(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0136598 A1
`(43) Pub. Date:
`May 28, 2009
`Chapin et al.
`
`US 20090l36598Al
`
`(54) COMPOSITIONS FOR THE TREATMENT
`AND PREVENTION OF EYELID SWELLING
`
`Inventors:
`
`Matthew Jonathan (Thapin,
`Amesbury, MA (US); Mark Barry
`Abelson, Andover, MA (US); Keith
`Jeffrey Lane, Somerville, MA
`(US); George Minno, Suwanee,
`GA (US)
`
`Correspondence Address:
`MINTZ, LEVIN, COHN, FERRIS, GLOVSKY
`AND POPEO, P.C
`ONE FINANCIAL CENTER
`BOSTON, MA 02111 (US)
`
`Assignee:
`
`ACIEX, INC., Westborough, MA
`(US)
`
`Appl. No.2
`
`12/266,396
`
`Filed:
`
`Nov. 6, 2008
`
`Related U.S. Application Data
`
`Continuation-in-part of application No. 11/796,278,
`filed on Apr. 26, 2007.
`Provisional application No. 60/794,983, filed on Apr.
`26, 2006, provisional application No. 60/845,479,
`filed on Sep. 18, 2006, provisional application No.
`61/007,511, filed on Nov. 8, 2007.
`Publication Classification
`
`Int. Cl.
`A61K 33/14
`A61l( 31/047
`A61K 31/4164
`A61P 27/02
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`........ .. 424/680; 514/738; 514/400; 514/396
`ABSTRACT
`
`(52) U.S. Cl.
`
`(57)
`
`The invention features topical formulations comprising an
`osmotieally active agent and/or a vasoeonstrietor and/or an
`astringent agent for the treatment and prevention of eyelid
`swelling, a11d methods of use thereof.
`
`CONDITIONS THAT PRESENT EYELID SWELLING
`
`Condition
`
`Eyelid presentation
`
`Other early ocular characteristics of
`presenting sign
`
`Exophthalmos, diplopia
`
`Granulomatosislz Unilateral
`swelling of upper lid
`Bilateral lid swelling
`
`Mass lesions, elevated lgE, eosinophil
`and lymphocyte infiltration
`Diffuse bilateral lid swelling Amyloid deposits (group of disorder]
`
`Wegener’s
`
`Kimura’s Disease
`
`Conjtinctival
`amyloidosis
`Orbital sarcoid
`
`Kikuchis disease
`(necrotizing histiocytic
`lymphadenitis)
`Pediatric leukemia
`
`Lid swelling
`
`Lid swelling
`
`Diplopiafionjunctival, retinal, optic nerve,
`and lacrimal gland involvement
`Additional cutaneous manifestations
`(nonspecific)
`
`Unilateral swelling of lower
`lid A
`
`Acute dacryocystitis, preseptal cellulitls
`
`Rosai-Dorfman disease
`Rosacea
`
`Lid swelling
`Periorbital edema
`
`Hemophagocytlc
`syndrome
`
`Unilateral swelling of upper
`lid
`
`Melkersson-Rosenthal
`synd tome
`
`Lid swelling
`
`Acute infectious
`mononucleosis
`
`Blepharochalasis
`syndrome
`
`Periorbital edema and lid
`swelling
`Recurrent, intermittent eyelid
`swelling, typically bilateral
`
`Ocular presentation rare (1 1%), orbital
`Blepharitis, conunctivitis
`Bilateral visual disturbance, optic disk
`edema, retinal hemorrhages, perivenous
`retinal white patches
`
`Facial edema, facial paralysis, furrowed
`tongue, perilymphatic granulomas, dermal
`edema
`Occur approximately one week prior to other
`
`Leaves lids with stretched excess skin, aged
`appearance
`
`Bilateral lid swelling
`_Nephrotic syndrome
`Chronic dacryoadenitls lnterinittent swelling of upper
`lid
`
`Swollen face
`Nonspecific
`
`Seborrheic dermatitis
`
`Lid swelling
`
`L mphoma
`
`Lid swelling/mass
`
`Blepharitis, scalp involvement,
`red lid margins
`Enlargedl mph nodes
`
`APOTEX EX1063
`
`Page 1
`
`

`
`Patent Application Publication May 28, 2009 Sheet 1 of 31
`
`US 2009/0136598 A1
`
`CONDITIONS THAT PRESENT EYELID SWELLING
`
`Condition
`
`Eyelid presentation
`
`swellin ofu erlid
`
`Kimura’s Disease
`
`Bilateral lid swelling
`
`amyloidosis
`orbital sarcoid
`
`Kikuchi's disease
`(necrotizing histiocytic
`lymphadenitis)
`
`Pediatric leukemia
`
`Lid swelling
`
`Lid swelling
`
`Other early ocularcharacteristics of
`presenting sign
`
`
`
`
`
`Mass lesions, elevated igE, eosinophil
`and lymphocyte infiltration
`
`Diplopia, conjunctival, retinal, optic nerve,
`and lacrimal gland involvement
`Additional cutaneous manifestations
`(nonspecific)
`
`
`
`
`Uniiateral swelling of lower Acute dacryocystitis, preseptal cellulitis
`lid A
`
`
`
`
`
`Hemophagocytic
`syndrome
`
`
`
`
`
`
`
`
`
`
`
`Recurrent, intermittent eyelid Leaves lids with stretched excess skin, aged
`Blepharochalasls
`
`swelling, typically bilateral
`appearance
`syndrome
`
`
`
`Swollen face
`Nephrotic syndrome
`Bilateral lid swelling
`Chronic dacryoadenitis intermittent swelling ofupper Nonspecific
`
`lid
`
`
`
`
`
`
`
`
`
`Blepharitis, scalp involvement,
`red lid mar ins
`Enlarged I mph nodes
`
`Seborrheic dermatitis
`
`
`
`
`
`Lid sweliing
`
`Lid swelling/mass
`
`Fig. 1
`
`Page 2
`
`Ocular resentation rare (1 1%), orbital
`Rosai-Dorfman disease Lid swellin
`Bleharitis, con'unctivitis
`Periorbital edema
`Unilateral swelling of upper Bilateral visual disturbance, optic disk
`
`lid
`edema, retinal hemorrhages, perivenous
`
`retinal white patches
`
`
`Lid swelling
`Facial edema, facial paralysis, furrowed
`tongue, perilymphatic granulomas, dermal
`edema
`Occur approximately one week prior to other
`
`
`
`Periorbital edema and lid
`swellin
`
`Melkersson—Rosenthal
`syndrome
`
`Acute infectious
`mononucleosis
`
`Page 2
`
`

