(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0010082 A1
`CHONG et al.
`(43) Pub. Date:
`Jan. 14, 2010
`
`US 20100010082A1
`
`(54) FORMULATIONS FOR TREATING EYE
`DISORDERS
`
`Related U.S. Application Data
`
`(75)
`
`Inventors:
`
`Eddie CHONG, North Vancouver
`(CA); Clive BURGE, Brentwood
`Bay (CA); Lee MIZZEN, Victoria
`(CA)
`
`Correspondence Address:
`DECHERT LLP
`P.O. BOX 390460
`MOUNTAIN VIEW, CA 94039-0460 (US)
`.
`(73) Assigneez
`
`Aspreva International Ltd.,
`Victoria (CA)
`
`(21) Appl. No.:
`
`12/500,399
`
`(22)
`
`Filed;
`
`Jul, 9, 2009
`
`(60) Provisional application No. 61/079,413, filed on Jul. 9,
`2008'
`
`(5 1)
`
`Int. Cl.
`A61K 31/365
`C07D 307/87
`A61P 27/02
`
`Publication Classification
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl. ....................................... .. 514/470; 549/310
`
`(57)
`
`ABSTRACT
`
`The present disclosure relates to ophthalmic solutions and
`methods of using the solutions to treat ocular disorders
`
`000001
`
`ARGENTUM PHARM. 1062
`
`ARGENTUM PHARM. 1062
`
`000001
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 1 of 14
`
`US 2010/0010082 A1
`
`NaMPA 4%, Cyclosporine 0.05%
`
`(administered topically x8/day for 14 days)
`
`100000000
`
`Q 100000.00
`3’
`10000.00
`V
`_§
`1000.00
`N
`‘
`§
`§
`.§
`100.00
`§
`V
`§
`§
`§
`§
`V
`§
`10.00
`8 %‘%%§%%.§
`09900
`Q>\OO
`.¢§‘€’§
`flab 4$‘®o\> 6°06‘ &'3& 9&0 %C}é
`\C’
`‘o
`.~{<>
`~09
`0°
`0*
`6‘
`V‘)
`\'«\°’\
`V
`05°
`
`V
`
`<‘\
`0°
`
`.
`
`1:: MPA
`El Cyclosporine
`
`9
`
`5
`
`A0
`
`.9
`
`o
`
`.\5
`
`*0
`
`Rabbit Ocular Tissue
`
`FIG. 1
`
`000002
`
`000002
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 2 of 14
`
`US 2010/0010082 A1
`
`NaMPA 4% & Cyclosporine 0.05% (administered x8/day for 14 days)
`
`Rabbit Ocular Tissue Ratio MPA/Cyclosporine
`
`Eyelids
`
`81.82
`
`Lacrimal sac
`
`766.56
`
`Conjunctiva
`
`189.09
`
`Sclera
`
`549.53
`
`Aqueous
`
`6062.11
`
`Iris/ciliary body
`
`574.30
`
`Hum. Vitreous
`
`101.31
`
`Retina/Choroid
`
`1151.50
`
`Blood
`
`29.40
`
`FIG. 2
`
`000003
`
`000003
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 3 of 14
`
`US 2010/0010082 A1
`
`MPA Tissue Concentrations 1-Day Acute Studies
`
`Test Article
`
`'
`
`1% MPA
`tromethamine
`
`Calculated
`
`Concentration
`(ug/9)
`
`-
`
`Calculated
`
`Concentration
`(HQ/Q)
`
`Eye tissue
`
`Rabbit #
`
`Lacrimal
`
`Sacl Eyelid R+L
`
`Aqueous Humor
`R+L
`
`Vitreous Humor
`R+L
`
`000004
`
`000004
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 4 of 14
`
`US 2010/0010082 A1
`
`MPA Tissue Concentrations 1-Day Acute Studies
`
`Test Article
`
`2% MPA
`tromethamine
`
`Calculated
`
`Calculated
`
`Calculated
`
`Calculated
`
`
`
`Eye tissue
`
`
`
`Concentration Concentration Concentration Concentration
`)
`)
`)
`(H9/9)
`(M9/9
`(H9/9
`(HQ/9
`
`
`
`
`
`
`
`
`Rabbit #
`
`1488
`
`1456
`
`1550
`
`1522
`
`Lacrimal
`Sac/Eyelid R+L
`
`23.90
`
`53.15
`
