(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(10) International Publication Number
`WO 2018/154440 Al
`
`= a
`
`WIPO! PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`30 August 2018 (30.08.2018)
`
`(51) International Patent Classification:
`A61K 31/46 (2006.01)
`A61P 27/10 (2006.01)
`
`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.
`
`(21) International Application Number:
`
`PCT/IB2018/051039
`
`(84)
`
`(22) International Filing Date:
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`20 February 2018 (20.02.2018)
`
`English
`
`English
`
`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).
`
`(30) Priority Data:
`62/461,723
`
`21 February 2017 (21.02.2017) US
`
`Published:
`
`with international search report (Art. 21(3))
`in black and white; the international application as filed
`contained color or greyscale andis availablefor download
`trom PATENTSCOPE
`
`(71) Applicant: SINGAPORE HEALTH SERVICES PTE
`LTD [SG/SG]; The Academia, 20 College Road, Discovery
`Tower Level 6, Singapore 169856 (SG).
`
`(72)
`
`Inventors: TAN, Donald Tiang Hwee; 49 Oci Tiong
`Ham Park, Singapore 267054 (SG). CHIA, Audrey; 205a
`Tembeling Road, Singapore 423699 (SG). BEUERMAN,
`Roger; 1 St. Thomas Walk, 14-02, Singapore 238096 (SG).
`VELUCHAMY, Amutha Barathi; 25, Springtide Place,
`Singapore 786428 (SG).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG,BIT, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FL, GB, GD, GE, GH, GM, GT, HN,
`IIR, IU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KIT, KN, KP,
`KR, KW, 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, PIL, PL, PT, QA, RO, RS, RU, RW, SA,
`
`(54) Tithe! COMPOSITION AND METHOD FOR PREVENTING OR DELAYING ONSET OF MYOPIA COMPRISING AT-
`ROPINE
`
`
`
`
`
`Changeinaxiallength
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`PG BA
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`(57) Abstract: Methods of preventing or delaying onset of myopia in pre-myopic patients and also methods of reducing or preventing
`progression of myopia in patients having low myopia through the use of compositions comprising less than 0.025% of atropine are
`disclosed.
`
`
`
`
`
`©2018/154440A.IMININNNMIITANTANTCTAAYAA
`
`

`

`WO 2018/154440
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`PCT/1IB2018/051039
`
`COMPOSITION AND METHOD FOR PREVENTING OR DELAYING ONSET OF
`MYOPIA COMPRISING ATROPINE
`
`RELATED APPLICATIONS
`
`[900%]
`
`This application claims the benefit of US Provisional Application No. 62/461,725, filed
`
`February 21,2017. The entire contents of the foregomeg provisional patent application is
`
`incorporated herem in its entirety for all purposes.
`
`TECHNICAL FIELD
`
`{8002}
`
`This application relates to methods of preventing or delaying the onset of myopia and
`
`methods of reducing or preventing the progression of myopia by administration of compositions
`
`comprising very low concentrations of atropine.
`
`BACKGROUND
`
`(0003) Myopia, otherwise knownas, nearsightedness or short sightedness, is a tvpe of
`
`refractive error of the eye, m which the visual image is focused in front of the retina, typically
`
`resulting in blurred vision of distant objects. Myopia is especially prevalent among Asians and
`
`has been reported to be as high as 70-90%in Asian countries. Myopia may be corrected by
`
`prescription lenses (for oxample, spectacles or contact lenses) or refractive surgery (for example,
`
`LASIKor phakic intraocular lens implantation).