`
`Patent Application Publication May 28, 2009 Sheet 2 of 31
`
`US 2009/0136598 A1
`
`PALPEBRAL
`CONJUNCTIVA
`
`EYELID BLOOD COLLAGEN
`
`
`
`
`
`
`
`DIFFUS!ON
`" éygug
`
`I
`AND REDUCTION
`nssug
`OF SWELLENG
`COLLOID/-\L OSMOTIC
`FAT DEPOSUS
`ASTRINGENT, HIGH
`CONCENTRATION NaCl
`
`OR OTHER AGENT
`
`Fig. 2
`
`Page 3
`
`Page 3
`
`

`
`Patent Application Publication May 28, 2009 Sheet 3 of 31
`
`US 2009/0136598 A1
`
`0..-.
`
`SUBJECT 1
`
`
`
`VOLUMEDIFFERENCE
`
`(mm/\3)
`
`-100-
`
`-200J
`
`-3004
`
`-400-
`
`u______________
`
`CI
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`TIME POINTS
`
`+ NAPHAZOLINE (01%) (OD)
`
`NOTREATMENT (OS)
`
`Fig. 3A
`
`SUBJECT2
`
`150
`
`I00
`
`
`
`BASELINE
`
`SMIN
`
`IoII/IIN
`
`ISMIN
`
`30M|N
`
`IZOMIN
`
`TIME POINTS
`
`LL]
`
`U 5
`
`50
`0
`$3
`§< -50
`..mg 1
`|_|_]
`Ev 00
`3
`-I50
`2
`-200
`—250
`
`-9- NAPHAZOLINE (0.1%) (OD)
`
`NOTREATMENT (OS)
`
`Fig. 3B
`
`Page 4
`
`Page 4
`
`

`
`Patent Application Publication May 28, 2009 Sheet 4 of 31
`
`US 2009/0136598 A1
`
`200
`
`SUBJECT 3
`
`150
`
`100
`
`50
`
`0
`
`-50
`
`(mm/\3)
`
`-100
`
`-150
`
`-zoo
`
`
`
`VOLUMEDIFFERENCE
`
`BASELINE
`
`SMIN
`
`IoIvIIN
`
`I5IvIIN
`
`3oIvIIN
`
`I2oIvIIN
`
`+~ NAPHAZOLINE (0.1%) (OD)
`
`NO TREATMENT (OS)
`
`TEME POINTS
`
`Fig. 3c
`
`SUBJECT4
`
`
`
`BASELINE
`
`5IvIIN
`
`IoIvIIN
`
`15 MIN
`
`30M|N
`
`12OM|N
`
`100
`
`0
`
`5
`
`Z 5
`
`-100
`
`;‘
`E?
`E; -200
`§§ -300
`
`-400
`
`-500
`
`3Q
`
`>-
`
`-o— NAPHAZOLINE (0.1%) (OD)
`
`NO TREATMENT (05)
`
`TIME POINTS
`
`Fig. 3D
`
`Page 5
`
`Page 5
`
`

`
`Patent Application Publication May 28, 2009 Sheet 5 of 31
`
`US 2009/0136598 A1
`
`SUBJECT 5
`
`___..
`
`_,.--' ' ’
`
`43-
`
`‘~._
`
`.-_-...__.._‘D-
`
`_
`
`- -.. - —...
`
`..... -
`
`.--
`
`.-C1
`
`_. __ ,.»:_‘
`_-v"
`
`u‘
`
`,.11
`
`\
`
`~.
`
`V
`
`_
`
`-50
`
`-I 50
`
`-I 00
`
`-200 -250
`
`
`
`VOLUMEDIFFERENCE
`
`(mm/\3)
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`-¢- NAPHAZOLINE (0.1%) (OD)
`
`NO TREATMENT (OS)
`
`TIME POINTS
`
`Fig. 3 E
`
`SUBJECT 6
`
`DIFFERENCE
`VOLUME
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`TIME POINTS
`
`-9- NAPHAZOLINE (0.1%) (OD)
`
`NO TREATMENT (OS)
`
`Fig. 3F
`
`Page 6
`
`Page 6
`
`

`
`Patent Application Publication May 28, 2009 Sheet 6 of 31
`
`US 2009/0136598 A1
`
`200
`
`SUBJECT 7
`
`
`
`VOLUMEDIFFERENCE
`
`150
`
`100
`
`U1 0
`
`(mm/\3)
`
`-50
`
`-100
`
`BASELINE
`
`SMIN
`
`IOMIN
`
`I5IvIIN
`
`3oIvIIN
`
`I20IvIIN
`
`TIME POINTS
`
`+ NAPHAZOL|NE(O.1%) (OD)
`
`NOTREATMENT(OS)
`
`Fig. 3G
`
`SUBJECT8
`
`0
`
`-50
`
`LIJ
`
`-100
`-150
`
`5
`Le‘?
`3:3?
`»;-< -200
`Q E
`gg -250
`3
`-300
`Q
`-350
`-400
`
`
`
`BASELINE
`
`SMIN
`
`I0IvIII\I
`
`15MlN
`
`30M|N
`
`I2oIvIII\I
`
`-0-» NAPHAZOLINE (01%) (OD)
`
`NO TREATMENT (05)
`
`TIME POINTS
`
`Fig. 3H
`
`Page 7
`
`Page 7
`
`

`
`Patent Application Publication May 28, 2009 Sheet 7 of 31
`
`US 2009/0136598 A1
`
`15o—
`
`100-
`
`SUBJECT 9
`
` VOLUME
`DIFFERENCE
`
`50-
`
`0
`
`-5o~
`
`-100-
`
`-150-
`
`«200-
`
`(mm/\3)
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`—o— NAPHAZOLiNE(O.1%) (OD)
`
`NO TREATMENT (05)
`
`TIME POENTS
`
`Fig. 3|
`
`400
`
`SUBJECT 10
`
`>
`
`300
`
`200
`
`100
`
`0
`
`-100
`-200
`
`-300
`
`E5
`2
`
`E E
`
`7;
`L_|_ <
`Q E
`5 E
`D
`S
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`I20 MIN
`
`-6- NAPHAZOLINE (0.1%) (OD)
`
`NO TREATMENT (05)
`
`TIME POINTS
`
`Fig. 3J
`
`Page 8
`
`Page 8
`
`