`107.50
`
`34.35
`
`
`
`32.55
`
`58.50
`
`21.95
`
`
`
`FIG. 3B
`
`000005
`
`
`
`Conjunctiva R+L 41.55
`
`Aqueous Humor
`
`Retina-Choroid
`
`Vitreous Humor
`
`000005
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 5 of 14
`
`US 2010/0010082 A1
`
`MPA Tissue Concentrations 1-Day Acute Studies
`
`Test Article
`
`4% MPA
`tromethamine
`
`Calculated
`
`Calculated
`
`Eye tissue
`
`Concentration Concentration Concentration Concentration
`(J49/9)
`(J49/9)
`
`Rabbit #
`
`1794
`
`1668
`
`Eyelid R+L
`
`214.00
`
`39.40
`
`Cornea R+L
`
`50.85
`
`43.45
`
`Conjunctiva R+L 86.20
`
`Sclera R+L
`
`15.65
`
`Aqueous Humor
`R+L
`
`F” N-l>
`
`54.60
`
`10.96
`
`N]
`
`l\) xi
`
`Iris/Ciliary R+L
`
`4.68
`
`0-: Are
`
`9‘ coco
`
`Retina-Choroid
`R+L
`
`Lacrimal Sac
`
`R+L
`
`Vitreous Humor
`R+L
`
`FIG. 3C
`
`000006
`
`000006
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 6 of 14
`
`US 2010/0010082 A1
`
`Con A
`
`Injection
`
`~
`
`---O--Vehicle
`
`
`—I—O.5%NaMPA
`
`
`
`—A—1.0%NaMPA
`
`-X— 2.0%NaMPA
`
`
`
`
`012 3
`
`4
`
`5
`
`6
`
`7
`
`8 91011 121314151617
`
`StudyDay
`
`FIG. 4
`
`000007
`
`70
`
`60
`
`50
`
`20
`
`A O
`
`
`
`
`
`
`
`TearBreak-upTime(sec)
`
`000007
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 7 of 14
`
`US 2010/0010082 Al
`
`O?0
`
`Con A
`
`Injection
`
`-I3 O
`
`
`
`
`
`
`
`()1 O
`TearBreak—upTime(sec) N00OO
`
`--+-- Vehicle
`
`—I— Restasis®
`
`
`
`
`
`_\ 3
`
`—A— Dexamethasone
`
`O1234567891011’I21314151617
`
`StudyDay
`
`FIG. 5
`
`000008
`
`000008
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 8 of 14
`
`US 2010/0010082 A1
`
`Exam Results — Post Challenge
`(baseline scores subtracted)
`
`
`
`ClinicalScore
`
`7 E V+NS
`
`1
`
`2%NaMPA
`
`2 ®1%NaMPA
`
`3 E 0.5"/uNaMPA
`
`4
`
`5
`
`Pred Forte®
`
`V+S
`
`6
`
`NT+S
`
`1234567
`
`1234567
`
`1234567
`
`1234567
`
`conjunctiva|
`Hyperemia
`
`Chemosis
`
`Discharge
`
`Lid Edema
`
`Group
`
`Exam
`
`FIG. 6
`
`000009
`
`000009
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 9 of 14
`
`US 2010/0010082 A1
`
`Itching/Face Washing
`
`1.80
`
`1.60
`
`1.40
`
`1'20
`1.00
`
`0.80
`
`0.40
`
`0.20
`
`0.00
`
`
`
`ClinicalScore
`
`
`
`35710
`2%
`NaMPA
`
`35710
`1%
`NaMPA
`
`35710
`0.5%
`NaMPA
`
`35710
`Pred
`Forte®
`
`35710
`V+S
`
`35710
`NT+S
`
`35710
`V+NS
`
`3 mm
`
`5 mm
`
`E 10 mm
`
`FIG. 7
`
`000010
`
`000010
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 10 of 14
`
`US 2010/0010082 A1
`
`Number of infiltrating CD4+ cells
`
`Number of infiltrating CD4+ cells
`
`Cells/0.01mm2.o.—\N5»U1—\U1|\J(J1O0O1-P
`Groupt Group 2 Group 3 Group 4 Group 5 Group 6 Group 7
`Cells/0.01mm2 O
`
`Group
`
`FIG. 8
`
`000011
`
`000011
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 11 of 14
`
`US 2010/0010082 A1
`
`Number of infiltrating Macrophages
`
`Number of infiltrating macrophages
`
`00
`
`Cells/0.01mm2
`
`0‘!
`
`Cells/0.01mm2 O Group1 Group2 Group3 Group4 Group5 Group6 Group?
