(22) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`~
`UDA A OU COVTT
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`(19) World Intellectual Property
`Organization
`International Bureau
`
`(10) International Publication Number
`WO 2021/021644 Al
`
`(43) International Publication Date
`04 February 2021 (04.02.2021)
`
`WIPOLPCT
`
`2)Zee
`
`DZ, EC, EE, EG, ES, FL GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL,IN,IR, IS, IT, JO, JP, KE, KG, KH, KN,
`KP. KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL NO,
`NZ, OM,PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW,
`SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
`(84) Designated States (unless otherwise indicated, for every
`kind ofregional 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,TI,
`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, CL, CM, GA, GN, GO, GW,
`KM,ML, MR,NE,SN, TD, TG).
`
`Published:
`with international search report (Art. 21(3))
`
`(31)
`
`International Patent Classification:
`
`A61K 31/439 (2006.01)
`A61K 31/4409 (2006.01)
`
`A61L1K 31/198 (2006.01)
`
`21)
`
`International Application Number:
`PCT/US2020/043530
`
`(22) InternationalFiling Date:
`
`24 July 2020 (24.07.2020)
`English
`English
`
`(25) Filing Language:
`oo.
`(26) Publication Language:
`(30) Priority Data:
`62/879,285
`26 July 2019 (26.07.2019)
`US
`—
`.
`(71) Applicant: ALLERGAN SALES, LLC [US/US]; 5 Giral-
`da Farms, Madison, NewJersey 07940 (US).
`(72) Inventors: DIBAS, Mohammed, 1658 Honors Circle,
`Corona, California 92883 (US). GIL, Daniel; 2541 Point
`Del Mar, Del Mar, California 92625 (US). BRADLEY,
`Arthur; 1735 East Durham Drive, Bloomington, Indiana
`47401 (US). XU, Renfeng; 16616 Davenport Plaza, #2,
`Omaha, Nebraska 68118 (US).
`
`(74)
`
`(81)
`
`Agent: SIDDIQI, Lorenz et al.; ALLERGAN,INC., 2525
`Dupont Drive, Irvine, California 92612 (US).
`
`Designated States (less 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,
`A, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`
` wo2021/021644AdTITNIITNIUITIAAAAI
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`
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`(54) Title: COMPOSITIONS AND METHODS FOR TREATMENT OF PRESBYOPIA
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`FIG.
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`7
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`(57) Abstract: The present invention is related to topical ophthalmic compositions comprising brimonidine. Also described herein
`are methods for the treatment of ocular conditions (e.g., presbyopia), methods for improving near reading speed in a subject with
`presbyopia, methods for improving near vision in a subject with presbyopia, and methods for reducing pupil diameter in a subject with
`prcsbyopia using the topical ophthalmic compositions.
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`COMPOSITIONS AND METHODS FOR TREATMENT OF PRESBYOPIA
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`Field of the Invention
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`Background of the Invention
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`[0001] Certain embodiments described herein relate to topical ophthalmic compositions
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`comprising brimonidine and methods of treating presbyopia using, such topical ophthalmic
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`compositions.
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`Background of the Invention
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`[0002] Ocular pupil size is determined by the opposing forces provided by the iris sphincter and
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`dilator muscles, with the former innervated by parasympathetic nerves using acetylcholineas a
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`neurotransmitter targeting muscarinic receptors, and the latter by sympathetic nerves which
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`release norepinephrine acting on adrenergic receptors.
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`[0003] Small pupils have become a promising alternative treatment for presbyopia due to their
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`ability to expand the depth of focus of the human eye. Reducing pupil size can improve near
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`visual acuity, near reading speed, and near image quality in distance corrected presbyopic eyes.