`
`Patent Application Publication May 28, 2009 Sheet 8 of 31
`
`US 2009/0136598 A1
`
`300-
`
`SUBJECT11
`
`200-
`ezj
`100-
`%
`u_ ("7
`__
`<
`0
`LEE
`Ev -200-
`
`
`
`~200-
`-300
`BASELINE
`5MIN
`IoMIN
`I5 MIN
`3oMIN
`I2oMIN
`
`TIME POINTS
`
`+ NAPHAZOLINE(O.1°/o) (OD)
`
`NOTREATMENT(OS)
`
`Fig. 3K
`
`NAPHAZOLINE (0.1%) VERSUS NO TREATMENT (N=1 1)
`
`BASELINE
`
`5MIN
`
`IoMIN
`
`1sMIN
`
`30M|N
`
`I2oMIN
`
`TIME POINTS
`
`+ NAPHAZOLINE (0.1%)
`
`NO TREATMENT
`
`Fig. 3L
`
`Page 9
`
`3(
`
`>3
`
`7; 200
`<
`I50
`E
`100
`E 50
`fl
`0
`at
`-50
`E -100
`5 -150
`L|.l
`-200
`
`§ -250
`9 ‘$28
`
`Page 9
`
`

`
`Patent Application Publication May 28, 2009 Sheet 9 of 31
`
`US 2009/0136598 A1
`
`200
`
`100
`0
`
`-100
`
`PATIENT 1 VISIT 2 OD OS COMPARISON
`
`
`
`OMIN
`
`SMIN
`
`IOMIN
`
`ISMIN
`
`30MlN
`
`120MIN
`
`TIME POINTS
`
`—o— OD (Muro 128)
`
`05 (NO TREATMENT)
`
`Fig. 4A
`
`Page 10
`
`& -200
`
`EL
`
`|..|
`_
`E 300
`
`3O>
`
`-500
`
`'5
`E
`E
`
`U E
`
`MI
`
`.J.I
`
`Page 10
`
`

`
`Patent Application Publication May 28, 2009 Sheet 10 of 31
`
`US 2009/0136598 A1
`
`PATIENT 2 VISIT 2 OD OS COMPARISON
`
`
`
`OMIN
`
`SMIN
`
`IOMIN
`
`ISMIN
`
`30 MIN
`
`120 MIN
`
`TIME POINTS
`
`+ OD (Muro 128)
`
`OS (NO TREATMENT)
`
`Fig. 4B
`
`A 300
`Q 200
`
`100
`
`0
`
`-100
`
`-200
`
`E ;
`
`;
`
`EL
`
`LI
`
`E L
`
`;
`
`C L
`
`”
`
`§ -
`
`4 -300
`9
`
`-400
`
`PATIENT 3 VISIT 2 OD OS COMPARISON
`
`
`
`OMIN
`
`SMIN
`
`I0 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`TIME POINTS
`
`~¢— OD (Muro 128)
`
`OS (NO TREATMENT)
`
`Fig. 4C
`
`Page 1 1
`
`6??
`
`< E EL
`
`UUZL
`
`IJ
`U
`LI...
`5».
`
`IL
`
`0L
`
`u §2
`
`3_J
`
`o>
`
`Page 11
`
`

`
`Patent Application Publication May 28, 2009 Sheet 11 of 31
`
`US 2009/0136598 A1
`
`250
`
`PATIENT 4 VISIT 2 OD OS COMPARISON
`
`:5 200
`
`I50
`
`< E
`
`
`
`oMIN
`
`5MIN
`
`Io MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`TIME POINTS
`
`4» OD (Muro 128)
`
`05 (NO TREATMENT)
`
`Fig. 4D
`
`PATIENT 5 VISIT 2 OD OS COMPARISON
`
`OMIN
`
`5MIN
`
`10 MIN
`
`I5MIN
`
`30 MIN
`
`I20 MIN
`
`TIME POINTS
`
`—o— OD (Muro 128)
`
`OS (NO TREATMENT)
`
`Fig. 4E
`
`Page 12
`
`6 I00
`
`50
`
`0
`-so
`
`-100
`
`-150
`
`5n
`
`:
`
`E5
`
`3‘
`
`3Q
`
`>
`
`6:<
`
`E EL
`
`U
`L)
`
`ZL
`
`UZL
`
`L]
`LL
`L_L
`
`QL
`
`JJ
`
`2D.
`
`_J
`
`C>
`
`Page 12
`
`

`
`Patent Application Publication May 28, 2009 Sheet 12 of 31
`
`US 2009/0136598 A1
`
`
`
`
`
`VOLUMEDIFFERENCE(mm’\3)
`
`PATIENT 6V|S|T 2 OD OS COMPARISON
`
`I\3I\JUUCU10OOO1II
`
`.....’
`
`....
`
`. -' '
`
`»
`
`T‘s
`
`N
`
`ISO-
`
`100-
`
`I
`
`U1 O
`
`N"
`
`.‘_
`
`I
`
`OMIN
`
`SMIN
`
`I0 MIN
`
`15 MIN
`
`30 MIN
`
`I20 MIN
`
`TIME POINTS
`
`-0- OD (Muro 128)
`
`OS (NO TREATMENT)
`
`Fig. 4F
`
`MEAN VOLUME DIFFERENCES OF MURO 128 NaCl 5% OPHTHALMIC SOLUTION
`
`(OD) AND NO TREATMENT (05) OF N = 6
`
`2‘ 200
`E
`150
`;;
`100
`u
`so
`E
`0-
`E
`soj
`L;
`-100
`D -150-
`§ -2503
`L“
`-200
`6!
`>
`
`
`
`BASELINE
`
`SMIN
`
`IOMIN
`
`ISMIN
`
`TIMEPOINTS
`
`I
`
`30MIN
`
`I
`
`120MIN
`
`I
`
`+ Muro 128 5% NaCl
`
`NO TREATMENT
`
`Fig. 4G
`
`Page 13
`
`Page 13
`
`