`
`—\Ix)00A
`
`Group
`
`FIG. 9
`
`000012
`
`000012
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 12 of 14
`
`US 2010/0010082 A1
`
`Conjunctival Hyperemia
`
`1 EI2% NaMPA
`
`2n1%NaMPA
`3 fi0.5°/o NaMPA
`4 Pred Forte®
`5 I Vehicle
`6 |:INo treatment
`
`Group
`
`
`
`
`123456
`123456
`123456
`123456
`10 Minutes
`15 Minutes
`20 Minutes
`30 Minutes
`
`._
`123456
`5 Minutes
`
`2.50
`
`2.00
`
`L50
`
`1'00
`
`0.50
`
`0-00
`
`
`
`ClinicalScore
`
`Time Post 48/80 Challenge
`
`FIG. 10
`
`000013
`
`000013
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 13 of 14
`
`US 2010/0010082 A1
`
`Discharge
`
`2.50
`
`2.00
`
`G,
`§ 1.50
`[9
`(Y5
`E’
`G
`
`0.50
`
`0.00
`
`
`
`1 EI2% NaMPA
`2E1%NaMPA
`3 a0.5% NaMPA
`Z5;T.‘LT.°”e®
`6 I:INo treatment
`
`123456
`5 Minutes
`
`123456
`10 Minutes
`
`123456 '123456
`15 Minutes
`20 Minutes
`
`123456
`30 Minutes
`
`Group
`
`Time Post 48/80 Challenge
`
`FIG. 11
`
`000014
`
`000014
`
`

`
`Patent Application Publication
`
`Jan. 14, 2010 Sheet 14 of 14
`
`US 2010/0010082 A1
`
`Chemosis
`
`CD
`é
`2
`(U
`
`5
`
`2.50
`
`2.00
`
`100
`
`050
`000
`
`
`
`..
`
`123456
`5 Minutes
`
`1 E12% NaMPA
`
`2 B1%
`3 &O.5% NaMPA
`
`4 Pred Forte®
`5 I Vehicle
`
`6ElNotreatment
`
`Group
`
`123456
`15 Minutes
`
`20 Minutes
`
`123456
`30 Minutes
`
`_I
`I
`
`.
`
`.
`
`10 Minutes
`
`Time Post 48/80 Challenge
`
`FIG. 12
`
`000015
`
`000015
`
`

`
`US 2010/0010082 A1
`
`Jan. 14, 2010
`
`FORMULATIONS FOR TREATING EYE
`DISORDERS
`
`1. CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
`[0001] This application claims benefit under 35 U.S.C. §
`119(e) of application Ser. No. 61/079,413, filed Jul. 9, 2008,
`the contents of which are incorporated herein by reference.
`
`2. BACKGROUND
`
`[0002] Many inflammatory diseases of the eye occur de-
`novo or as secondary complications to various systemic dis-
`eases such as autoimmune diseases or infections. Standard
`
`treatments, such as the use of topically applied steroids, are
`directed to controlling the inflammatory symptoms in the eye.
`However, a complication with steroid treatments is that a
`significant percentage of treated subjects
`suffer
`from
`increased intraocular pressure, which can exacerbate eye dis-
`orders, such as glaucoma and cataracts. In some instances, the
`ocular disorder is refractory to the effects of the topically
`applied steroid.
`[0003]
`In some instances, systemic treatments with anti-
`inflammatory steroids or other immunosuppressive agents
`are used to treat the ocular inflammation. However, adverse
`effects from systemic treatments can limit their use. Side
`effects can include hypertension, hyperglycemia, peptic
`ulceration, osteoporosis, growth limitation, myopathy, and
`kidney dysfunction. Even systemic steroid therapies also
`have potentially sight-threatening side effects such as glau-
`coma, cataract and susceptibility to eye infection. Some alter-
`native therapies,
`for example,
`topical administration of
`cyclosporine A (RestasisTM, Allergan Inc.) (Tauber. J., 1998,
`Adv Exp Med Biol. 438:969-72) have been approved for use
`in the treatment of certain ocular disorders. However, topi-
`cally applied cyclosporine A (CsA) is indicated as being
`poorly tolerated and having low bioavailability (Lallemand et
`al., 2003, Eur J Pharm Biopharm. 56(3):307-18). Thus, it is
`desirable to find other therapies that can be used to treat ocular
`disorders associated with inflammatory conditions and
`autoimmune diseases.
`
`[0004] Citations of the above documents, and in this appli-
`cation, is not intended as an admission that any of the fore-
`going is pertinent prior art. All statements as to the date or
`representation as to the contents of these documents is based
`on the information available to the applicants and does not
`constitute any admission as to the correctness of the dates or
`contents of these documents. Further, all documents referred
`to throughout this application are hereby incorporated in their
`entirety by reference.
`
`3. SUMMARY
`
`[0005] The present disclosure relates to ocular solutions for
`treating various eye disorders associated with inflammatory
`and autoimmune conditions. In one aspect, the ocular solu-
`tion has a composition consisting essentially of sodium
`mycophenolic acid (NaMPA), where the pH ofthe solution is
`from about pH 6.0 to 8.5. Although the NaMPA is highly
`soluble in aqueous solutions, the MPA in the ocular solution
`is found to penetrate into the eye to achieve levels suflicient to
`have therapeutic benefit. In some embodiments, the ocular
`solutions has a composition consisting essentially ofNaMPA
`and one or more additives selected from a preservative, vis-
`cosity enhancing agent, wetting agent, buffering agent, lubri-
`
`cating agent, antioxidant, and tonicity agent. The levels of
`NaMPA can be up to the solubility limits of the drug in
`aqueous solution at the indicated pH ranges. In some embodi-
`ments, the amount of NaMPA in the solution can be up to
`4.5% w/v. In various embodiments, the levels of sodium in the
`ocular solution can be from 0.4 to 2.0% w/v. In some embodi-
`
`ments, sodium levels above the isotonic condition (e.g.,
`equivalent to 0.9% NaCl) can be used.
