(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`8 December 2016 (08.12.2016)
`
`\
`=<
`
`WIPO!IPCT
`
`(10) International Publication Number
`WO 2016/196367 Al
`
`(51) International Patent Classification:
`AG1K 9/00 (2006.01)
`A6IK 47/30 (2006.01)
`A6L1K 31/00 (2006.01)
`A61P 27/02 (2006.01)
`AGIK 47/02 (2006.01)
`
`(21) International Application Number:
`
`PCT/US2016/034823
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`27 May 2016 (27.05.2016)
`
`English
`
`English
`
`(30) Priority Data:
`62/168,538
`
`29 May 2015 (29.05.2015)
`
`US
`
`(71) Applicant: SYDNEXIS, INC. [US/US]; 14051 Caminito
`Vistana, San Diego, California 92130 (US).
`
`(72)
`
`14051 Caminito
`Inventors: OSTROW, Gregory I;
`Vistana, San Diego, California 92130 (US). WIDDER,
`Kenneth J.; P.O. Box 676250, Rancho Santa Fe, Califor-
`nia 92067 (US). BAKER, David S.; 7205 Aviara Drive,
`Carlsbad, California 92011 (US).
`
`(74)
`
`Agent: YANG, Frank; Wilson Sonsini Goodrich & Ros-
`ati, 650 Page Mill Road, Palo Alto, California 94304 (US).
`
`(81) 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, LE, LG, ES, FI, GB, GD, GE, GII, GM, GT,
`HN, HR, HU,ID,IL,IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG,
`MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK,EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, KM,ML, MR, NF, 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: D,0 STABILIZED PHARMACEUTICAL FORMULATIONS
`
`Fig. 1
`
`Ciliary body
`
`Suapasary
`Ugqamedt
`Cerne
`
`Pupil
`
`mon,
`
`noe ~ Ghoraid
`
`
`soe Sclera
`
`~ Foves cantralia
`
`prreeetemn Optic nerve
`
`
`
`
`-—---
`
`a
`
`Aqueous
`huror
`(in anterior
`segment)
`
`Scteral various sintes
`isanal of Bohlen
`Vitreaus Ramer
`Cin posterior seqment}
`
` — =.~
`
`
`~~tC
`
`aa
`
`eee Cytle dige
`
`(57) Abstract: Provided herein is an ophthalmic composition formulated in deuterated water. Also disclosed herein are methods of
`treating, ameliorating, or reducing ophthalmic conditions or diseases by administering to an eye of an individual in need thereof an
`effective amount of an ophthalmic composition as described herein.
`
`wo2016/196367A1IIITINNIIMTAIMTATAAT
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`D.0 STABILIZED PHARMACEUTICAL FORMULATIONS
`
`[0001] This application claims the benefit of U.S. provisional patent application serial number
`
`62/168,538, filed May 29, 2015, which is herein incorporated by referencein its entirety.
`
`CROSS REFERENCE
`
`[0002] Pharmaceutical formulations have an expiration date which is based on the degradation
`
`BACKGROUND OF THE DISCLOSURE
`
`of the active ingredient.
`
`SUMMARYOF THE DISCLOSURE
`
`[0003] Provided herein are D2O stabilized pharmaceutical compositions and formulations.
`
`[0004] According to one aspect, an ophthalmic composition disclosed herein comprises an
`
`ophthalmic agent and deuterated water, at a pD of from about 4 to about8.
`
`[0005] According to another aspect, an ophthalmic composition disclosed herein comprises an
`
`ophthalmic agent and deuterated water, at a pD of from about 4 to about 8, wherein the
`
`ophthalmic agent is not a muscarinic antagonist, and wherein the ophthalmic agent does not
`
`extend singlet oxygen lifetime.
