or