`[0006]
`In some embodiments, the ocular solution includes
`NaMPA and a preservative. In particular, the preservative is
`EDTA, which can be present from about 0.005 to about
`0.050% w/v, 0.005 to about 0.040% w/v, 0.010 to about
`0.030% w/v, 0.010 to about 0.020% w/v, or from about 0.010
`to about 0.015% w/v. In some embodiments, the EDTA can be
`present at 0.005, 0.01, 0.012, 0.014, 0.016, 0.018, 0.020,
`0.030, 0.040, or 0.050% w/v. In some embodiments, the
`EDTA (as disodium dehydrate) is present at about 0.012%
`w/v.
`
`In some embodiments, the ocular solution includes
`[0007]
`NaMPA, a preservative and a buffering agent. An exemplary
`formulation of this type can include the preservative EDTA,
`in amounts as noted above; a buffering agent of borate or
`tromethamine, with an amount of buffer to provide a buffer-
`ing capacity of 0.01 to about 0.1; and a solution pH of about
`7.0 to 8.0.
`
`[0008] The ocular solution can be used to treat various
`de-novo inflammatory eye disorders or those associated with
`autoimmune diseases or infections affecting the eye. In some
`embodiments, these eye conditions include “front of the eye”
`disorders such as blepharitis; keratitis; rubeosis iritis; Fuchs’
`heterochromic iridocyclitis; chronic uveitis or anterior uvei-
`tis; conjunctivitis; allergic conjunctivitis (including seasonal
`or perennial, vernal, atopic, and giant papillary); keratocon-
`junctivitis sicca (dry eye syndrome);
`iridocyclitis;
`iritis;
`scleritis; episcleritis; corneal edema; scleral disease; ocular
`cicatrcial pemphigoid; pars planitis; Posner Schlossman syn-
`drome; Beh(;et’s disease; Vogt-Koyanagi-Harada syndrome;
`hypersensitivity reactions; conjunctival edema; conjunctival
`venous congestion; periorbital cellulitis; acute dacryocystitis;
`non-specific vasculitis; and sarcoidosis. In some embodi-
`ments, the eye conditions include “back of the eye” disorders
`such as macular edema; angiographic cystoid macular
`edema; retinal ischemia and choroidal neovascularization;
`macular degeneration; retinal diseases (e.g., diabetic retin-
`opathy, diabetic retinal edema, retinal detachment); inflam-
`matory diseases such as uveitis (including panuveitis) or
`choroiditis (including multifocal choroiditis) of unknown
`cause (idiopathic) or associated with a systemic (e.g., autoim-
`mune) disease; episcleritis or scleritis; Birdshot retinochor-
`oidopathy; vascular diseases (e.g., retinal ischemia, retinal
`vasculitis, choroidal vascular insufficiency, choroidal throm-
`bosis); neovascularization of the optic nerve; and optic neu-
`ritis.
`
`[0009] The ocular solutions can be applied at doses sufli-
`cient to provide a therapeutic benefit. In some embodiments,
`the ocular solution can be applied topically to the affected eye
`one to eight times per day. In some embodiments, the ocular
`solutions can be administered once or two times per day. In
`some embodiments, the ocular solutions can be applied once
`every two days, once every four days, or once a week as
`needed to treat the ocular disorder.
`
`000016
`
`000016
`
`

`
`US 2010/0010082 A1
`
`Jan. 14, 2010
`
`4. BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 shows studies on ocular tissue penetration of
`[0010]
`NaMPA and cyclosporine achieved in rabbits following topi-
`cal administration to the eye 8 times daily for 14 days. In these
`studies, animals received either NaMPA or cyclosporine as
`topical solutions applied to both eyes. Tissues were harvested
`for analysis at the end of drug dosing, on day 14. Data are
`expressed as ng drug per gram (ng/g) of ocular tissue. These
`studies demonstrated that the NaMPA formulation penetrated
`all ocular tissues examined, including anterior tissues (e.g.,
`conjunctiva, lacrimal sac, aqueous humor) and posterior tis-
`sues (e.g., retina/choroid), in particular, the aqueous humor;
`iris/ciliary body; lachrymal sac; sclera; and retina/choroid.
`[0011]
`FIG. 2 shows the levels of NaMPA or cyclosporine
`measured in ocular tissues, expressed as a ratio, derived from
`the results described in FIG. 1.