`
`[0006]
`
`In some embodiments, the ophthalmic agent comprises aflibercept (also known as
`
`VEGFTrap), ranibizumab, pegaptanib, cyclopentolate, phenylephrine, homatropine,
`
`scopolamine, cyclopentolate/phenylephrine, phenylephrine/scopolamine, tropicamide,
`
`ketorolac/phenylephrine, hydroxyamphetamine/tropicamide, cysteamine, ocriplasmin,
`
`mitomycin, dapiprazole, lidocaine, proparacaine, tetracaine, benoxinate, azithromycin,
`
`bacitracin, besifloxacin, boric acid, chloramphenicol, ciprofloxacin, erythromycin, ganciclovir,
`
`gatifloxacin, gentamicin, idoxuridine, levofloxacin, moxifloxacin, natamycin, norfloxacin,
`
`ofloxacin, bacitracin/polymyxin b, tobramycin, polymyxin b/trimethoprim, povidone iodine,
`
`trifluridine, gramicidin/neomycin/polymyxin b, sulfacetamide sodium, sulfisoxazole,
`
`bacitracin/neomycin/polymyxin b, oxytetracycline/polymyxin b, phenylephrine/sulfacetamide
`
`sodium, vidarabine, bromfenac, nepafenac, ketorolac, cyclosporine, flurbiprofen, suprofen,
`
`diclofenac, alcaftadine, azelastine, bepotastine, cromolyn, emedastine, epinastine, ketotifen,
`
`levocabastine, lodoxamide, nedocromil, naphazoline, naphazoline/pheniramine,
`
`naphazoline/zinc sulfate, olopatadine, oxymetazoline, pemirolast, phenylephrine,
`
`phenylephrine/zinc sulfate, tetrahydrozoline, tetrahydrozoline/zinc sulfate, fluorescein,
`
`fluorescein/proparacaine, benoxinate/fluorescein, indocyanine green, trypan blue, acetylcholine,
`
`apraclonidine, betaxolol, bimatoprost, brimonidine, brinzolamide, brimonidine/brinzolamide,
`
`carbachol, carteolol, demecarium bromide, dipivefrin, dorzolamide, dorzolamide/timolol,
`
`-l-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`echothiophate iodide, epinephrine, epinephrine/pilocarpine, latanoprost, levobunolol,
`
`levobetaxolol, metipranolol, physostigmine, pilocarpine, tafluprost, timolol, travoprost,
`
`unoprostone,artificial tear, dexamethasone, difluprednate, fluocinolone, fluorometholone,
`
`loteprednol, medrysone, prednisolone, rimexolone,triamcinolone,
`
`fluorometholone/sulfacetamide sodium, dexamethasone/neomycin, dexamethasone/tobramycin,
`
`dexamethasone/neomycin/polymyxin b, loteprednol/tobramycin, prednisolone/sulfacetamide
`
`sodium, bacitracin/hydrocortisone/neomycin/polymyxin b, hydrocortisone/neomycin/polymyxin
`
`b, chloramphenicol/hydrocortisone/polymyxin b, neomycin/polymyxin b/prednisolone,
`
`gentamicin/prednisolone, ketorolac/phenylephrine, diphenhydramine, dimenhydrinate,
`
`dicyclomine, flavoxate, oxybutynin, tiotropium, hyoscine, scopolomine (L-hyoscine),
`
`hydroxyzine, ipratropium, pirenzapine, solifenacin, darifenacin, benzatropine, mebeverine,
`
`procyclidine, aclidinium bromide, trihexyphenidyl/benzhexol, tolterodine, or any combinations
`
`thereof.
`
`[0007]
`
`In some embodiments, the ophthalmic composition comprises at least about 80% ofthe
`
`ophthalmic agent based oninitial concentration after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 85% of
`
`the ophthalmic agent based oninitial concentration after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 90% of
`
`the ophthalmic agent based on initial concentration after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 95% of
`
`the ophthalmic agent based on initial concentration after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 97% of
`
`the ophthalmic agent based oninitial concentration after extended period oftime under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 98% of
`
`the ophthalmic agent based oninitial concentration after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition comprises at least about 99% of
`
`the ophthalmic agent based on initial concentration after extended period of time understorage
`
`condition.
`
`[0008]
`
`In some embodiments, the ophthalmic composition has a pD of less than about 8 after
`
`extended period of time under storage condition. In some embodiments, the ophthalmic
`
`composition has a pD ofless than about 7.5 after extended period of time understorage
`
`condition.
`
`In some embodiments, the ophthalmic composition has a pD of less than about 7
`
`after extended period of time under storage condition.
`
`In some embodiments, the ophthalmic
`
`composition has a pD of less than about 6.5 after extended period of time understorage
`
`condition.
`
`In some embodiments, the ophthalmic composition has a pD of less than about 6
`
`-2-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`after extended period of time under storage condition.
`
`In some embodiments, the ophthalmic
`
`composition has a pD of less than about 5.5 after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition has a pD of less than about 5
`
`after extended period of time understorage condition.