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`To maximizethe near vision gains, very small, e.g. 1-2 mm pupils are ideal, but these very small
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`pupils can compromise distance vision, especially at low light levels. However, at night small
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`pupils can reduce vision complaints of halos and starbursts. At photopic light levels with a
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`focused retinal image, maximum visual acuity is achieved with small pupils (2-3mm), but as
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`retinal illuminance decreases larger pupils are needed to optimize focused vision. Therefore,
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`employing a fixed small pupil ideal for high light levels, will compromise distancevision at low
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`light environments, and a pupil miosis that is ideal for distance vision at low light levels will
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`provide reduced near vision gain at high lightlevels.
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`[0004] There is a need in the art for improved topical ophthalmic compositions that produce
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`sufficient pupil miosis to improve near acuity and reading while maintaining distance vision over
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`a range of environmental light levels. The present disclosure addresses this need.
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`Summary of the Invention
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`[0005] Certain embodiments relate to methods of treating presbyopia in a subject in need of
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`treatment thereof. The methods comprise administering to at least one eye of the subject a
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`therapeutically effective amountof a topical ophthalmic composition comprising brimonidine.
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`[0006] Certain embodiments further provide methods for improvementof near vision in a
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`subject with presbyopia in need of treatment thereof. The methods comprise administering to at
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`least one eye of the subject a therapeutically effective amount of a topical ophthalmic
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`composition comprising brimonidine.
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`[0007] Certain embodiments also provide methods of reducing pupil diameter in a subject with
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`presbyopia in need of treatment thereof. The methods comprise administering to at least one eye
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`of the subject a therapeutically effective amount of a topical ophthalmic composition comprising
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`brimonidine.
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`[0010] Certain embodiments further provide methods of improving near reading speed in a
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`subject with presbyopia in need of treatment thereof. The methods comprise administering to at
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`least one eye of the subject a therapeutically effective amount of a topical ophthalmic
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`composition comprising brimonidine.
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`[0011] In some embodiments, there is provided a methodof treating presbyopia in a subject in
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`need of treatment thereof, comprising administering to at least one eye of the subject a
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`therapeutically effective amountof a topical ophthalmic composition comprising 0.1% (w/v)
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`brimonidine, 0.5% (w/v) carboxymethyl cellulose, 0.005% (w/v) stabilized oxychloro complex,
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`0.6% (w/v) boric acid, 0.045% (w/v) sodium borate decahydrate, 0.37% (w/v) sodium chloride,
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`0.14% (w/v) potassium chloride, 0.006% (w/v) calcium chloride, 0.006%(w/v) magnesium
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`chloride, and NaOH and/or HCI. Additionally, the topical ophthalmic composition has a pH of
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`77.
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`[0012] In some embodiments, there is provided a topical ophthalmic composition for use in the
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`treatment of presbyopia. The topical ophthalmic composition comprises 0.1% (w/v)
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`brimonidine, 0.5% (w/v) carboxymethyl!cellulose, 0.005% (w/v) stabilized oxychloro complex,
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`0.6% (w/v) boric acid, 0.045% (w/v) sodium borate decahydrate, 0.37% (w/v) sodium chloride,
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`0.14% (w/v) potassium chloride, 0.006% (w/v) calctum chloride, 0.006% (w/v) magnesium
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`chloride, and NaOH and/or HCI. Additionally, the topical ophthalmic composition has a pH of
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`7.7.
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`Brief Description of the Figures
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`[0013] FIG. 1 shows Pupil plane image (404 x 134 pixels) excerpted from a single video frame.
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`Custom pupilometer software fit red and blue circles, respectively, to both the 6 mm white
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`calibration dots and the pupils.
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`[0014] FIG. 2 shows Pupil diameter in mm plotted as a function of time in hours after early
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`morning brimonidine dosing. Data points represent the mean of 3 repeat measures and 30
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`subjects (19 subjects <SOy and 11 subjects >SOy). In each panel, pupil diameter for right (filled
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`symbols) and left (open symbols) eyes are plotted as subjects viewed high reflectance materials
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`with the room illuminated with 2000, 200, 20, and 0 lux. Pupil diameters observed when
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`viewing distant (5 m, top panels) and near (40 cm, bottom panels) stimuli are plotted for ages >
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`50 years (left column), ages 40-50 years (right column).