`
`FIGS. 3A, 3B and 3C show the ocular tissue pen-
`[0012]
`etration data for the MPA salts (1%, 2%, 4% w/v) for the
`combined
`1-day
`studies: NaMPA; NaMPA+borate;
`tromethamine MPA; and morpholine MPA. Note that concen-
`trations are given in micrograms/mL. One animal per treat-
`ment group was randomly selected, euthanized, and both eyes
`harvested for determining MPA levels (average of both eyes
`taken). The cyclosporine data is not presented in this table.
`[0013]
`FIG. 4 shows the tear break up time (TBUT) values
`in rabbits where dry eye was induced by bilateral lacrimal
`gland injection of concanavalinA (ConA). Results are shown
`for rabbits treated with NaMPA orVehicle from Day 0 to Day
`17. Con A was injected on Day 8. Induction of dry eye was
`observed as measured by a reduction in tear break up time
`(TBUT) values over Days 9-12. Statistically significant
`increases in TBUT values (e.g., Days 14-17) are indicated
`with an asterisk for the NaMPA groups vs. Vehicle.
`[0014]
`FIG. 5 shows the TBUT values for the Restasis®,
`dexarnethasone and Vehicle groups from the same study as
`described in FIG. 4. Statistically significant increases in
`TBUT values (e.g., Days 14-17) are indicated with an asterisk
`for Restasis® or dexarnethasone groups vs. Vehicle.
`[0015]
`FIG. 6 shows the clinical scoring for conjunctival
`hyperemia, chemosis, discharge and lid edema graded on a
`0-4 scale (see Grading Systems for Allergic Response) in
`animals systemically sensitized on Day 0 to short ragweed
`allergen (SRW) then given a topical ocular challenge on Day
`27 with SRW. Scoring was done 15 minutes after SRW chal-
`lenge. Groups were treated on Days 21 to 27 with NaMPA,
`Pred Forte® (prednisolone acetate) or Vehicle or
`left
`untreated. Statistically significant reductions in conjunctival
`hyperemia were seen for the 2%, 1% and 0.5% NaMPA
`groups and the Pred Forte® group vs. negative control
`groups. There was also a statistically significant reduction in
`chemosis for the Pred Forte® group vs. negative control
`groups.
`FIG. 7 shows the clinical scoring for itching/face
`[0016]
`washing behaviour 3, 5, 7 and 10 minutes after SRW chal-
`lenge for the same groups of animals shown in FIG. 6. Sta-
`tistically significant reductions were seen at the 10 minute
`interval for the 2% and 1% NaMPA groups vs. negative
`controls.
`
`FIG. 8 shows the number of infiltrating CD4+ cells
`[0017]
`(CD4+ T cells) viewed by light microscopy in conjunctival
`tissue for the same animals as depicted in FIGS. 6 and 7, that
`were sacrificed on Day 27 after clinical scoring was done.
`Immunostaining for CD4+ cells was done by standard proce-
`dures as described in Studies Based on Ragweed Induced
`
`Allergic Conjunctivitis. Statistically significant reductions
`were seen for the 2% NaMPA and Pred Forte® groups vs.
`negative controls.
`[0018]
`FIG. 9 shows the number of infiltrating macroph-
`ages viewed by light microscopy in conjunctival tissue for the
`same tissue samples as described in FIG. 8. Immunostaining
`for macrophages was done as described in Studies Based on
`Ragweed Induced Allergic Conjunctivitis. Statistically sig-
`nificant reductions were seen for the 2% NaMPA and Pred
`
`Forte® groups vs. negative controls.
`[0019]
`FIG. 10 shows the clinical scoring for conjunctival
`hyperemia in animals 5, 10, 15, 20 and 30 minutes after
`topical ocular challenge with compound 48/80. Animals were
`treated with NaMPA, Pred Forte® orVehicle or left untreated
`from Days 1-7, then challenged on Day 7 with compound
`48/80. Statistically significant reductions were seen for the
`1% NaMPA group vs. the untreated group at the 15 and 20
`minute intervals.
`
`FIG. 11 shows the clinical scoring for discharge in
`[0020]
`animals 5, 10, 15, 20 and 30 minutes after challenge with
`compound 48/80 for the same groups of animals depicted in
`FIG. 10. Statistically significant reductions were seen in the
`2% and 1% NaMPA groups and the Pred Forte® group vs.
`controls at the 20 or 30 minute time intervals.
`
`FIG. 12 shows the clinical scoring for chemosis 5,
`[0021]
`10, 15, 20 and 30 minutes after challenge with compound
`48/80 for the same groups of animals depicted in FIGS. 10
`and 11. Statistically significant reductions were seen in the
`2% NaMPA and Pred Forte® groups vs. Vehicle control at the
`and/or 30 minute time interval.