`
`In some embodiments, the ophthalmic
`
`composition has a pD ofless than about 4.5 after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition has a pD of less than about 4
`
`after extended period of time under storage condition.
`
`[0009]
`
`In some embodiments, the ophthalmic composition has a pD that is about 0.4 unit
`
`higher than the measured pH.
`
`[0010]
`
`In some embodiments, the ophthalmic composition further has a potency of at least 80%
`
`after extended period of time understorage condition.
`
`In some embodiments, the ophthalmic
`
`composition further has a potency of at least 85% after extended period of time under storage
`
`condition.
`
`In some embodiments, the ophthalmic composition further has a potencyofat least
`
`90% after extended period of time under storage condition.
`
`In some embodiments, the
`
`ophthalmic composition further has a potency of at least 93% after extended period of time
`
`under storage condition. In some embodiments, the ophthalmic composition further has a
`
`potency ofat least 95% after extended period of time under storage condition.
`
`In some
`
`embodiments, the ophthalmic composition further has a potency of at least 97% after extended
`
`period of time under storage condition.
`
`In some embodiments, the ophthalmic composition
`
`further has a potency ofat least 98% after extended period of time under storage condition.
`
`In
`
`some embodiments, the ophthalmic composition further has a potencyof at least 99% after
`
`extended period of time under storage condition.
`
`[0011]
`
`In some embodiments, the extended period of time is about 1 week.
`
`In some
`
`embodiments, extended period of time is about 2 weeks.
`
`In some embodiments, the extended
`
`period of time is about 3 weeks.
`
`In some embodiments, the extended period of time is about 1
`
`month.
`
`In some embodiments, the extended period of time is about 2 months.
`
`In some
`
`embodiments, the extended period of time is about 3 months.
`
`In some embodiments the
`
`extended period of time is about 4 months.
`
`In some embodiments, the extended period of time
`
`is about 5 months.
`
`In some embodiments, the extended period of time is about 6 months.
`
`In
`
`some embodiments, the extended period of time is about 8 months.
`
`In some embodiments,the
`
`extended period of time is about 10 months.
`
`In some embodiments, the extended period oftime
`
`is about 12 months.
`
`In some embodiments, the extended period of time is about 18 months.
`
`In
`
`some embodiments, the extended period of time is about 24 months.
`
`In some embodiments, the
`
`extended period of time is about 36 months.
`
`In some embodiments, the extended period of time
`
`is about 4 years.
`
`In some embodiments, the extended period of time is about 5 years.
`
`-3-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`[0012]
`
`In some embodiments, the ophthalmic composition of any one of the claims 1-44,
`
`wherein the storage condition has a storage temperature of from about 16°C to about 30°C or
`
`about 20°C to about 25°C.
`
`In some embodiments, the storage condition has a relative humidity
`
`of about 60%. In some embodiments, the ophthalmic composition of any one of the claims 1-
`
`45, wherein the storage condition has a relative humidity of about 75%.
`
`[0013]
`
`In some embodiments, the ophthalmic composition is in the form of an aqueous
`
`solution.
`
`[0014]
`
`In some embodiments, the ophthalmic agent is present in the formulation at a
`
`concentration of from about 0.001 wt% to about 20 wt%.
`
`[0015]
`
`In some embodiments, the ophthalmic 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 combinationsthereof.
`
`[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 comprisesa 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 ophthalmic composition is stored in a plastic container.
`
`[0020]
`
`In some embodiments, the ophthalmic composition has a dose-to-dose ophthalmic agent
`
`concentration variation of less than 50%.
`
`In some embodiments, the ophthalmic composition
`
`has a dose-to-dose ophthalmic agent concentration variation of less than 40%.
`
`In some
`
`embodiments, the ophthalmic composition has a dose-to-dose ophthalmic agent concentration
`
`variation of less than 30%.
`
`In some embodiments, the ophthalmic composition has a dose-to-
`
`dose ophthalmic agent concentration variation of less than 20%.
`
`In some embodiments, the
`
`ophthalmic composition has a dose-to-dose ophthalmic agent concentration variation of less than
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`10%.
`
`In some embodiments, the ophthalmic composition has a dose-to-dose ophthalmic agent
`
`concentration variation of less than 5%.
`
`[0021]
`
`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
`
`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 ophthalmic composition has a pD of from about 4 to about 8.
`
`In some embodiments, the ophthalmic composition has a pD of from about 4.5 to about 7.5.