`
`[0004]
`
`Patients having a higher degree of myopia are at a higher risk of developing sight-
`
`threatening disorders such as degenerative retina changes such as peripheral lattice changes, tears
`
`and detachment, mvopic choroidal neo-vascularization, myopic macular schisis and holes,
`
`posterior staphylomas, myopic macular degeneration, early-onset cataracts (in the 30s-40s},
`
`open angle slancoma, and peri-papillary atrophy, optic disc tilt and pits. These disorders, if not
`
`properlytreated, mayresult in visual loss later in lite. Children with carly onset myopia are
`
`more likely to eventually develop high myopia. A recent Singapore-based paper pooling data
`
`fromthe Smgapore, Chinese, Indian and Malaysian adult studies showed that pathological
`
`symptoms of myopia, in particular staphyloma and chorioretinal atrophy, worsened with the
`
`progression of age, myopic refraction and axial length (Chang et ai (2013)}. As such, controlling
`
`the development and progression of myopia ofa patient in childhood years, so that the eventual
`I
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`myopia ts less than would have otherwise been (e.g., -5.00D rather than -10.00D), would have a
`
`major beneficial impact on the life of the patient.
`
`BRIEF SUMMARY
`
`{0005}
`
`This application relates to using compositions comprising very low concentration of
`
`atropine to prevent or delay onset of myopia, before myopia occers, or preventing or rechicing
`
`the progression of myopia.
`
`{8006}
`
`in one aspect, this disclosure provides a method for preventing or delaying the onset of
`
`myopia comprising administering to a subject in an cye a composition comprise less than
`
`0.025%atropine. In some embodiments, the atropine is present in the form of atropine sulphate.
`
`In some embodiments, composition comprises about 0.01%atropine. In some embodiments,
`
`wherein the composition comprises about 0.001%to 0.0249%atropine. In some embodiments,
`
`the composition comprising about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%,
`
`0.008%, 0.000%, 0.01 %, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, G.017%, 0.018%,
`
`0.019%, 6.02%,
`
`0.021%, 0.022%, 0.023%, 0.024%, 0.0245%or 0.0249%atropine. In some
`
`embodiments, the subject is 4 to 21 years old. In some embodiments, the subject is 5 to 9 years
`
`old. In some envbodiments, the subject has pre-myopia.
`
`(0007)
`
`tn some embodiments, the composition is administered every other day, or at least once
`
`daily, or at least twice daily. In some embodiments, cach administration is performed by
`
`instilling at least one drop, at least two drops, or at least three drops to the eye, wherein each
`
`drop contains about 20-100 microliter liquid.
`
`In some embodiments, the administration
`
`continues for the period of at least six months, one year, two years, three years, four years, five
`
`years, SIX years, seven years, ten years or longer.
`
`10008]
`
`in some embodiments, the composition further conyprises at least one pharmaceutically
`
`acceptable excipient. In some embodiments, at least one pharmaceutically acceptable excipient is
`
`selected fromthe proup consisting of benzalkoniumchloride and hydroxypropyl
`
`methylcellulose. In some embodiments, benzalkonnumchioride is present in the composition at
`
`a concentration of about 0.01%. In some embodiments, hydroxypropyl! methylcellulose is
`
`present in the composition at a concentration of about 1%. Tn some embodiments, no
`
`proscrvative cxcipicnts arc present m the composition.
`
`[0009]
`
`In some embodiments, the Spherical Equivalent (SE) of the eve is within the range of
`
`from +1.00D to -0.49D before administration of the composition.
`
`In some embodiments, the SE
`
`is measured by Autorefractor after administration of cylcoplegia.
`
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`({O01G]
`
`tn some embodiments, the subject has no astigmatism or has astigmatism of not more
`
`than 1.50D as measured by cycloplegic or nen-cycloplegic autorefraction before administration
`
`ofthe composition.
`
`OL]
`
`In some embodiments, the pupil of the eve has no dilation or a dilation of no greater
`
`than 2mm, ¢.g., no greater than 1.9 mm, no greater than 1.8 mm, no greater than 1.7 mm, no
`
`greater than 1.5 mm, no greater than 1.49 mmduring the period of administration of the
`
`composition. In some embodiments, the eye has no clmicaliy significant loss of accommodation
`
`or experience a loss of accommodation of no greater than 10D, c.¢., no greater than 9D, no
`
`greater than &.5D, no greater than 8.8D, or no greater than 8D. In some embodiments, the eye
`
`has no clinically significant loss of near visual acuity from loss of accommodation.