`
`5. DETAILED DESCRIPTION
`
`[0022] Delivery of drugs to the eye are challenging given
`the anatomical and physiologic barriers that limit ocular
`access of drug compounds into the eye, such as low corneal
`permeability. In order to enhance bioavailability, it has been
`suggested that the drug be lipid soluble to enhance penetra-
`tion through the cornea and the lipophilic endothelium
`(Ahmed et al., 1987, “Physicochemical determinants of drug
`diffusion across the conjunctiva, sclera, and cornea,” J Pharm
`Sci. 76: 583-586; Wang et al., 1991, “Lipophilicity influence
`on conjunctival drug penetration in the pigmented rabbit: a
`comparison with corneal penetration,” Curr Eye Res 10: 571-
`579). For lipophilic molecules that have poor solubility in
`aqueous solutions, e.g., steroids, complexes to drug carriers
`such as cyclodextrins have been used to solubilize and deliver
`the drug to the membrane surface where they can partition
`into the lipophilic membrane from the carrier molecule
`(Loftsson T and Masson M, 2001, “Cyclodextrins in topical
`drug formulations: theory and practice,” Int J Pharm 212:
`29-40).
`[0023] The immunosuppressive compounds mycophenolic
`acid (MPA) and its ester prodrug form, mycophenolate
`mofetil (MMF) have been mainly used to prevent rejection of
`allogenic organ transplants and for treatment of certain
`autoimmune diseases, such a systemic lupus erythematosus
`and myasthenia gravis. MPA is known to specifically inhibit
`the enzyme inosine monophosphate dehydrogenase (IM-
`PDH), which is used preferentially by T and B cells to gen-
`erate de novo guanosine nucleotides required for cell repli-
`cation. Approved prescription drug versions of MMF
`(CellCept®) and an enteric-coated sodium salt of MPA (My-
`fortic®) are marketed for prevention of solid organ transplant
`rejection. Both are given orally to achieve systemic immuno-
`
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`
`suppression. In addition, MMF and MPA are known to pos-
`sess other biological effects, including those that are anti-
`inflammatory. Because of its immunosuppressive and anti-
`inflammatory effects, orally administered MMF has been
`tested as a treatment for certain eye disorders, such as uveitis
`and refractory inflammatory eye disease (Zierhut et al., 2005,
`“MMF and eye disease,” Lupus 14 Suppl 1:s50-4; Choudhary
`et al., 2006, J Ocul Pharmacol Ther. 22(3):168-75). Formu-
`lations of MMF for topical administration to the eye have
`been recently described (Knapp et al., 2003, J Ocul Pharma-
`col Ther. 19(2): 181-92). Ocular solutions containing at least
`one macrolide and/or mycophenolic acid is described in the
`PCT application publication WO2005/030305A1. MMF is
`more lipophilic than MPA, being soluble in alcohol and only
`slightly soluble in water (CellCept® label), while the sodium
`salt of MPA is indicated as being highly soluble in aqueous
`solutions at physiological pH (Myfortic® label). To increase
`the bioavailability of MMF in the eye, it has been formulated
`with cyclodextrins (Knapp, supra).
`[0024]
`It has now been found by the inventors that the
`sodium salt of MPA formulated at physiological pH is effec-
`tive in penetrating anterior and posterior eye structures when
`applied topically to the eye. The MPA levels achieved within
`the eye structures with this formulation can be at levels suf-
`ficient to have a therapeutic benefit. The penetration into the
`eye occurs even though the sodium salt of MPA is highly
`soluble in aqueous solutions at physiological pH and is sig-
`nificantly less lipophilic than MMF. Accordingly, the disclo-
`sure provides ocular solutions containing mycophenolic acid
`and methods of using the formulations to treat various ocular
`disorders. Preferably, the disclosure provides formulations
`containing the sodium salt of MPA to treat various ocular
`disorders.
`
`For the descriptions provided in this specification
`[0025]
`and the appended claims, the singular forms “a”, “an” and
`“the” include plural referents unless the context clearly indi-
`cates otherwise. Thus, for example, reference to “an agent”
`includes more than one agent, and reference to “a compound”
`refers to more than one compound.
`[0026]
`It is to be further understood that where descriptions
`of various embodiments use the term “consisting essentially
`of,” those skilled in the art would understand that in some
`specific instances, an embodiment can be alternatively
`described using language “consisting of.”
`[0027]
`It is to be understood that both the foregoing general
`description,
`including the drawings, and the following
`detailed description are exemplary and explanatory only and
`are not restrictive of this disclosure.
`
`In some embodiments, the ocular solution is a com-
`[0028]
`position consisting essentially of sodium mycophenolic acid
`(NaMPA), where the pH ofthe solution can be from about 6.0
`to about 8.5. In some embodiments, the ocular solution is a
`composition consisting essentially of sodium mycophenolic
`acid, and one or more additives selected from a preservative,
`viscosity enhancing agent, wetting agent, buffering agent,
`lubricating agent, antioxidant, and tonicity agent, where the
`pH of the solution can be from about 6.0 to about 8.5.