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`[0015] FIG. 3 showspupil diameter plotted as a function of environmentallight level (lux)
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`before (solid) and 1 hour after (dashed) bilateral instillation of a single drop of 0.1%
`ALPHAGANP™(brimonidinetartrate ophthalmic solution). Red and blue symbols represent
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`pupil while viewing distant (5 m) and near (40 cm) stimulus, respectively. Error bars are the
`
`standard error of the mean.
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`[0016] FIG. 4 shows logMAR visual acuity plotted as a function of time in hoursafter bilateral
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`early morning dosing with a single drop of 0.1% ALPHAGAN P™_ Visual acuities are plotted
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`as subjects viewed high reflectance materials with the room illuminated at 2000, 200, 20 lux,
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`when binocularly viewing distant (5 m, top panels) and near (40 cm, bottom panels) stimull1.
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`Acuities for subjects > 50 years and ages 40- 50 years are plotted in the left and right panels,
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`respectively
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`[0017] FIG. 5 illustrates Scatter plots showing change in NEAR logMAR visual acuity produced
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`by brimonidine (1.e., trHR — to) as a function of subject age in years (FIG. 5A) and pupil change in
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`mm (FIG. 5B). Red arrowsindicate improvements in visual acuity and reductions in pupil
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`diameter.
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`[0018] FIG. 6 showspercent of subjects experiencing a 0.1 logMAR (A)or 0.2 logMAR (B)
`improvementin visual acuity 1 hour after dosing with 0.1% ALPHAGAN P™. Percentages for
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`the younger (40-50, blue) and older (50, red) are plotted for 20, 200 and 2000 lux of room
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`illumination
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`[0019] FIG. 7 showsreading speed (words per minute) at 1 hour after dosing (FIG. 7A) and the
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`improvementin reading speed (in words per minute) due to pupil miosis at 1 hour (FIG. 7B) are
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`plotted as a function of letter size. The red, blue, and purple solid curves represent reading speed
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`(FIG. 7A) or reading speed improvement (FIG. 7B) at 20, 200, and 2000 lux, respectively. The
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`open circles, squares, and triangles in both FIGS. 7A and 7B indicate typical font size seen in
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`newspaper (0.45 logMAR at 40 cm) and cellphone text message (0.45 logMAR at 40 cm),
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`grocery labels (0.38 logMAR at 40 cm), and OTC labels (0.3 logMAR at 40 cm), respectively.
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`Detailed Description of the Invention
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`[0020] Unless defined otherwise, all technical and scientific terms used herein have the same
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`meaning as commonly understood by one of ordinary skill in the art to which the subject matter
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`pertains.
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`[0021] As used in this specification and the appended claims, the singular forms“a,”
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`“‘an”’ and
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`“the” include plural referents unless the context clearly dictates otherwise.
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`99 66
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`[0022] The invention provides topical ophthalmic compositions comprising brimonidine. The
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`invention further provides topical ophthalmic compositions for use in the treatment of
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`presbyopia, wherein the topical ophthalmic compositions comprise brimonidine. The term
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`“topical” as used herein refers to an ophthalmic composition intended for direct application to
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`the corneal surface of an eye of a subject in need thereof. The term topical does not include
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`injections to the eye of a subject (e.g., anterior chamberinjections).