`
`10012]
`
`In some embodiments, wherem the onset of myopia is delayed for greater than 6
`
`months, 12 months, 18 months, two years, three years, five years, six years, eight vears, or
`
`longer.
`
`[0013]
`
`in another aspect, this disclosure provides a method for reducing or preventing myopia
`
`progression comprising administering to a subject in an eve a composition comprising less than
`
`0.025%atropine, wherein the composition is administered na more frequently than once every
`
`iwo days, ones every three days, or once every four days. In some ombodiments, cach
`
`administration is performed by instilling at least one drop, at least two drops, or at least three
`
`drops to the eye, wherein cach drop contains about 20-100 microliter liquid.
`
`In some
`
`embodiments, the SE of the eve is less than -1.50D before administration of the composition.
`
`In
`
`some cmbodiments, the SE of the cve is within the range of from -0.50D to -1. 50D before
`
`administration of the composition. In some embodiments, the subject is between 4 to 21 years
`
`old. In some embodiments, the subject is between 5 and 9 years old. In some embodiments, the
`
`atropine is present in the form of atropine sulphate.
`
`In some cmbodiments, the composition
`
`comprises about 0.001%to 0.0249%atropine, ¢.2.. comprising about 0.001%, about 0.002%,
`
`about 6.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about
`
`0.009%, about 0.01 %, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about
`
`0.015%, about 0.016%, about 0.017%, about 6.018%, about 0.019%, about 0.02%, about
`
`0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0243%or about 0.0249%atropime.
`
`In some embodunents, the composition further comprises at least one pharmaceutically
`
`acceptable excipient. In some embodiments, the at least one pharmaceutically acceptable
`
`excipient is selected from benzalkoniumchloride and hydroxypropyl methvicellulose. In some
`
`embodiments, no preservative excipients are present in the composition.
`
`3
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`(O014]
`
`tn some embodiments, the mean change of SE during a two year period followme the
`
`start of administration of the composition is reduced by at least 20%as compared to controls. In
`
`some embodiments, treating a patient, e.g., a patient having pre-nryopia, reduces the change in
`
`refraction byat least 10%, at leat 20%, at loast 30%, or at loast 40%, or at Icast 50%, o.g., at loast
`
`53% over a period of 2 weeks, | month, 2 months, 6 months, one year, two years or more from
`
`the initiationof the treatment.
`
`In some embodiments, treating the patient, e.g., a patient having
`
`pro-myopia, reduces the inercase of Axial longth byat Icast 109%, at Icast 15°, at lcast 20%, at
`
`least 30%over a period of 1 week, 2 weeks, 1 month, 2 months, 6 months, one year, two years or
`
`more from or more, from the ination of the treatment. In some embodiments, treating the
`
`patient, ¢.g., a patient having pre-myopia, with the composition disclosed herein, can reduce
`
`changein refraction by at least 10%, at leat 20%, at least 30%, orat least 40%, or at least 50%,
`
`©.g., at
`
`least 53%.
`
`{80135}
`
`in some embodiments, administration of the atropine composition disclosed herem
`
`reduces the change in refraction G.e., myopic refractive error shift) byat least 10%, e.9., at least
`
`20%, at least 30%, or at least 40%, at least 50%, orat least 53%as compared to controls. In
`
`some cmbodiments, treating the pationt, c.g., a patient having pre-myopia, with the composition
`
`disclosed herein reduces the rate of myopia progresssion or myopia shift by at least 10°, ¢.2., at
`
`least 20%, at least 30%, or at least 40%, at least 50%, or at least 53%after onset of nvyopia as
`
`compared to controls.
`
`in some embodiments, treating the pationt with the composition discloscd
`
`herein increases the length of the time period from initiation ofthe treatment to onset of myopia
`
`byat least 10%, e.g., at least 20%, at least 30%, or at least 40°, at least 56%, or at least 53%as
`
`comparedto controls.