`
`In
`
`some embodiments the ophthalmic composition has a pD of from about 5 to about 7.0.
`
`In some
`
`embodiments, the ophthalmic composition has a pD of from about 6 to about 7.0.
`
`[0023]
`
`In some embodiments, the ophthalmic composition further comprises a pD adjusting
`
`agent.
`
`[0024]
`
`In some embodiments, the ophthalmic composition further comprises a
`
`pharmaceutically acceptable carrier.
`
`In some embodiments, the pharmaceutically acceptable
`
`carrier further comprisesat least one viscosity-enhancing agent.
`
`In some embodiments, the
`
`viscosity-enhancing agent is selected from cellulose-based polymers, polyoxyethylene-
`
`polyoxypropylenetriblock copolymers, dextran-based polymers, polyvinyl alcohol, dextrin,
`
`polyvinylpyrrolidone, polyalkylene glycols, chitosan, collagen, gelatin, hyaluronic acid, or
`
`combinations thereof.
`
`[0025]
`
`In some embodiments, the ophthalmic composition comprises less than 60% of H20. In
`
`some embodiments, the ophthalmic composition comprises less than 55% of H,O. In some
`
`embodiments, the ophthalmic composition comprises less than 50% of H20. In some
`
`embodiments, the ophthalmic composition comprises less than 45% of H2O. In some
`
`embodiments, the ophthalmic composition comprisesless than 40% of H2O. In some
`
`embodiments, the ophthalmic composition comprises less than 35% of HO. In some
`
`embodiments, the ophthalmic composition comprisesless than 30% of H2O. In some
`
`embodiments, the ophthalmic composition comprises less than 25% of H2O. In some
`
`embodiments, the ophthalmic composition comprises less than 20% of H2O. In some
`
`embodiments, the ophthalmic composition comprisesless than 15% of H20.
`
`[0026]
`
`In some embodiments, the ophthalmic composition comprises less than 10% of H2O. In
`
`some embodiments, the ophthalmic composition comprises less than 8% of H,O.
`
`In some
`
`embodiments, the ophthalmic composition comprisesless than 6% of H,O.
`
`In some
`
`-5-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`embodiments, the ophthalmic composition comprisesless than 5% of H,O.
`
`In some
`
`embodiments, the ophthalmic composition comprisesless than 4% of HO.
`
`In some
`
`embodiments, the ophthalmic composition comprisesless than 3% of H,O.
`
`In some
`
`embodiments, the ophthalmic composition comprises less than 2% of H,O.
`
`In some
`
`embodiments, the ophthalmic composition comprises less than 1% of HzO.
`
`In some
`
`embodiments, the ophthalmic composition comprisesless than 0.5% of H20.
`
`In some
`
`embodiments, the ophthalmic composition comprises less than 0.1% of H,O. In some
`
`embodiments, the ophthalmic composition comprises 0% of H,O.
`
`[0027]
`
`In some embodiments, the ophthalmic composition is formulated as an ophthalmic
`
`solution for the treatment of an ophthalmic condition or disease.
`
`[0028]
`
`In some embodiments, the ophthalmic agent is not atropine. In some embodiments, the
`
`ophthalmic agentis not atropine sulfate.
`
`In some embodiment, the ophthalmic agentis not a
`
`muscarinic antagonist.
`
`[0029]
`
`In some embodiments, the ophthalmic agent is not an alpha-amino-carboxylic acid or an
`
`alpha-hydroxy-carboxylic acid.
`
`In some embodiments, the ophthalmic agent is not benactyzine
`
`hydrochloride.
`
`[0030]
`
`In some embodiments, the ophthalmic agent quenches photogenerated singlet oxygen
`
`species in the composition.
`
`In some embodiments, the ophthalmic composition is not saturated
`
`with oxygen.
`
`In some embodiments, the ophthalmic composition does not comprise a
`
`photosensitizer.
`
`[0031]
`
`In some embodiments, the ophthalmic agent is dissolved in the ophthalmic composition.
`
`In some embodiments, the ophthalmic agent is suspended in the ophthalmic composition.
`
`[0032] According to another aspect, a method oftreating an ophthalmic condition or disease
`
`comprises administering to an eye of an individual in need thereof an effective amountof the
`
`ophthalmic composition disclosed in the present disclosure. According to another aspect, a
`
`method of ameliorating or reducing an ophthalmic condition or disease comprises administering
`
`to an eye of an individual in need thereof an effective amount of the ophthalmic composition
`
`disclosed in the present disclosure.