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`[0023] The term “ophthalmic composition” or “ophthalmic compositions of the invention” as
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`used herein refers to compositions suitable for application to an eye of a subject, which are in
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`such form as to permit the biological activity of brimonidine to be effective, and which contain
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`no additional components that are unacceptably toxic to the subject to which the composition
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`would be administered. Such ophthalmic compositions will generally be sterile. Thus, for
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`topical application to the eye, the ophthalmic compositions of the present invention will
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`generally be formulated as sterile aqueous compositions (e.g., suspensions, solutions, emulsions
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`or the like) and typically include at least 70 w/v %, more typically 80 w/v % and even more
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`typically at least 90 or 95 w/v %purified water. Such ophthalmic compositions may be in the
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`form of liquid preparations, e.g., eye drops. The ophthalmic compositions may be suitable for
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`single-dose or multiple-dose topical application. The ophthalmic compositions suitable for
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`multi-dose topical application are often disposed in a dispenser(e.g., an eye dropper), which can
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`dispense the ophthalmic composition (e.g., as individual drops) to the corneal surface of the eye.
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`[0024] In certain aspects, the topical ophthalmic compositions of the invention comprise at least
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`about 0.01% w/v brimonidine. In other aspects, the topical ophthalmic compositions of the
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`invention comprise less than about 0.01% w/v brimonidine. In some embodiments, the topical
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`ophthalmic compositions of the invention comprise brimonidineat a concentration from about
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`0.01% w/v to about 20% w/v. In additional embodiments, the topical ophthalmic compositions
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`of the invention comprise brimonidine at a concentration from about 0.01% w/v to about 2%
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`wiv. In specific embodiments, the topical ophthalmic compositions of the invention comprise
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`brimonidine at a concentration from about 0.1% w/v to about 0.2% w/v. In certain
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`embodiments, brimonidine is used in combination with one or more active ingredients. In
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`certain embodiments, brimonidineis present in the topical ophthalmic compositions of the
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`invention as the sole active ingredient. The term “active ingredient’ as used herein refers to a
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`component of a composition whichis responsible for the physiologic or therapeutic effect of
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`composition in the amountpresent in the compositions of the present invention, whereas the
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`other components of the composition (e.g., excipients, carriers, and diluents) are not responsible
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`for a physiologic or therapeutic effect of composition in the amount present in the compositions
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`of the present invention, even if they have other functions in the composition which are
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`necessary or desired as part of the formulation (such as lubrication, pH control, emulsification,
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`stabilization, preservation, and other functions other than the effect of composition as described
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`herein). In some embodiments, compositions described herein in which brimonidineis the sole
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`active ingredient which has therapeutic activity are compositions in which there are no other
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`components which would be considered to have therapeutic activity for the treatment of ocular
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`conditions (e.g., presbyopia) or improvement of vision parameters (é.g., near vision or near
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`reading speed).
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`[0025] In certain embodiments, the brimonidinein the topical ophthalmic compositions of the
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`present invention is present as a pharmaceutically acceptable salt or as a free base. As used
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`herein, the term “pharmaceutically acceptable salts” refers to salts of brimonidine that are
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`substantially non-toxic to living organisms, e.g., subjects in need of the topical ophthalmic
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`compositions. Typical pharmaceutically acceptable salts include those salts prepared by reaction
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`of the brimonidine with an inorganic or organic acid, or an organicbase.
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`[0026] Inorganic acids which may be used to prepare pharmaceutically acceptable salts of
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`brimonidineinclude, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid,
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`hydrobromic acid, hydroiodic acid, phosphorous acid and the like. Organic acids which may be
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`used to prepare pharmaceutically acceptable salts of brimonidine include, without limitation,
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`aliphatic mono- and dicarboxylic acids, such as tartaric acid, oxalic acid, carbonic acid,citric
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`acid, succinic acid, phenyl-heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric
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`acids and the like. Pharmaceutically acceptable salts prepared from inorganic or organic acids
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`thus include, but are not limited to, hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate,
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`bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
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`metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate,
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`oxalate, citrate, lactate, p-toluenesulfonate, methanesulfonate, and maleate. Suitable
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`pharmaceutically acceptable salts may also be formed by reacting the active components with an
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`organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and thelike.