`
`{0016}
`
`in some embodiments, the pupil of the eve has no dilation or a dilation of no greater
`
`than 1.9 nim, no greater than 1.8 mm, no greater than 1.7 mm, no greater than 1.5 mim, no greater
`
`than 1.49 mm daring the penod of administration of the composition. In some embodiments,the
`
`eye has no loss of accommodation or a loss of accommodation of no greater than LOD, e.2., no
`
`greater than 9D, no greater than 8.5D, no greater than 8.8D, or no greater than 8D.
`
`[0017] Also provided in this disclosure is a use of atropine in the preparation of a composition
`
`for preventing or delaying the onset of myopia progression and the composition comprises less
`
`than 0.025%atropine.
`
`{0018} Also provided in this disclosure is a use of atropine in the preparation of a composition
`
`for reducing or preventing myopia progression in a subject that has a SE of less than -1 50D,
`
`4
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`PCT/1IB2018/051039
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`wherein the composition comprises less than 0.025%atropine, wherein the compositionis
`
`administered no more frequently than once every two days.
`
`[8019] Also provided herem is a composition for use in a method of preventing or delaying the
`
`onset of myopiaprogression, wherein the composition comprises less than 0.025%atropine. In
`
`some embodiments the composition comprises 0.001%to 0.0249%atropine.
`
`(6026) Also provided hercin is a composition for use in a method of reducmmg or preventing
`
`myopia progression m a subject, wherein the composition comprises less than 0.023%atropin,
`
`wherein the composition is administered no more frequently than once every two days.
`
`In some
`
`embodiments, the subject has a SE of icss than -1. 50D. In some cmbodiments, the subject has a
`
`SEof less than -0.350D.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`0029}
`
`FiGs. LA and LB showeffect of atropine treatment on axial elongation andrefractive
`
`error, respectively.
`
`{0022}
`
`FIG. 218 a schematic of a flowchart illustrating the study design ofATOMS.
`
`[0023]
`
`FIGs. 3A and 3B showthe effect of pre-treatment with 0.01%atropine on ocular
`
`biometry in lens-induced myopia in C37BL/6J mice.
`
`DETAILED DESCRIPTION
`
`[0024]
`
`Several studies on mvopia control (preventing the progression of myopia) inchide the
`
`use of contact lenses, spectacles and pharmacological agents in the form of topical eye drops,
`
`mostly pertains to the usc of atropme or anti-muscarinic agents. All of these forms of myopia
`
`control therapy aim to slow down progression of myopia of children who have already become
`
`myopic,
`
`e025]
`
`Previously, Atropine in the Treatment Of Myopia study (ATOM)trials ATOM] and
`
`ATOM), involved young children between ages 6-12 old, who were already ovyopic, having SE
`
`ofat least -2.00D, and were progressing in myopic degree, prior to study recruitment. Various
`
`concentrations of atropme when administered at least once daily have been shown to effective in
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`preventing or reducmg progression in these myopic children. See, for example, WO
`
`2012/1616455.
`
`[8026] However, no clinical trials to date have been performedto assess the feasibility of
`
`preventmg the onset of myopia using very low concentration of atropine, before myopia occurs.
`
`No studies have been performed assessing the effect of using a composition comprising very low
`
`concentration atropine at no more frequently than every other day on progression of myopia.
`
`[6027]
`
`The apphcation is directed to using a composition comprising very low concentration
`
`of atropine to prevent or delay onset of myopia, before myopia occurs, and also using the
`
`composition no more frequently than once every two days, to reduce progression of myopia after
`
`the patient has already developed low myopia.
`
`DEFINITIONS
`
`[6028] Unless otherwise noted, ail concentration unit refers to weight to volume. When a value
`
`of a parameteris referred as bemg within a range, the parameter’s value can be the lower limit or
`
`ficher limit, or any value in between.