`
`[0033]
`
`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 a day. 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 compositionis
`
`administered over 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 moths, 1 year, 2 years, 3
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, or 12-15 years. In
`
`some embodiments, the ophthalmic composition is administered only once.
`
`[0034]
`
`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 about 4 °C to about8 °C priorto first use.
`
`[0035]
`
`In some embodiments the ophthalmic composition is stored at room temperature prior to
`
`first use.
`
`In some embodiments, the ophthalmic composition is stored at between about 16 °C to
`
`about 26 °C priorto first use.
`
`[0036]
`
`In some embodiments, the ophthalmic composition is stored below room temperature
`
`after first use.
`
`In some embodiments, the ophthalmic composition is stored at between about 2
`
`°C to about 10 °C after first use.
`
`In some embodiments, the ophthalmic composition is stored at
`
`between about 4 °C to about 8 °C after first use.
`
`[0037]
`
`In some embodiments, the ophthalmic composition is stored at room temperature after
`
`first use.
`
`In some embodiments, the ophthalmic composition is stored at between about 16 °C to
`
`about 26 °C after first use.
`
`[0038] Other features and technical effects of the methods and compositions described herein
`
`will become apparentfrom the following detailed description. It should be understood, however,
`
`that the detailed description and the specific examples, while indicating specific embodiments,
`
`are given by wayofillustration only.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0039] The novel features of the disclosure are set forth with particularity in the appended
`
`claims. A better understanding of the features and advantages ofthe present disclosure will be
`
`obtained by referenceto the following detailed description that sets forth illustrative
`
`embodiments, in which the principles of the disclosure are utilized, and the accompanying
`
`drawings of which:
`
`[0040] Fig. 1 illustrates a conceptual representation of the eye anatomy.
`
`DETAILED DESCRIPTION OF THE DISCLOSURE
`
`[0041] The present disclosure recognizes that stability and eye tolerance are parameters to
`
`consider when formulating an ophthalmic composition. In someinstances, to extend the shelf-
`
`life or stability of an ophthalmic composition, the pH of the composition is subsequently
`
`reduced. In some instances, the lowered pH reducesor prevents base catalyzed hydrolysis and
`
`thereby stabilizes the active agent. However, in some cases, the formulation with the reduced
`
`pHleads to poor eye tolerance as the acidic formulation stings the eye, leading to tear
`
`-7-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`production. In such cases, the tears then dilute the composition and/or wash the composition out
`
`of the eye, thereby reducing the effectiveness of the ophthalmic composition.
`
`[0042]
`
`In addition, the present disclosure recognizes that deuterated water stabilizes ophthalmic
`
`compositions. In somecases, the deuterated water is a weak acid as compared to H2O, as such
`
`deuterated water comprises a lower concentration of the reactive species (e.g., -OD) which in
`
`some instances leads to base catalyzed hydrolysis of an active agent in the ophthalmic
`
`composition. As such, in some instances compositions comprising deuterated water leads to
`
`reduced base catalyzed hydrolysis when compared to compositions comprising HO. In some
`
`instances, deuterated water further lowers the buffering capacity of an ophthalmic composition,
`
`leadingto less tear reflex in the eye.
`
`[0043] Disclosed herein are ophthalmic compositions that comprise an ophthalmic agent and
`
`deuterated water, at a pD of from about 4 to about 8. Also disclosed herein are ophthalmic
`
`solutions that comprise an ophthalmic agent and deuterated water, at a pD of from about 4 to
`
`about 8. Further disclosed herein are methodsoftreating an ophthalmic condition or disease that
`
`comprises administering to an eye of an individual in need thereof an effective amount of an
`
`ophthalmic composition or an ophthalmic solution described infra. Additionally disclosed herein
`
`are methods of ameliorating or reducing an ophthalmic condition or disease that comprises
`
`administering to an eye of an individual in need thereof an effective amount of an ophthalmic
`
`composition or an ophthalmic solution described infra.
`
`Ophthalmic Agents
`
`[0044] Disclosed herein are pharmaceutical compositions formulated in the presence of
`
`deuterated water. As used herein, deuterated water refers to D20, DHO, heavy water, and/or
`
`deuterium oxide. In someinstances, the pharmaceutical compositions are ophthalmic
`
`compositions containing one or more ophthalmic agents. In somecases, the ophthalmic
`
`compositions are formulated as an aqueoussolution, gel, or as an ointment.