`
`Patent Application Publication May 28, 2009 Sheet 13 of 31
`
`US 2009/0136598 A1
`
`COMPARISON OF NAPHAZOLINE (0.1 %),
`
`MURO 128 5°/o NaCI, AND COMBINATION
`
`—-Nooooo
`
`
`
`
`
`-I 00
`
`-200
`
`-300
`
`-400
`
` -500 VOLUMEDIFFERENCE(mm/\3)
`
`BASELINE
`
`5 MIN
`
`10 MIN
`
`15 MIN
`
`30 MIN
`
`120 MIN
`
`TIMEPOINTS
`
`—o— Muro128 5% NaC|+ NAPHAZOLINE (0.1%)
`
`Muro 128 NaC (5%)
`
`NAPHAZOLINE (0.1%)
`
`+ NO TREATMENT
`
`Fig.5
`
`NAPHAZOLINE (0.1%) IN MURO 128 SOLUTION VS NO TREATMENT
`
`(N=6) USING STEEL BITE PLATES
`
`NAPHAZOLINE (0.1%)
`+ MURO I28 SOLUTION NO TREATMENT
`
`-50
`
` 5
`
`-100
`
`-150
`
`-200
`
`-250
`
`-300
`
`-350
`
`E g
`
`LLI
`
`5
`Eé‘
`LLJ
`LL
`
`&Q
`
`E3
`
`.....J
`
`9
`
`-400
`
`TREATMENT
`
`Fig. 6
`
`Page 14
`
`Page 14
`
`

`
`Patent Application Publication May 28, 2009 Sheet 14 of 31
`
`US 2009/0136598 A1
`
`
`
`%
`mOsm Reduce
`
`(CM)
`
`Normalized °/o
`Reduction
`
`
`Std
`Err
`
`
`
`
`NaCl 5% +
`
`Naphazoline
`0.1%
`
`Nacl 5%
`Naphazoline 0.1%
`
`
`
`1712
`
`1 11.9%
`
`-23.4%
`
`-20.9%
`
`-88.5%
`
`-15%
`-16.9%
`
`22.6%
`
`10-6%
`
`PERCENT REDUCTION OF TEST ARTICLES
`
`NaCl5%+
`
`Naphazoline
`0_1%
`
`Nag 5%
`
`
`
`
`
`_
`Naphazoline 0.1%
`..
`
`0%
`
`-20%
`
`-40%
`
`-60%
`
`-80%
`
`-100%
`
`-120%
`
`%REDUCTION
`
`TEST ARTICLE
`
`Fig. 7B
`
`Page 15
`
`Page 15
`
`

`
`Patent Application Publication May 28, 2009 Sheet 15 of 31
`
`US 2009/0136598 A1
`
`MEAN MORNING EYELID SWELLING POST NAPHAZOLINE 8:
`
`600-
`
`MU R0 OINTMENT TREATMENT (N=4)
`
`
`
`
`
`EYELIDVOLUMEINCREASE
`
`TREATMENT
`
`NO TREATMENT
`
`EYE
`
`Fig. 8
`
`NaCl (2.5%) & NAPHAZOLINE (0.1%) vs NO TREATMENT (N=6)
`
`TREATMENT
`
`NO TREATMENT
`
`
`
`'50
`
`En‘
`
`EE
`
`E“;
`Z -100
`LU
`C1:
`LU
`
`-150
`
`E;
`'5Lu
`2 -200
`
`-250
`
`§>
`
`TREATMENT
`
`Fig.9
`
`Page 16
`
`Page 16
`
`

`
`Patent Application Publication May 28, 2009 Sheet 16 of 31
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`US 2009/0136598 A1
`
`SUCROSE (50%) 8: NAPHAZOLINE (0.1%) vs NO TREATMENT (N=6)
`
`TREATMENT
`.
`
`NO TREATMENT
`
`
`
`0
`
`E
`is
`E -50
`
`-100
`
`-150
`
`-200
`
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`
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`LLJ
`
`tE
`
`LLI
`
`E 3
`
`O>
`
`TREATMENT
`
`Fig. 10
`
`Page 17
`
`Page 17
`
`

`
`Patent Application Publication May 28, 2009 Sheet 17 of 31
`
`US 2009/0136598 A1
`
`
`
`
`Normalized %
`Reduction
`
`
`
`Std
`Err
`
`
`
`-13 4%
`
`
`
`%
`Reduce
`
`—72.4%
`
`—20.9%
`
`Active
`
`Sucrose 50% +
`
`Naphazoline 0.1% 1460
`
`
`
`mo
`
`
`
`Naphazoline 0.1%
`
`Fig. 11A
`
`PERCENT REDUCTION OF TEST ARTICLES
`
`Sucrose 50%
`+
`
`Naphazoline 0.1%
`
`Sucrose 50%
`
`Naphazoline 0.1%
`
`
`
`0% —
`
`-20%-
`
`E -40%-
`
`E3
`
`D %
`
`0
`3 -80%)-
`
`-60%-
`
`-1oo%—
`
`-120%-
`
`TESTARTICLE
`
`Fig. 113
`
`Page 18
`
`Page 18
`
`

`
`Patent Application Publication May 28, 2009 Sheet 18 of 31
`
`US 2009/0136598 A1
`
`DIURNAL CHANGES IN EYELID VOLUME (N=8)
`
`500
`
`400
`
`(mm/\3)
`VOLUMECHANGE
`
`
`300
`
`200
`
`1 00
`
`-100
`
`-200
`
`O
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`TIME POINT (HOURS)
`
`-9- OD
`
`OS
`
`OU
`
`Fig. 12
`
`PHENYLEPHRINE 0.1% OINTMENT vs NO TREATMENT
`
`LOWER EYELID (N=6)
`NO
`TREATMENT
`.
`
`PHENYLEPHRINE .1%
`1,
`
`.
`
`
`
`
`
`VOLUMEDIFFERENCE(MM/\3)
`
`00/
`0
`
`—20%
`
`-40%
`
`-60%
`
`-80%
`
`-1 00%
`
`-1 20%
`
`-1 40%
`
`—1 60%
`
`TREATMENT
`
`Fig. 13
`
`Page 19
`
`Page 19
`
`