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`Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate
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`groups that may be found on someof the active components and inorganic cations, such as
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`sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium,
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`trimethylammonium, tetramethylammonium, and imidazolium. All of these salts may be
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`prepared by conventional means from the active components of the invention by reacting, for
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`example, the appropriate acid or base with the active components of the invention. In specific
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`aspects, the brimonidineis present in the topical ophthalmic compositions of the invention as
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`brimonidinetartrate.
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`[0027] In certain embodiments, the brimonidinetartrate is present at a concentration from about
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`0.01% (w/v) to about 10% (w/v). In other embodiments, the brimonidinetartrate is present at a
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`concentration from about 0.05% (w/v) to about 0.25% (w/v), about 0.075% (w/v) to about
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`0.175%(w/v), and 0.100% (w/v) to about 0.150% (w/v). In other embodiments, the brimonidine
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`tartrate is present at a concentration from about 0.1% (w/v) to about 0.2% (w/v). In some
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`embodiments, the brimonidinetartrate is present at a concentration of 0.15% (w/v). In specific
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`embodiments, the brimonidinetartrate is present at a concentration of 0.1% (w/v). Other
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`amounts of brimonidinetartrate that may be used include 0.01% (w/v), 0.02% (w/v), 0.025%
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`(w/v) 0.03% (w/v), 0.04% (w/v), 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v), 0.09%
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`(w/v), 0.095% (w/v), 0.099% (w/v), 0.10% (w/v), 0.11% (w/v), 0.12% (w/v), 0.125% (w/v),
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`0.13% (w/v), 0.135% (w/v), 0.14% (w/v), 0.145% (wiv), 0.15% (w/v), 0.155% (w/v), 0.16%
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`(w/v), 0.17% (w/v), 0.18% (w/v), 0.19% (w/v), 0.195% (w/v), 0.20% (w/v), 0.205% (w/v),
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`0.21% (w/v), 0.22% (w/v), 0.23% (w/v), 0.24% (wv), 0.25% (w/v), 0.26% (w/v), and ranges and
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`amounts between any of these selected amounts of brimonidinetartrate.
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`[0028] The topical ophthalmic compositions of the invention further include a suitable buffer.
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`As used herein, the term “buffer” refers to a component of a solution that resists changes in pH
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`of the solution when an acid or alkali is added to it. Buffers typically involve a weak acid or
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`alkali together with oneofits salts. For example, a buffer may comprise one or more of sodium
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`phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, sodium hydroxide,
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`or hydrochloric acid. In certain embodiments, the buffer comprises monobasic and dibasic
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`sodium phosphate. The quality of a buffer is determined by its buffer capacity, 7.e. its resistance
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`to changes in pH whenstrongacids or bases are added. In other words, the buffer capacity
`
`correspondsto the amount of H* or OHionsthat can be neutralized by the buffer. Buffer
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`capacity is related to the buffer concentration. A graph described by the relation of the pH to the
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`addition of H7/OH:ionsis called the titration curve. The point of inflection of the curve
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`corresponds to the pKa value of the buffer. The buffer capacity of a buffer is at its maximum at
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`the pKa value. The pKavalue of a buffer therefore corresponds to the mid-point of the pH range
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`covered by the buffer and represents the point at which the concentration of acid and baseis the
`
`same. In the area of this pH range,therefore, relatively large amounts of H*/OHionsresult in
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`only small changes in pH. Therefore, a buffer with more than one pKaresists changes to the pH
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`of a solution over a broad range of H*/OHions. Examples of buffers with more than one pKa
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`include, but are not limited to, citrate buffer and phosphate buffer.
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`[0029] In certain embodiments, the buffer is present at a concentration of less than about 0.001%
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`(w/v). In other embodiments, the buffer is present at a concentration of at least about 0.001%
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`(w/v). In other embodiments, the buffer is present at a concentration from about 0.001%(w/v) to
`
`about 5% (wv). In certain embodiments, the buffer is selected from the group consisting of
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`phosphate, borate, borate citrate, sodium citrate dehydrate, and lactate buffer. In specific
`
`embodiments, the buffer is a borate buffer. In additional embodiments, the borate buffer is
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`sodium borate decahydrate buffer. In certain aspects, the sodium borate decahydrate buffer is
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`present at a concentration from about 0.01% (w/v) to about 0.1% (w/v). In specific aspects, the
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`sodium borate decahydrate buffer is present at a concentration of about 0.045% (w/v).