`[0029] The amount of NaMPA in the ocular solution can be
`up to the solubility limits ofthe drug in aqueous solution at the
`indicated pH range. In some embodiments, the amount of
`NaMPA in the ocular solution can be up to 4.5% w/v. In some
`embodiments, the ocular solution can have an NaMPA level
`of from about 0.01% w/v to about 4.5% w/v of NaMPA. In
`some embodiments, the ocular solution can have an NaMPA
`
`level of from about 0.1% w/v to about 4.5% w/v ofNaMPA.
`In some embodiments,
`the ocular solution can have an
`NaMPA level of from about 0.5% w/v to about 4.5% w/v of
`
`NaMPA. In some embodiments, the ocular solution can have
`an NaMPA level of from about 0.01% w/v to about 4.0% w/v
`of NaMPA. In some embodiments, the ocular solution can
`have an NaMPA level of from about 0.1% w/v to about 4.0%
`w/v of NaMPA. In some embodiments, the ocular solution
`can have an NaMPA level of from about 0.5% w/v to about
`4.0% w/v of NaMPA. In some embodiments, the ocular solu-
`tion can have an NaMPA level of from about 0.05% w/v to
`about 3.0% w/v ofNaMPA. In some embodiments, the ocular
`solution can have an NaMPA level of from about 0.1% w/v to
`about 3.0% w/v ofNaMPA. In some embodiments, the ocular
`solution can have an NaMPA level of from about 0.5% w/v to
`about 3.0% w/v ofNaMPA. In some embodiments, the ocular
`solution can have an NaMPA level of from about 0.1% w/v to
`about 2.0% w/v ofNaMPA. In some embodiments, the ocular
`solution can have an NaMPA level of from about 0.2% w/v to
`about 1.0% w/v ofNaMPA. In some embodiments, the ocular
`solution can have an NaMPA level of from about 2% to about
`4% w/v of NaMPA. In some embodiments, the ocular solu-
`tion ofNaMPA has levels ofthe drug selected from 0.05, 0.06,
`0.08, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0% w/v. In
`some embodiments, the NaMPA levels are selected from 2.0,
`2.5, 3.0, 3.5, or 4.0% w/v. The levels ofNaMPA selected can
`be based on the amounts required to achieve therapeutically
`beneficial levels in the eye. The sodium salt of MPA is
`described in, among others, WO97/38689.
`[0030]
`In some embodiments, the pH of the ocular solution
`can be within 1.0 to 1.5 pH units from physiological pH,
`particularly the physiological pH in the external environment
`of the eye. The pH of human tears is approximately pH 7.4.
`Hence, the pH of the ocular solution can be about 1.0 to 1.5
`pH units above or below pH 7.4. In some embodiments, the
`pH ofthe ocular solution is from about pH 6.0 to about pH 8.5.
`In some embodiments, the pH of the ocular solution is from
`about pH 6.0 to about pH 8.0. In some embodiments, the pH
`of the ocular solution is from about 6.5 to about 8.0. In some
`
`embodiments, the pH of the ocular solution is from about 7.0
`to about 8.0. In some embodiments, the pH of the ocular
`solution is from about 7.0 to about 7.5. A person of skill in the
`art can select a pH that balances the stability and efficacy of
`the NaMPA formulation at the indicated pH and the tolerabil-
`ity of the eye to differences in pH from the natural condition.
`[0031]
`In some embodiments of the ocular solutions, the
`total sodium level in the solution is from about 0.4 to about
`2.0% w/v. In some embodiments, the total sodium in the
`solution is from about 0.4 to about 1.0% w/v. In some embodi-
`ments, the total sodium in the solution is from about 0.6 to
`about 0.9% w/v. In some embodiments, the total level of
`sodium in the ocular solution is selected from 0.4, 0.5, 0.6,
`0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.6, 1.8, and 2.0% w/v. In general,
`the level of sodium is that contributed by the NaMPA and any
`additional Na+ ions added to the solution from other sources,
`such as EDTA used as a preservative and/or NaOH used to
`adjust the pH of the ocular solution. In some embodiments,
`NaCl can be added to adjust the sodium levels. In some
`embodiments, the total sodium in the solution can be the
`amount isotonic to the natural environment of the eye. In
`general, the isotonicity of the lacrimal fluid corresponds to
`that of a 0.9% sodium chloride solution. However, the eye can
`tolerate values as low as that of a 0.6% sodium chloride
`
`solution and as high as that of a 2.0% sodium chloride solu-
`
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`tion without marked discomfort. The total osmolarity of tears
`in normal eyes have been reportedbetween 31 1-350 mOsl\/I/L
`(Ophthalmic Drug Delivery Systems, Ed. A Mitra, Dekker,
`1993) and between 284-311 mOsl\/I/L (Farris R., 1986; Tr.