`
`Patent Application Publication May 28, 2009 Sheet 19 of 31
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`US 2009/0136598 A1
`
`MANNITOL (12.5%) & NAPHAZOLINE (0.1 °/o)
`
`IN 5%NaC| SOLUTION vs NO TREATMENT (N=6)
`
`Mannitol (12.5%) +
`NO
`Naphazoline (0.1%) +
`5%NaCl Solution
`TREATMENT
`>«‘:-
`e--->r-
`‘ya:
`u 3-:
`
`"’
`
`
`
`TREATMENT
`
`Fig. 14A
`
`0
`E
`-50-
`E
`5 -1oo—
`§ -150-
`E:
`E -200-
`$ -250*
`
`E (
`
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`95,
`> -350-
`
`Active
`
`NaCl 5% +
`
`°/o
`
`Reduce
`
`Naphazoline 0.1%
`
`1712
`
`-111.9%
`
`
`
` Normalized %
`Reduction
`
`—23.4%
`
`-88.5%
`
`22.6%
`
`NaCi 5%
`
`1712
`
`-6.8%
`
`8.9%
`
`-15.7%
`
`10.6%
`
`Sucrose 50% +
`
`Naphazoline 0.1 %
`
`1460
`
`-72.4%
`
`-13.4%
`
`-59.0%
`
`1.3%
`
`Sucrose 50%
`
`1460
`
`0.0%
`
`5-9%
`
`2.3%
`
`
`
`
`
`
`
`
`NaCl 5% + Mannitol
`12.5% +
`
`Naphazoline 0.1%
`
`
`
`
`
` Mannitoi12.5%
`Naphazo|ine0.1%
`
`
`
`
`
`
`
`2398
`
`-50.8%
`
`—19.9%
`
`-30.9%
`
`21.4%
`
`
`
`127%
`
`-24.1%
`-20.9%
`
`Fig. 143
`
`-36.8%
`—16.9%
`
`8.9%
`3.1%
`
`
`
`Page 20
`
`Page 20
`
`

`
`Patent Application Publication May 28, 2009 Sheet 20 of 31
`
`US 2009/0136598 A1
`
`PERCENT REDUCTION OF TEST ARTICLES
`
`NaCl 5% +
`Mannitol 12.5% +
`Naphazoline 0.1%
`
`Mannitol 12.5%
`
`Naphazoline 0.1%
`
`%REDUCTION
`
`-20%
`
`-40%
`
`-60%
`
`—80%
`
`-100%
`
`-120%
`
`TEST ARTICLE
`
`Fig. 14C
`
`MANNITOL 12.5% VS PBS TREATMENT (N=6)
`
`—\NooooII
`OooI_E__
`
`I II
`
`I
`
`I
`
`(mm/\3)
`
` [UC OCL. VOLUMEDIFFERENCE
`
`
`
`-300-
`
`'400“1
`
`I
`
`BASELINE
`
`5 MIN
`
`I5 MIN
`
`30 MIN
`
`60 MIN
`
`+ MANN|TOL12.5%
`
`PBS
`
`TIME POINTS
`
`Fig. 1 5
`
`Page 21
`
`Page 21
`
`

`
`Patent Application Publication May 28, 2009 Sheet 21 of 31
`
`US 2009/0136598 A1
`
`%
`
`
`
`%
`Reduce
`
`Reduce
`(Ctfl)
`
`
`
`Normalized %
`Reduction
`
`Std
`Err
`
`
`
`
`
`
`1712
`
`1712
`
`
`
`
`Test Article
`
`NaCl 5% +
`
`Naphazoline 0.1%
`
`
`
`Sucrose 50% +
`Naphazoline 0.1%
`
`Sucrose 50%
`
`
`
`
`
`NaCl 5% + Mannitol
`12.5% +
`
`Naphazoline 0.1%
`
`Mannitol 12.5%
`
`
`
`
`Naphazoline 0.1%
`
`
`
`
`
`
`
`
`
`-111.9%
`
`-23.4%
`
`-88.5%
`
`22.6%
`
`-6.8%
`
`-15.7%
`
`10.6%
`
`
`
`
`
`1460
`
`-72.4%
`
`-13.4%
`
`-59.o%
`
`1460
`
`0-0%
`
`2398
`
`-50.8%
`
`—19.9%
`
`12.7%
`
`—24.1%
`~20-9%
`
`Fig. 16A
`
`
`
`
`8.9%
`31%
`
`
`
`
`
`
`-30.9%
`
`—36.8%
`469%
`
`Page 22
`
`PERCENT REDUCTION OF TEST ARTICLES
`
`§
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`
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`ED
`
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`§
`
`TESTARTICLE
`
`Fig. 16B
`
`Page 22
`
`

`
`Patent Application Publication May 28, 2009 Sheet 22 of 31
`
`US 2009/0136598 A1
`
`PERCENT REDUCTION SUCROSE (50%) vs NO TREATMENT (N=6)
`
`%REDUCTION
`
`8%
`
`6%
`
`4%
`
`2% *
`
`0%
`
`-2% '
`
`—4% “
`
`-6% "
`
`-8%‘l
`-10% "‘
`
`
`
`SUCROSE (50%)
`
`NO TREATMENT
`
`TREATMENT A
`
`Fig. 17
`
`Page 23
`
`Page 23
`
`

`
`Patent Application Publication May 28, 2009 Sheet 23 of 31
`
`US 2009/0136598 A1
`
`(mOsm/kg)
`
`Osmolality
`Value
`
`2398
`
`Test Article
`
`NaC| 5% + Mannitol 12.5% +
`
`Naphazoline 0.1%
`
`Fig. 18A
`
`OSMOLALITY vs COMFORT
`
`
`
`10.0
`
`9.0
`
`E 8.0
`5 7.0
`U’)
`
`9 6.0
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`
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`
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`1000
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`2000
`
`I
`2500
`
`I
`3000
`
`OSMOLALITY (mOsm/Kg)
`
`R2 = 0,4915
`
`Fig. 18B
`
`Page 24
`
`Page 24
`
`

`
`Patent Application Publication
`
`May 28, 2009 Sheet 24 of 31
`
`US 2009/0136598 A1
`
`
`
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`Page 25
`
`Page 25
`
`
`