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`[0030] A buffer may control the pH of the topical ophthalmic compositions of the invention. In
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`certain embodiments, the topical ophthalmic compositions of the invention have a pH of about
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`1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about
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`5.5, about 6.0, about 6.5, about 7.0, about 7.5, or about 8.0. In other embodiments, the topical
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`ophthalmic compositions of the invention have a pH of lower than about8.0, lower than about
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`7.5, lower than about 7.0, lower than about 6.5, lower than about 6.0, lower than about 5.5, lower
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`than about 5.0, lower than about 4.5, lower than about 4.0, lower than about 3.5, lower than
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`about 3.0, lower than about 2.5, lower than about 2.0, or lower than about 1.5. In certain aspects,
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`the topical ophthalmic compositions of the invention have a pH in the range of about 1.0 to about
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`8.0, about 1.5 to about 8.0, about 2.0 to about 8.0, about 2.5 to about 8.0, about 3.0 to about 8.0,
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`about 3.5 to about 8.0, about 4.0 to about 8.0, about 4.5 to about 8.0, about 5.0 to about 8.0,
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`about 5.5 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0, about 7.0 to about 8.0, or
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`about 7.5 to about 8.0. In other aspects, the topical ophthalmic compositions of the invention
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`have a pH inthe range of about 3.0 to about 7.5, about 3.0 to about 7.0, about 3.0 to about 6.5,
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`about 3.0 to about 6.0, about 3.0 to about 5.5, about 3.0 to about 5.0, about 3.0 to about 4.5,
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`about 3.0 to about 4.0, or about 3.0 to about 3.5. In someaspects, the topical ophthalmic
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`compositions of the invention have a pH of about 3.0 to about 8.0. In other aspects, the topical
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`ophthalmic compositions of the invention havea pH of about 3.0 to about 5.5. In certain
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`embodiments, the topical ophthalmic compositions of the invention have a pH ofat least about
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`5.0. In other embodiments, the topical ophthalmic compositions of the invention have a pH ofat
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`least about 6.6. In yet other embodiments, the topical ophthalmic compositions of the invention
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`have a pH of about 6.6 to about 8.0. In additional embodiments, the topical ophthalmic
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`compositions of the invention have a pH of about 7.4 to about 8.0. In specific embodiments, the
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`topical ophthalmic compositions of the invention have a pH of 7.7
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`[0031] The topical ophthalmic compositions of the invention may further comprise one or more
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`viscosity enhancers. As used herein, the term “viscosity” of a topical ophthalmic composition of
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`the invention is used as it normally is used for liquids and means a measure ofthe liquid’s
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`resistance to deformation at a given rate. Thus, viscosity is a quantity expressing the magnitude
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`of internal friction, as measured by the force per unit area resisting a flow in whichparallel
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`layers of the topical ophthalmic compositions, unit distance apart, have unit speed relative to one
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`another. A fluid that has no resistance to shear stress is known asan ideal or inviscid fluid. Zero
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`viscosity is observed only at very low temperatures in superfluids. Otherwise, the second law of
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`thermodynamics requiresall fluids to have positive viscosity; such fluids are technically said to
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`be viscous or viscid. A fluid with a relatively high viscosity, such as pitch, may appear to be a
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`solid.
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`In certain embodiments, the topical ophthalmic compositions of the invention have a
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`viscosity from about | centipoise (cps) to about 10 cps.
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`In certain aspects, the topical ophthalmic
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`compositions of the invention have a viscosity close to that of pure water (1 cps).