`
`[0045]
`
`In some embodiments, the ophthalmic agents used in the ophthalmic compositionsare
`
`susceptible to degradation through hydrolysis.
`
`In some embodiment, the ophthalmic agents used
`
`in the ophthalmic compositions are susceptible to degradation through base-catalyzed
`
`hydrolysis.
`
`[0046]
`
`In some embodiments, ophthalmic agents include anti-angiogenic ophthalmic agents,
`
`mydriatics, antimydriatic agents, ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic
`
`anti-inflammatory agents, ophthalmic antihistamines and decongestants, ophthalmic diagnostic
`
`agents, ophthalmic glaucoma agents, ophthalmic lubricants and irrigation agents, ophthalmic
`
`steroids, ophthalmic steroids with anti-infectives, or ophthalmic surgical agents.
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`[0047]
`
`In some embodiments, an ophthalmic composition formulated in the presence of
`
`deuterated water include anti-angiogenic ophthalmic agents, mydriatics, antimydriatic agents,
`
`ophthalmic anesthetics, ophthalmic anti-infectives, ophthalmic anti-inflammatory agents,
`
`ophthalmic antihistamines and decongestants, ophthalmic diagnostic agents, ophthalmic
`
`glaucoma agents, ophthalmic lubricants and irrigation agents, ophthalmic steroids, ophthalmic
`
`steroids with anti-infectives, ophthalmic surgical agents, or combinations thereof.
`
`[0048] Anti-angiogenic ophthalmic agents are vascular endothelial growth factor (VEGF)
`
`antagonists that prevent generation of new blood vessels by a process termed neovascularization.
`
`In some instances, anti-angiogenic ophthalmic agents are used to inhibit neovascularization in
`
`age related macular degeneration. In some instances, anti-angiogenic ophthalmic agents are used
`
`to treat diabetic macular edema,diabetic retinopathy, or macular edema. In some embodiments,
`
`macular edemais a swelling or thickening of the eye’s macula, or the region of the eye
`
`responsible for central vision. In some embodiments, diabetic retinopathy refers to damagesto
`
`the blood vessels in the retina. Examplary anti-angiogenic ophthalmic agents include, but are not
`
`limited to, aflibercept (also known as VEGFTrap) (e.g., Eylea), ranibizumab (e.g., Lucentis), or
`
`pegaptanib (e.g., Macugen).
`
`[0049]
`
`In some embodiments, an ophthalmic composition formulated in the presence of
`
`deuterated water includes anti-angiogenic ophthalmic agents such as for example aflibercept
`
`(also known as VEGFTrap), ranibizumab, or pegaptanib. In some embodiments, an ophthalmic
`
`composition formulated in the presence of deuterated water includes aflibercept (also known as
`
`VEGFTrap), ranibizumab, pegaptanib, or combinations thereof.
`
`[0050] Mydriatic agents are agents that dilate the pupil of the eye. In some instances,
`
`mydriatics are used to treat eye dryness, redness, or itching, uveitis, organophosphate poisoning,
`
`or inflammary eye conditions such asiritis and cyclitis. Examplary mydriatic agents include, but
`
`are not limited to, cyclopentolate (e.g., Cyclogyl, Ak-Pentolate, Cylate, Ocu-Pentolate, or
`
`Pentolair), phenylephrine (e.g., AK-Dilate, AK-Nefrin, Altafrin, Isopto Frin, Mydfrin, Neo-
`
`synephrine Ophthalmic, Neofrin, Ocu-Phrin, Prefrin, or Refresh Redness Relief), homatropine
`
`(e.g., Homatropaire, Isopto Homatropine), scopolamine(e.g., Isopto Hyoscine),
`
`cyclopentolate/phenylephrine (e.g., Cyclomydril), phenylephrine/scopolamine(e.g., Murocoll
`
`2), tropicamide(e.g., Mydral, Ocu-Tropic, or Tropicacyl), ketorolac/phenylephrine(e.g.,
`
`Omidria), or hydroxyamphetamine/tropicamide (e.g., Paremyd).