`
`Patent Application Publication May 28, 2009 Sheet 25 of 31
`
`US 2009/0136598 A1
`
`
`
`MEANLIDSWELLINGSCORE
`
`
`
`
`
`MEANGLOBALLIDSWELLINGSCORE
`
`{N
`
`N U1
`
`N)
`
`(0-3SCALE) 3
`
`._A
`
`0-5 '
`
`VISIT 1 AND VISIT 2: MEAN SCORES BY REGION AND TIME
`
`(N=20) NO TREATMENT
`
`L
`
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`
`—<>— REGIONI —-— REGION 2
`—w— REGION 3 ~-«:-- REGION 4
`—a<—- GLOBAL
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`
`10
`
`20
`
`3o
`
`40
`
`so
`
`so
`
`Fig. 20
`
`DIARY RESULTS: MEAN GLOBAL SCORE BY TIME OF DAY
`
`(N=19) NO TREATMENT
`
`2_50_
`
`MORNING SWELLING
`
`(0-3SCALE) 5G9‘P
`
`0.50-
`
`EVENING SWELLING
`
`DAY
`DAY
`DAY
`DAY
`DAY
`DAY DAY
`DAY
`DAY
`DAY
`DAY
`0'00‘ DAY
`IPM 2AM 2PM 3AM 3PM 4AM 4PM 5AM 5PM 6AM 6PM 7AM
`
`Fig. 21
`
`Page 26
`
`Page 26
`
`

`
`Patent Application Publication May 28, 2009 Sheet 26 of 31
`
`US 2009/0136598 A1
`
`VISIT 4 MEAN REGION 1 SWELLING SCORES
`
`BY TREATMENT: PER PROTOCOL (N=12)
`
`
`
`-O-ACT|VE —I-PLACEBO
`
`I
`
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`
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`
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`
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`
`20
`
`30
`
`40
`
`50
`
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`
`[A I
`
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`
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`
`Fig. 22
`
`VISIT 4 MEAN REGION 2 SWELLIN
`
`ORES
`
`BY TREATMENT: PER PROTOC0
`
`=10)
`
`
`
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`:3
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`
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`
`20
`
`30
`
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`
`Fig. 23
`
`Page 27
`
`Page 27
`
`

`
`Patent Application Publication May 28, 2009 Sheet 27 of 31
`
`US 2009/0136598 A1
`
`VISIT 4 MEAN REGION 3 SWELLING SCORES
`
`BY TREATMENT: PER PROTOCOL (N=15)
`
`3.00
`
`2.50
`
`1.00
`
`
`
`
`
`MEANLIDSWELLINGSCORE(0-3SCALE)
`
`2.00 1.50
` *0‘ ACTIVE
`0.50 0.00
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`-—I- PLACEBO
`
`BASELINE
`
`0
`
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`
`20
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`
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`
`Fig. 24
`
`VISIT 4 MEAN REGION 4 SWELLING SCORES
`
`BY TREATMENT: PER PROTOCOL (N=16)
`
`.
`
`_
`P_0.020
`
`
`
`—O— ACTIVE
`
`—I— PLACEBO
`
`BASELINE
`
`0
`
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`
`20
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`
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`
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`
`Fig.25
`
`Page 28
`
`1
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`
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`
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`
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`
`Page 28
`
`

`
`Patent Application Publication May 28, 2009 Sheet 28 of 31
`
`US 2009/0136598 A1
`
`VISIT 4 MEAN GLOBAL SWELLING SCORES
`
`BY TREATMENT: PER PROTOCOL (N=18)
`
`3.00‘
`
`2.50‘
`
`
`
`0.50-
`
`
`
`MEANGLOBALLIDSWELLING
`
`-0- ACTIVE
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`
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`SCORE(0-3SCALE) 5G‘i_3
`
`
`
`
`000 BASELINE
`o
`10
`20
`30
`4o
`50
`60
`
`Fig. 26
`
`MEAN COMFORT SCORE BY TREATMENT (N=2o)
`
`“ 4.5
`
`ACTIVE
`
`
`
`
`
`
`
`
`
`MEANCOMFORTSCORE(0-10SCALE
`
`Page 29
`
`Page 29
`
`

`
`Patent Application Publication May 28, 2009 Sheet 29 of 31
`
`US 2009/0136598 A1
`
`MEAN GLOBAL LID SWELLING SCORE BY TREATMENT:
`
`3%NaCI GROUP (N-1 1)
`
`-°- NAPHAZOLINE 0.09%
`
`'°‘OXYMETAZOLINE 0.05%
`
`
`
`U)
`
`IV U1
`
`Ix)
`
`.9...J
`
`__I
`
`U1U1
`
`NAPHAZOLINE DECREASE -0.82 (P=0.0111)
`
`OXYMETAZOLINE DECREASE -1.09 (P=0.0004)
`66.6% SUBJECTS PREFERRED NAPHAZOLINE
` O
`O
`20
`40
`60
`90
`120
`
`BASELINE
`
`180 I 240 I 300 I 360 I
`
`TIME (MIN) POST DROP
`
`Fig. 28
`
`MEAN GLOBAL LID SWELLING SCORE BY TREATMENT:
`
`7.5% GLYCEROL GROUP (N-11)
`
`U)
`
`-*NAPHAZOLINE 0.09%
`
`'”'OXYMETAZOLINE 0.05%
`
`I‘) U‘!
`
`I\)
`
`NAPHAZOLINE DECREASE -1.72 (P<0.0001)
`
`
`
`
`
`MEANGLOBALLIDSWELLINGSCORE
`
`(0-3SCALE)
`
`
`
`
`
`MEANGLOBALLIDSWELLINGSCORE
`
`
`(0-3SCALE) 5 _|
`
`0-5 OXYMETAZOLINE DECREASE -1.64 (P=0.O0O2)/V
`66.6% SUBJECTS PREFERRED NAPHAZOLINE
`
`LL:
`0
`20
`40
`60
`90
`120
`180
`240
`300
`360
`
`TIME (MIN) POST DROP
`
`Fig. 29
`
`Page 30
`
`Z3L
`
`L!
`U‘)
`<co
`
`Page 30
`
`