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`In specific
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`aspects, the topical ophthalmic compositions of the invention have a viscosity of about 1 cps.
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`[0032] As used herein, the term “viscosity enhancer” refers to any substance that increases the
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`viscosity of the topical ophthalmic compositions of the invention. A viscosity enhancer may bea
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`polymerincluding, but not limited to hypromellose, carboxymethyl] cellulose, hydroxyethyl
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`cellulose, hydroxymethyl] cellulose, methylcellulose, methyl cellulose 4000, hydroxypropyl
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`cellulose, hydroxypropylmethy] cellulose, hydroxyl propyl methyl] cellulose 2906,
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`carboxypropylmethyl cellulose, hydroxypropylethyl cellulose, and hydroxyethyl cellulose,
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`polyethylene glycol, polyvinyl alcohol, pyrrolidone, polyvinyl pyrrolidone, gellan, carrageenan,
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`alignic acid, carboxyvinyl polymer, glycerol, acrylic polymers (e.g., carbomer, polycarbophil), or
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`combinations thereof. In other aspects, a viscosity enhancer may be non-polymeric including,
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`without limitation, hydroxypropyl-guar (hp-guar), xanthan gum, alginate, chitosan,gelrite,
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`hyauluronic acid, dextran, or combinations thereof. In certain embodiments, the viscosity
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`enhanceris present at a concentration of less than about 0.01% (w/v). In other embodiments, the
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`viscosity enhanceris present at a concentration of at least about 0.01% (w/v). In certain aspects,
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`the viscosity enhancer is present at a concentration from about 0.01% (w/v) to about 20%(w/v).
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`In other aspects, the viscosity enhanceris present at a concentration from about 0.01% (w/v) to
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`about 10% (w/v). In certain embodiments, the viscosity enhancer is carboxymethyl cellulose. In
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`specific embodiments, the carboxymethyl]cellulose is present at a concentration of about 0.5%
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`(w/v).
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`[9033] The topical ophthalmic compositions of the invention may further include one or more
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`osmolality agents in an amount that renders the topical ophthalmic compositions of the invention
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`roughly isotonic. “Osmolality” is a measure of the total number of dissolved particles in a given
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`volumeof a solution. As used here, the term “osmolality agent” include any compoundor
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`substance useful for adjusting the osmolality of a topical ophthalmic composition. Any suitable
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`ophthalmically acceptable osmolality agent may be used, provided that such component or
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`components are compatible with the other ingredients of the topical ophthalmic compositionsof
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`the invention and do not have deleterious or toxic properties which could harm the subject to
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`whom the compositions are administered. Examples of osmolality agents include, but are not
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`limited to, salts, particularly sodium chloride or potassium chloride, organic compounds such as
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`propylene glycol, mannitol, sorbitol, dextrose, and glycerin.
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`In certain embodiments, the
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`osmolality agents of the topical ophthalmic compositionsof the invention include, but are not
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`limited to, glycerin, propylene glycol, mannitol, sorbitol, sodium chloride, potassium chloride
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`and dextrose.
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`[0034] “Tonicity” is a measure of the effective osmotic pressure gradient, as defined by the
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`water potential of two solutions separated by a semipermeable membrane. In other words,
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`tonicity is the relative concentration of solutes dissolved in solution which determine the
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`direction and extent of diffusion. The term is commonly used when describing the response of
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`cells immersed in an external solution. Unlike osmotic pressure, tonicity is influenced only by
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`solutes that cannot cross the membrane, as only these exert an effective osmotic pressure.
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`Solutes able to freely cross the membrane do not affect tonicity because they will always be in
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`equal concentrations on both sides of the membrane. Thereare three classifications of tonicity
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`that one solution can haverelative to another: hypertonic, hypotonic, and isotonic. A solution is
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`“isotonic” when its effective osmole concentration is the sameasthat of another solution. In
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`biology, the solutions on either side of a cell membrane, for example, are isotonic if the
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`concentration of solutes outside the cell is equal to the concentration of solutes inside the cell.