`
`{0029} Unless otherwise noted, whenever the language refer to that an SEvalue is greater or
`
`higherthan a negatrve reference valuc, it means that the SE value is a negative value and the
`
`absolute value of which is greater than that of the negative reference value. For example, an SE
`
`value that is sreater than -O.5D can be -1.0D.
`
`10030,
`
`Unless otherwise noted, whenever the language refers to an expression “At/-B”, A
`
`refers to the mean and B refers to the standard deviationSD"). For example, a dilation of 0.74
`
`+/~ 0,75 mim, refers to a mean dilation of 0.74 mm with a SD of 6.75.
`
`(603%)
`
`The term “about” when used m conjunction with a value means any valuc that is
`
`reasonably close to the value, 1.e., withthe range of + 10%of the value. In particular, 1 would
`
`include the value tiself. For example, both a value of 0.009%and a value of 0.011%are deemed
`
`to be “about 0.01%”,
`
`i8032}
`
`The term “myopia” refers to a patient’s condition im which the patient has at least one
`
`eye with an SEvaluc greater than -0.5D, for example, -1.0D,-2.0D. Depending on context,
`
`“myopia” also refers to the condition of the eve, the SE value of which is higher than -0.5D.
`
`{0033}
`
`The term “pre-myopia”refers to a patient's condition in which the patient has at least
`
`one eye with an SE value within the range of -0.49D to 1.00D. Depending on context, myopic
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`can also reter to the condition ofthe eve, the SE value of which is within the range of -0.49Dto
`
`L.GOD,
`
`[0034]
`
`The term “low myopia” refers to a patient’s condition in which the patient has at least
`
`one oye with an SE value within the range of -0.50D to -1.50D. Depending on context, “low
`
`myopia” can also refer to the condition of the eye, the SE value of which is within the range of -
`
`0.501 to -1.S50D.
`
`[6035]
`
`The term “high myopia” refers to a person having at least one eve with an SE value that
`
`is greater than -5.0D. Depending on context, “high mevepia” can also refer to the condition of the
`
`cyc, the SE valuc of whichis greater than -5.0D.
`
`{8036}
`
`The term “drop”refers to the a unit of measare of volume, whichis equal to the amount
`
`dispensed as one drop from a dropper or drip chamber to the eve. Typically, a drop contains 20 -
`
`100 microliter liquid.
`
`In some cases, a drop contains between 30 microliter to 70 microliter,
`
`¢.g., about 30 microliter liquid.
`
`10037,
`
`Phe term “patient” or the term “subicct”’, used mterchangcably im this disclosure, refers
`
`to any individual, regardless of the status of myopia.
`
`In some embodiments, the patient is a child
`
`between 5 and 12 years old, e.g., between 3 and 9 vears old.
`
`In some embodiments, the patient is
`
`a child between 5 and 9 years old who has pre-myopia.
`
`{8038} The term “atropine composition”refers to a composition comprising atropine or an
`
`atropine salt, e.g. atropine sulfate or atropine acetate. As such, in the case when atropine is
`
`present in the salt form, o.g., atropime sulfate, the concentrations of atropine referred to weight to
`
`volume concentration of the atropine salt in the atropine composition,
`
`19039]
`
`The term “unit dosage regimen,” as used herein, refers to physically discrete units
`
`suitable as unitary dosages for human subjects, cach unit containing a predetermmed quantity of
`
`a compound (e.g., atropine, as described herein) or compounds, calculated in an amount
`
`sufficient to produce the desired treatment offect. In some cases, the compound, e.g., atropme, is
`
`present in each unit in association with a pharmaceutically acceptable diluent, carner or vehicle.
`
`In some cases, each unit contains no preservatives.
`
`MYOPTA
`
`[0040]
`
`Refractive errors refer to conditions in whichthe eye does not bend heht correctly,
`
`resulting ima blurred mage. The main types of refractive crrors mclude myopia
`
`7
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`{nearsightedness}, hyperopia (arsightedness}, presbyopia Goss of near vision with age}, and
`
`astigmatism. Myopia is associated with axial elongation, which results in the eve ball being
`
`elongated and/or the comea becomes too curved. As axial elongation progresses, the eyeball
`
`may become too long or the comea (the clear front cover of the cyc} is too curved, and as a
`
`result, the light enterme the eye is not focused correctly, and distant objects look blurred.