`
`Patent Application Publication May 28, 2009 Sheet 30 of 31
`
`US 2009/0136598 A1
`
`MEAN GLOBAL LID SWELLING SCORE BY TREATMENT:
`
`BASELINE ADJUSTED (N=11)
`
`+ NAPHAZOLINE 0.09%
`
`'”'OXYMETAZOL|NE 0.05%
`
`-—-~==-r-21.‘.
`
`—«s-- NAPHAZOLINE 0.09%
`
`"X"'OXYMETAZOL|NE 0.05%
`.
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`
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`
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`
`I—————————ISSSSSSSSS
`GLYCEROL
`
`“‘~~II-..'I'.'fi'.'l'_'J§
`/v
`NAPH (GLYCEROL-NaCl) DIFFERENCE OF -0.91
`oxv (GLYCEROL—NaC|) DIFFERENCE OF -0.55
`
`§
`0
`20
`40
`60
`90
`I20
`180
`240
`300
`360
`
`TIME (MIN) POST DROP
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`FIg. 30
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`3 5
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`E
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`Patent Application Publication May 28, 2009 Sheet 31 of 31
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`US 2009/0136598 A1
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`
`
`m:m<Eo&2ouz:mEO_>_
`
`
`
`SéomSmaoumEoezoums.
`
`6543210
`
`NAPH
`
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`
`GLYCEROL GROUP MORE COMFORTABLE
`
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`
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`
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`
`Fig. 31
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`US 2009/0136598 A1
`
`May 28, 2009
`
`COMPOSITIONS FOR THE TREATMENT
`AND PREVENTION OF EYELID SWELLING
`
`RELATED APPLICATIONS
`
`[0001] This application is a continuation-in-part of U.S.
`application Ser. No. 11/796,278, filed Apr. 26, 2007, which
`claims the benefit of U.S. Provisional Application No.
`60/794,983, filed Apr. 26, 2006 and U.S. Provisional Appli-
`cation No. 60/845,479, filed Sep. 18, 2006; and this applica-
`tion claims priority to U.S. Provisional Application No.
`61/007,51 1 filed Nov. 8, 2007, the contents ofwhich are each
`hereby incorporated by reference in their entireties.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention relates to novel ophthalmic
`compositions and methods useful for the prevention and treat-
`ment of eyelid swelling. Specifically, the invention relates to
`an ophthalmic composition comprising an osmotically active
`agent, an astringent, a vasoconstrictor, or a combination
`thereof, useful for the prevention and treatment of eyelid
`swelling. The invention additionally relates to methods of
`administering such compositions to a subject in need thereof.
`
`BACKGROUND OF THE INVENTION
`
`[0003] Eyelid swelling and inflammation of the lids has
`both long and short-term significance in terms of histologic
`impact, patient quality of life, and general patient comfort.
`The human eyelid is made of the thinnest skin layers of the
`body, the mo st well-defined layers oftissues and muscles, and
`the most fragile collagen fibers. Because ofthese delicate skin
`layers, the eyelid is very susceptible to swelling, acute inflam-
`mation, and possible long-term damage.
`[0004] The eyelids have several important roles that allow
`the eye to function as it does. They protect the eye and shield
`the cornea by reflexive closing. It is this mechanism that often
`prevents the entry of particles or foreign objects into the eye
`and possible damage. The lids also control the amount of light
`that enters the eye, just as a shutter in a camera does. They also
`add to the components ofthe tear film (via the lid margin) and
`maintain distribution of the smooth liquid over the eye by
`their spreading action during blinking. The eyelids play a very
`large role in maintaining not only the health ofthe eye, but the
`overall function of the ocular system. When inflammation of
`this crucial protection mechanism occurs, the ocular health of
`the individual is compromised.
`[0005] Repeated stretching and damage to the lids as a
`result of swelling of various etiologies can cause the tempo-
`rary development of sagging, drooping skin layers above and
`below the eye. This swelling of the lids can provide a very
`undesirable appearance and can even restrict the field of
`vision. While these signs are often only temporary, the actual
`damage that occurs on the physiologic and anatomic levels
`can eventually result in permanent changes because it accu-
`mulates with each recurrence.
`
`[0006] This symptom of eyelid swelling is not often con-
`sidered to be of primary concern when assessing ocular
`health, although it is a major concern for many patients,
`physicians and researchers. Morning eyelid swelling is very
`common and has both extensive social concerns in addition to
`
`concerns relating to patient health. Patients’ armoyance and
`overall
`intolerance with puffy, sagging eyelids is clearly
`shown by the fact that eyelid surgery (229,092) and botuli-
`num toxin injection (1,658,667) were two of the most com-
`
`mon procedures performed by plastic surgeons in the U.S. in
`2002. Despite this significant desire to reduce the presence of
`eyelid edema, there has been a lack of attention to the symp-
`tom. It is often classified among other signs and symptoms
`but is rarely a primary variable in clinical studies, as histori-
`cally it has been diflicult to precisely measure. Various ocular
`allergy medications, like olopatadine 0.1% (Patanol) begin to
`reduce eyelid swelling relating to allergic conjunctivitis, but
`there is no medication available to specifically combat this
`symptom directly and effectively. With such a powerful pres-
`ence of so many forms in society, a treatment that directly
`impacts the condition of lid swelling is necessary.
`
`SUMMARY OF THE INVENTION
`
`Provided are novel compositions and methods for
`[0007]
`treating and preventing eyelid swelling, particularly non-al-
`lergic eyelid swelling. In certain embodiments, novel topical
`ophthalmic formulations comprising an osmotically active
`agent and/or a vasoconstrictor and/or an astringent agent is
`provided. In particular the invention provides acceptable topi-
`cal ophthalmic formulations comprising a combination of an
`osmotically active agent and/or a vasoconstrictor and/or
`astringent agent, which act synergistically to treat and prevent
`eyelid swelling. The extraordinary eflicacy of these formula-
`tions is attributed to, among other things, the synergistic
`effect of the combination of ingredients in them. The combi-
`nation of an osmotically active agent and/or a vasoconstrictor
`and/or an astringent agent act synergistically to treat signs and
`symptoms of eyelid swelling, which have never been previ-
`ously contemplated to be accomplished in one product con-
`taining each of these separate ingredients.