`Am. Ophth. Soc. Vol LXXXIV). In some embodiments, the
`osmolarity can be from about 250 to about 450 mOsl\/I/L, or
`about 250 to about 350 mOsl\/I/L. In some embodiments, the
`higher levels of sodium, e.g., above 0.9% w/v, such as 1.0,
`1.2, 1.4, 1.6, 1.8, or 2.0% w/v, can be used to increase the
`levels of un-ionized MPA (e.g., NaMPA) in the ocular solu-
`tion
`
`In some embodiments, the counter ion to the sodium
`[0032]
`in solution is chloride. In some embodiments, the chloride in
`the ocular formulation can be from HCl, which is used to
`adjust the pH ofthe ocular solution, or from sodium chloride,
`which can be used to adjust the tonicity of the formulation.
`Other examples of chloride sources include potassium chlo-
`ride.
`In some embodiments, various buffers, as further
`described below, can also be a source of other types of coun-
`terions.
`
`In some embodiments, the ocular solutions can con-
`[0033]
`sist essentially of NaMPA and one or more additives such as
`preservatives, viscosity increasing agents, wetting agents,
`buffering agents, lubricating agents, antioxidants, and tonic-
`ity agents. It is to be understood that the categories of agents
`are not meant to be mutually exclusive such that some agents
`can fall into multiple categories. For example, a wetting agent
`can also have viscosity enhancing properties, and therefore
`can be a wetting agent as well as a viscosity enhancing agent.
`[0034]
`In some embodiments, the additive can be one or
`more buffering agents for adjusting and/or maintaining the
`pH of the ocular solution at a specified pH range. Buffering
`agents are usually composed of a weak acid or base and its
`conjugate salt, where the “buffer capacity” 8 is defined as:
`
`AB
`
`18%
`
`where AB is the gram equivalent of strong acid/base to change
`pH of 1 liter of buffer solution, and ApH is the pH change
`caused by the addition of strong acid/base. The relationship
`between buffer capacity and buffer concentrations can be
`defined by the following formula:
`
`Ka[H3O*]
`= 2.30%
`(K61 + [H30*l)2
`
`'8
`
`where C is the total buffer concentration (i.e., the sum of the
`molar concentrations of acid and salt). Generally, buffer
`capacity should be large enough to maintain the product pH
`for a reasonably long shelf-life but also low enough to allow
`rapid readjustment of the product to physiologic pH upon
`administration. Generally, buffer capacities of from about
`0.01 to 0.1 can be used for ophthalmic solutions, particularly
`at concentrations that provide sufiicient buffering capacity
`and minimizes adverse effects, e.g., irritation, to the eye.
`Exemplary buffering agents include, by way of example and
`not limitation, various salts (e.g., sodium, potassium, etc.),
`acids or bases, where appropriate, of the following: acetate,
`borate, phosphate, bicarbonate, carbonate, citrate, tetrabo-
`rate, biphosphate, tromethamine, hydroxyethyl morpholine,
`
`In some
`and THAM (trishydroxymethylarnino-methane).
`embodiments, the buffer can be present from about 0. 5 mM to
`about 100 mM, from about 1 mM to about 50 mM, from about
`1 mM to about 40 mM, from about 1 mM to about 30 mM,
`from about 1 mM to about 20 mM, or from about 1 mM to
`about 10 mM.
`
`the ocular solution of
`In some embodiments,
`[0035]
`NaMPA can have one or more preservatives, for example, to
`extend shelf life or limit bacterial growth in the solutions
`during storage as well as when administered therapeutically
`onto the eye. Preservatives that can be used, include, among
`others, benzalkonium chloride, benzethonium chloride, ben-
`zododecinium bromide, cetylpyridinium chloride, chlorobu-
`tanol, ethylenediamine tetracetic acid (EDTA), thimerosol,
`phenylmercuric nitrate, phenylmercuric acetate, methyl/pro-
`pylparabens, phenylethyl alcohol, sodium benzoate, sodium
`propionate, sorbic acid, and sodium perborate. The amount of
`preservative in the solution can be a level that enhances the
`shelf life, limits bacterial growth, or otherwise preserves the
`ocular solution, with minimal toxicity to the eye tissues (see,
`e.g., The United States Pharrnacopeia, 22nd rev., and The
`National Formulary, 17th ed. Rockville, Md.: The United
`States Pharmacopeial Convention; pages 1692-3 (1989)).
`Levels of preservative suitable for use in the ocular formula-
`tions can be determined by the person skilled in the art. In
`some embodiments,
`the preservatives can be used at an
`amount of from about 0.001 to about 1.0% w/v. For example,
`the preservative can be a divalent metal ion chelator, such as
`EDTA, and can be from about 0.005 to about 0.050% w/v,
`0.005 to about 0.040% w/v, 0.010 to about 0.030% w/v, 0.010
`to about 0.020% w/v, or from about 0.010 to about 0.015%
`w/v. In some embodiments, the amount of preservative in the
`ocular solution, such as EDTA, can be about 0.005, 0.01,
`0.012, 0.014, 0.016, 0.018, 0.020, 0.030, 0.040, or 0.0