`
`Mvopia is also dependent on cornea curvature and lens power. Although myopia can develop at
`
`any age, typically the onsct of myopia occurs durme the grade school vears and progrcascs until
`
`growth of the eve ts compieted.
`
`[0041] Myopia is commonlyassessed using spherical equivalent (SE) in ophthalmology
`
`clinics. The spherical equivaient is a single mumber in dioptres, and may be defined as a
`
`spherical power whose focal point comceides with the circle of least confusion ofa
`
`spherocyclindrical lens. SE is determined based on the values of sphere and cylinder of the cye
`
`and commonly expressed as the sum of the sphere value and one half of the cylinder value. The
`
`spherical equivalent is thus a convenient clinical method of representing data from several
`
`sources reearding refractive power. As nryopia progresses, the refractive power changes into a
`
`negative valic—arefractive crror devclops—, the axial longth increases, and the absolute valuc
`
`of SE increases (the SE changes into a more negative value). Myopia occurs as a result offailure
`
`of the normal process of emmetropization, which is essentially endogenous to the eye. There is a
`
`mismatch between the focal length and the axial length of the cyc, with the latter being too long
`
`for the refractive power of the lens and cornea. So, as myopia progresses, there is a shift in
`
`refractive power from byperopic to myopic. In animal studies, myopia is typically assessed by
`
`measuring this refractive power G.c., refractive error) in diopters and also measuring the axial
`
`length elongation. A diopter is a unit of refractive power that is equal to the reciprocal of the
`
`focal length Gn meters) of a given lens. Refractive error change was recorded in chopters for
`
`arumal studies as with spherical cquivaicnt in the ophthalmologyclinic.
`
`[0042] Myopic patients have at least one eye the Spherical Equivaient CSE”) of whichis
`
`-0.5Dor higher, ¢.g., -2.0D or higher. The higher the absolute SE value, the higher degree of
`
`myopia. Patents do not have myopia typically have a positive SE value or a negative SE value
`
`less than -0.5D.
`
`PATIENTS
`
`{0043}
`
`tn one aspect, the disclosure provides methods for preventing or delaving the onset of
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`rmivopia by aciministering to a subject a composition comprising a very low concentration of
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`atropme. For this aspect of the invention, the subjects are not myopic before the atropine
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`treatment, i.¢.. the SE of the eye is a positive value or a negative value less than -0.5D. In some
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`embodiments, the subject is at a pre-myopic stage before being treated with atropine andthey
`
`have a SE value within the range of +1.00Dto -0.49D, e.g., 0.80D to -0.49D, or 0.50D to-
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`0.40D.
`
`[0044]
`
`In another aspect, the disclosure provides methods for reducing or preventing myopia
`
`progression in a subject comprising administering a composition comprising very low
`
`concentration of atropine, which ts admmmistered to the patient no more frequently than once
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`every two days. In some cases, the subject has low myopia, Le., having a negative SE value
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`higher than -0.5D but fess than -1.50D.
`
`{0045] A patient who can benefit from atropine treatments as disclosed herein can be of any
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`age group.
`
`In some embodiments, the patient is at least S years old. In preferred embodiments,
`
`the patient is a child at an age that is within the range of5-17, ¢.2., 5-12, e.¢., 5-9 years old. In
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`some cases, the paticnt is at an age that is within the range of 5-6 years or 7-9 years old. In
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`some cases, the patient has no history of cardiac or significant respiratory illness. In some cases,
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`the patient has distance vision correctable to looMARO.? or better m both eyes determined bythe
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`log Mar vision chart. In some cases, the subjects have normal intraocular pressure of not greater
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`than 21 mmHgas determined by tonometry.