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`[0035] In certain embodiments, the one or more osmolality agents is selected from the group
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`consisting of glycerin, propylene glycol, mannitol, sorbitol, sodium chloride, potassium chloride,
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`and dextrose. The amount of an osmolality agent may vary depending upon whetherthe topical
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`ophthalmic compositions are isotonic, hypertonic, or hypotonic. In certain embodiments, the
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`amount of an osmolality agent such as those listed above may beat least about 0.0001% (wv) up
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`to about 1% (w/v), about 2% (w/v), about 5% (w/v), about 10% (w/v), or about 20% (w/v). In
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`some embodiments, at least one of the one or more osmolality agents is present at a
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`concentration of at least about 0.0001% (w/v). In other embodiments, the one or more
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`osmolality agents are each present at a concentration of at least about 0.0001% (w/v). In some
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`embodiments, at least one of the one or more osmolality agents is present at a concentration from
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`about 0.001% (w/v) to about 20% (w/v). In other embodiments, the one or more osmolality
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`agents are each present at a concentration from about 0.001% (w/v) to about 20% (w/v). In
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`additional embodiments, at least one of the one or more osmolality agents is present at a
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`concentration from about 0.001% (w/v) to about 5% (w/v). In further embodiments, the one or
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`more osmolality agents are each present at a concentration from about 0.001% (w/v) to about 5%
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`(w/v). In yet other embodiments, at least one of the one or more osmolality agents is present at a
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`concentration from about 0.001% (w/v) to about 2.5% (w/v). In additional embodiments, the one
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`or more osmolality agents are each present at a concentration from about 0.001% (w/v) to about
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`2.5% (w/v). In still other embodiments, at least one of the one or more osmolality agents is
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`present at a concentration from about 0.001% (w/v) to about 1% (w/v). In further embodiments,
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`the one or more osmolality agents are each present at a concentration from about 0.001% (w/v)
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`to about 1% (w/v). In certain embodiments, the topical ophthalmic compositions of the
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`invention further comprise calcium chloride and magnesium chloride.
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`[0036] The topical ophthalmic compositions of the invention may further include a strong acid
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`or a strong base. Examples of strong acids and strong bases are well knownin the art and
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`include, without limitation, NaOH, KOH, HCI, and H2SOg4. In specific aspects, the topical
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`ophthalmic compositions of the invention further comprise NaOH or HCl
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`[0037] The topical ophthalmic compositions of the invention may also include boric acid. In
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`certain embodiments, the boric acid is present at a concentration from about 0.01% (w/v) to
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`about 5% (w/v). In additional embodiments, the boric acid is present at a concentration from
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`about 0.1% (w/v) to about 1.5% (w/v).
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`In certain embodiments, the boric acid is present at a
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`concentration of about 1% (w/v)
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`[9038] The topical ophthalmic compositions of the invention may be packaged for single use,
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`and contain no preservative or essentially no preservative. Alternatively, the topical ophthalmic
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`compositions of the invention may be packaged for multiple uses, and comprise a suitable
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`preservative to prevent contamination over multiple uses. As used herein, the term
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`“preservative” means any substance that prevents or retards contamination in the form of
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`bacterial or fungal growth in the topical ophthalmic solutions of the invention. Examples of
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`suitable preservatives include, but are limited to, benzalkonium chloride (BAK),
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`Polyquaternium-1 (Polyquad®), chlorobutanol, stabilized chlorine dioxide, and a stabilized
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`oxychloro complex comprising chlorite, chlorate and chlorine dioxide. Stabilized oxychloro
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`complex or stabilized chlorine dioxide, also known as Purite®, may be described as an aqueous
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`solution of sodium chlorite (NaC1lO2). U.S. Patent Number 5,424,078, which is incorporated
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`herein by referencein its entirety, further discusses the use of stabilized chlorine dioxide as