`
`[0051]
`
`In some embodiments, an ophthalmic composition formulated in the presence of
`
`deuterated water includes mydriatic agents such as for example cyclopentolate, phenylephrine,
`
`homatropine, scopolamine, cyclopentolate/phenylephrine, phenylephrine/scopolamine,
`
`tropicamide, ketorolac/phenylephrine, or hydroxyamphetamine/tropicamide. In some
`
`-9-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`embodiments, an ophthalmic composition formulated in the presence of deuterated water
`
`includes cyclopentolate, phenylephrine, homatropine, scopolamine,
`
`cyclopentolate/phenylephrine, phenylephrine/scopolamine, tropicamide,
`
`ketorolac/phenylephrine, hydroxyamphetamine/tropicamide, or combinations thereof. In some
`
`embodiments, an ophthalmic composition formulated in the presence of deuterated water does
`
`not include atropine, atropine sulfate, noratropine, atropine-N-oxide, tropine, tropic acid, or
`
`atropine methonitrate. In some embodiments, an ophthalmic composition formulated in the
`
`presence of deuterated water does not include atropine. In some embodiments, an ophthalmic
`
`composition formulated in the presence of deuterated water does not include atropinesulfate.
`
`[0052] Antimydriatic agents are agents that decrease the size of the pupil. Examplary
`
`antimydriatic agents include, but are not limited to, cysteamine (e.g., Cystaran), ocriplasmin
`
`(e.g., Jetrea), mitomycin (e.g., Mitosol), or dapiprazole (e.g., Rev-Eyes).
`
`[0053]
`
`In some embodiments, an ophthalmic composition formulated in the presence of
`
`deuterated water includes antimydriatic agents such as for example cysteamine, ocriplasmin,
`
`mitomycin, or dapiprazole. In some embodiments, an ophthalmic composition formulated in the
`
`presence of deuterated water includes cysteamine, ocriplasmin, mitomycin, dapiprazole, or
`
`combinations thereof.
`
`[0054] Ophthalmic anesthetics are local anesthetics that block pain signals at the nerve endings
`
`in the eyes. Examplary ophthalmic anesthetics include, but are not limited to, lidocaine (e.g.,
`
`Akten), proparacaine (e.g., Alcaine, Ocu-Caine, Ophthetic, or Parcaine), tetracaine(e.g.,
`
`Altacaine, Opticaine, or TetraVisc), or benoxinate (or oxybuprocaine) (e.g., Novesine, Novesin).
`
`[0055]
`
`In some embodiments, an ophthalmic composition formulated in the presence of
`
`deuterated water includes ophthalmic anesthetics such as for example lidocaine, proparacaine,
`
`tetracaine, or benoxinate. In some embodiments, an ophthalmic composition formulated in the
`
`presence of deuterated water includeslidocaine, proparacaine, tetracaine, benoxinate, or
`
`combinations thereof.
`
`[0056] Ophthalmic anti-infectives are ophthalmic formulations that comprise antibiotics and/or
`
`antiviral agents. In some embodiments, ophthalmic anti-infectives are used to treat blepharitis,
`
`blepharoconjunctivitis, CMVretinitis, conjunctivitis, corneal ulcer, eye dryness or redness,
`
`Herpes Simplex dendritic keratitis, Herpetic keratitis, hordeolum,keratitis, keratoconjunctivitis,
`
`neonatol conjunctivitis, or trachoma, or are used during surgery. Examplary ophthalmic anti-
`
`infectives include, but are not limited to, azithromycin (e.g., Azasite), bacitracin (e.g., AK-
`
`Tracin, Ocu-Tracin), besifloxacin (e.g., Besivance), boric acid (e.g., Collyrium Fresh),
`
`chloramphenicol (e.g., AK-Chlor, Chloromycetin ophthalmic, Chloroptic, Ocu-Chlor),
`
`ciprofloxacin (e.g., Ciloxan), erythromycin (e.g., Eyemycin, Ilotycin, Roymicin), ganciclovir
`
`-10-
`
`

`

`WO 2016/196367
`
`PCT/US2016/034823
`
`(e.g., Vitrasert, Zirgan), gatifloxacin (e.g., Zymar, Zymaxid), gentamicin (e.g., Garamycin
`
`ophthalmic, Genoptic, Gentacidin, Gentak, Gentasol, Ocu-Mycin), idoxuridine (e.g., Herplex),
`
`levofloxacin (e.g., Iquix, Quixin), moxifloxacin (e.g., Vigamox, Moxeza), natamycin (e.g.,
`
`Natacyn), norfloxacin (e.g., Chibroxin), ofloxacin (e.g., Ocuflox)