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`In some cases, the subject has at least one parent
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`who istmyopic.
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`. In some cases, the patient has normal ocular health other than bemg myopic or
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`pre-myoplc.
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`[0046] Methods that can be used to determing the ocular health of a patient are well known.
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`Non-limiting cxemplar mcthods mecludc sht lamp cxamination, fundus photography, Intraccalar
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`jens GOL} Master biometry, and/or cycloplegic autorefraction/ autokeratometry. In some cases,
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`two, three or all of the aforementioned methods are performed to evaluate the pationt’s ocular
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`health, incliding assessing the degree of mryopia by dcetcrmiming SEvalucs.
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`ATROPINE
`
`[0047] Atropine is a non-selective muscarmic antagonist, which degrades slowly, typically
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`wearing offin 7 to 14 days. Currently, atropine is used as a cycloplegic to temporarily paralyze
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`the accommodation reflex to dilate the pupus. Atropine can also be used to treat a numberof
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`disease related to eye, such as uveitis and early amblyopia, and has been used previously for
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`treating patients already have moderate to high mvopia, t.c., havmye a negative SE value of
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`higher than -2.00B. In both human and mouse, atropine can bind to five types of muscarinic
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`receptors that are prumarily present in the fibroblasts of the sclera. These sclera fibroblasts are
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`responsible for controlime the sclera growth.
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`{0048]
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`Throughout the disclosure, the term “accommodation amplitude” , used
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`interchangeably with the term “acconimedation”’, refers to the ability of the oye ta focus on near
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`objects. Atropine can cause systemic as well as local side effects such as pupil dilation and a
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`decrease of accommodation amplitude. An increase in pupil size would result in an exponential
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`increase in the amount oflisht entering the eve and may cause glare and photophobia. Excessive
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`amounts of ultraviolet light entering an eve may increase the risk of cataract or macular
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`degeneration. A decrease in accommodation amplitude may reduce near vision such that
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`children affected by this need bifocal or progressive glasses to read or see close objects.
`
`[0049]
`
`This disclosure provides methods of preventing or delaying the onset of myopia by
`
`administering to the eye a composition comprising a very low concentration of atropine. Also
`
`provided are methods of reducing or preventing the progression of myopia by administering the
`
`low concentrations of atropme in a Jow frequency, 1.¢. no more frequently than once every two
`“koe
`g., about 0.001%to
`
`days. The composition typically comprises less than 0.025%atropine, ¢
`
`about 0.0249%atropine, about 0.005%to about 0.002%, about 0.008%to about O.015%, ¢.8.,
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`about 0.000%to about 0.012%. In particular embodiments, the composition comprises about
`
`0.01% atropine. In some embodiments, the composition comprises about 0.001%, about 0.002%,
`
`about G.003°%>, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about
`
`0.009%, about 0.01 %, about 0.011%, about 0.012%, about 0.013%, about 0.014%, about
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`0.015%, about 0.016%, about 0.017%, about 0.018%, about 0.019%, about 0.02%, about
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`0.021%, about 0.022%, about 0.023%, about 0.024%, about 0.0245%or about 0.0249%atropine.
`
`In some embodiments, atropine in the composition is present as a salt, ¢.g., atropine sulfate.
`
`jO0SG}
`
`in some embodiments, treating the pationt with the composition disclosed hercim can
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`delay the onset of myopia for greater than 1 month, greater than 3 months, greater than 4 months,
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`greater than 5 months, sreater than 6 months, greater than 12 months, greater than 18 months,
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`grcatcr than two years, grcatcr than three years, greater than five years, srcatcr than six yoars, or
`
`greater than eight years as compared to controls. For purpose ofthis disclosure, controis refer to
`
`individuals who are not treated with the atropine composition disclosed herem. In preferred
`
`embodiments, the individuals imthe control group are trom the same age group and at the same
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`premyopic or myopic stage as the individuals who are treated with the compositions disclosed
`
`herem,
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`{O05%]
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`tn some embodiments, treating the patient, c.¢., a patient having pre-myopia, with the
`
`composition disclosed herein can reduce the increase of Axial length ( the length of the axis trom
`
`the center of the cornea to where the image is most clear on retina) by at least 10%, at least 15%,
`
`at Ioast 20%, at least 30%over a period of one week to cight years, o.g., onc month to five years,
`
`four months to four years, six months to three years, or one year to two years from the initiation
`
`of the treatment.
`
`{G052]
`
`tn some embodiments, treating the patient, c.¢., a patient having pre-myopia, with the
`
`composition disclosed herein, can reduce change in refraction (.c., nryopic refractive error shift)
`
`by at least 10%, e.¢., at least 20%, at least 30%, or at least 40%, at least 50%, or at least 53% as
`
`compared to controls. In some embodiments, treating the patient, e.g.. a patient having pre-
`
`myopia, with the composition disclosed herein can reduce the rate of mvopia progresssion or
`
`nryopia shift byat least 10%, e.g., at least 20%, at least 30%, or at least 40%, at least 50%, or at
`
`icast 53%after onset of myopia as compared to controls. In some embodiments, treating the
`
`patient with the composition disclosed herein can increase the length of the time period from
`
`initiation of the treatment to onset of myopia byat least 10%, c.g., at least 20%, at least 30%, or
`
`at Icast 40%, at least 50%, or at least 53%as compared to controls.
`
`PHARMACEUTICALCOMPOSITIONS
`
`[0053]
`
`In some embodiments, the present invention provides a pharmaceutical composition
`
`including a pharmaceutically acceptable excipient and atropine and the method of administering
`
`the composition for preventing or delaymeg the onset of myopia or reducing or preventing
`
`progression of myopia.
`
`[8034]
`
`Phe pharmaceutically acceptable oxcipienis include carbohydrate or protein fillers
`
`miclude, but are not lumtted to sugars, including lactose, sucrose, mannitol, or sorbite!; starch
`
`from corm, wheat, ricc, potato, or other plants; ccllulosc such as methyl ccllulosc, hydroxvpropy!
`
`methyicellulose, or sodium carboxymethyicellulose: and gums mecliding arabic and tragacanth;
`
`as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents
`
`may be added, such as the cross-linked polyviny! pyrrolidonc, agar, algimic acid, or a salt thereof,
`
`such as sodiumalginate. In some embodunents, the pharmaceutically acceptable excipient
`
`comprises benzalkoniumchloride, at a concentration withm the range of G.005% to 0.02%, e.g.,
`
`about 0.01%.
`
`In some embodiments, the pharmaceutically acceptable excipient comprises
`
`hydroxypropy! methylcellulose at a concentration within the ranges of 0.5% to 2%, ¢.g., about
`
`1%. In some embodiments, the pharmaceutically acceptable excipient comprises both
`
`hydroxypropyl methyleciiuiose and Benzalkonium Chloride,
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`il
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`(G055]
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`in some embodiments, the atropine composition is prepared in liquid form for eve
`
`administration. Details on techniques for formulation and admunistration are well described in
`
`the scientific and patent literature, sec, e.g, the latest edition of Remington's Pharmaceutical
`
`Sciences, Maack Publishing Co, Easton PA ("Remington's").
`
`(O0S6]
`
`Liquid form preparations include sohitions, suspensions, and ermuisions, tor example,
`
`water or water/propylene glycol sohitions. Soletions suitable for cye administration can be
`
`prepared by dissolving the active component in water and adding suitable colorants, stabilizers,
`
`buffers, dispersants, solubilizing agents, preservatives, and/or thickening agents as desired. In
`
`some embodiments, the solution can be made bydispersing the finely divided atropine in water
`
`with viscous matertal, such as natural or svnthetic gums, resins, methylcellulose, sodium
`
`carboxymethylcellulose, brydroxypropylmethylicellulose, sodiumalginate, polyvinyipyrrolidone,
`
`gum tragacanth and gum acacia, an