`[0008]
`In one embodiment, the present invention provides a
`target osmolarity and/or osmolality range for the formulation
`of an effective ophthalmic composition having an acceptable
`(i.e., tolerable) comfort profile, for treating and preventing
`eyelid swelling. To be osmotically active, the osmolarity and/
`or osmolality ofa solution must be greater than the osmolarity
`and/or osmolality of its surrounding environment. Osmolar-
`ity is a measure of the osmoles of solute per liter of solution,
`while the osmolality is a measure ofthe osmoles of solute per
`kilogram of solvent. Molarity and osmolarity are not com-
`monly used in osmometry because they are temperature
`dependent; that is, water changes its volume with tempera-
`ture. One skilled in the art would readily recognize that if the
`concentration is very low (such as the concentrations of the
`composition of the invention), then the terms osmolarity and
`osmolality are considered equivalent and have been used
`interchangeably herein, as applied to the compositions of the
`invention.
`
`[0009] The osmolality of the human tear film ranges from
`approximately 250-350 mOsn1/Kg in the average human eye
`up to average of approximately 450 mOsn1/Kg in individual
`suffering from ocular conditions, including without limita-
`tion, dry eye disease (with a maximum of over 700 mOsn1/
`Kg). Therefore, in order to exert a therapeutic effect and
`reduce edema, the osmolality of an ophthalmic solution must
`be constrained by a minimum to the osmolality of the human
`eye environment (i.e., approximately 250 to 450 mOsn1/Kg).
`However, with increasing osmolality comes increased dis-
`comfort upon instillation. High levels of ions activate nerve
`endings which can cause ocular stinging. Through comfort
`testing, it was herein discovered that ophthalmic solutions
`should have an osmolality ranging from less than 2000
`mOsn1/Kg, and more preferably less than 1050 mOsn1/Kg to
`
`Page 33
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`US 2009/0136598 A1
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`May 28, 2009
`
`have acceptable, i.e., tolerable comfort profiles. Therefore,
`the target osmolality range for a drop formulated for the
`treatment of eyelid swelling is preferably within 200 and
`2000 mOsn1/Kg, preferably 250 mOsn1/Kg-1500 mOsn1/Kg,
`more preferably 260 mOsn1/Kg-1250 mOsn1/Kg, more pref-
`erably 265mOsn1/Kg to 1200 mOsn1/Kg and more preferably
`400 mOsn1/Kg to 1150 mOsm/Kg and more preferably 500
`mOsn1/Kg to 1100 mOsn1/Kg.
`the compositions of the
`[0010]
`In some embodiments,
`invention comprise an osmotically active agent including but
`not limited to a colloidal osmotic agent and a crystalloid
`osmotic agent. Crystalloid osmotic agents suitable for use in
`the compositions of the invention include but are not limited
`to sodium chloride (NaCl), dextrose, sucrose, glycerol, man-
`nitol, sorbitol, polyethylene glycol 3350 NF, magnesium cit-
`rate and lactulose. In certain embodiments,
`the effective
`amount of the crystalloid osmotic is selected from the group
`consisting of: about 1% to about 10% w/v sodium chloride,
`about 1% to about 10% w/v dextrose, about 1% to about 20%
`w/v glycerol, about 1% to about 20% w/v mannitol, about 1%
`to about 95% w/v sucrose, and about 1% to about 95% w/v
`sorbitol. Preferably, the crystalloid osmotic is sodium chlo-
`ride, and the effective amount is about 1% to about 10% w/v,
`more preferably about 2% to about 5% w/v.
`[0011] Colloidal osmotic agents suitable foruse in the com-
`positions of the invention include but are not limited to:
`hetastarch, pentastarch, gelatin polypeptides cross-linked
`with urea, dextran 70, dextran 40, albumin, icodextrin, ben-
`tonite USP, MgAl silicate NF type 2A, alginic acid/sodium
`alginate NF, microcrystalline cellulose and CMC NF, car-
`bomer and gellan gum.
`[0012]
`In certain embodiments, the effective amount of the
`colloidal osmotic is selected from the group consisting of:
`about 1% to about 10% w/v hetastarch, about 1% to about
`20% w/v pentastarch, about 1% to about 10% w/v dextran 70,
`about 1% to about 10% w/v dextran 40, about 1% to about
`50% w/v albumin, and about 1% to about 50% w/v microc-
`rystalline cellulose.
`[0013] Other osmotic agents suitable for use in the methods
`of the invention include but are not limited to: magnesium
`sulfate, magnesium chloride, lithium chloride, potassium sul-
`fate, sodium carbonate, sodium sulfite, lithium sulfate, cal-
`cium bicarbonate, sodium sulfate, calcium sulfate, potassium
`acid phosphate, calcium lactate, magnesium succinate, tar-
`taric acid- and soluble carbohydrates such as raffinose, glu-
`cose, caffeine, carbomer 934P, tannic acid, ascorbic acid,
`dextran-40,000, inulin, menthol, polysorbate 80, and mix-
`tures thereof. In certain embodiments, the effective amount of
`the osmotic is about 0.001 % to about 10% w/v caffeine, about
`0.001% to about 10% w/v carbomer 934P, about 0.001% to
`about 10% w/v tarmic acid, about 0.001% to about 10% w/v
`ascorbic acid, about 0.001% to about 10% w/v dextran-40,
`000, about 0.001% to about 10% w/v inulin, about 0.001% to
`about 10% w/v menthol, about 0.001% to about 10% w/v
`polysorbate-80, or mixtures thereof.
`[0014]
`In some embodiments,
`the compositions of the
`invention comprise a vasoconstrictor. Vasoconstrictors suit-
`able for use in the compositions of the invention include but
`are not limited to naphazoline, oxymetazoline, phenyleph-
`rine, tetrahydrozoline, and other agents that are alpha recep-
`tor agonists that are vasoactive. In a preferred embodiment,
`the vasoconstrictor is naphazoline and the effective amount is
`in the range of about 0.01% to about 10% w/v, preferably
`about 0.01% to about 1% w/v, more preferably about 0.01%
`
`to about 0.5% w/v, even more preferably about 0.01% to
`about 0.2% w/v, even more preferably about 0.09% to about
`0.1% w/v. In another preferred embodiment, the vasocon-
`strictor suitable for use in the invention is oxymetazoline, and
`the effective amount is in the range of about 0.01% to about
`0.2% w/v, more preferably 0.01% to about 0.1% w/v, even
`more preferably about 0.03% to about 0.05% w/v. In yet
`another preferred embodiment, the vasoconstrictor suitable
`for use in the invention is phenylephrine and the effective
`amount is in the range of about 0.01% to about 10% w/v,
`preferably about 0.01% to about 1% w/v, more preferably
`about 0.01% to about 0.5% w/v, even more preferably about
`0.05% to about 0.2% w/v.
`
`In still other embodiments, the compositions of the
`[0015]
`invention comprise an astringent agent. Astringents suitable
`for use in the compositions ofthe invention include but are not
`limited to witch hazel, zinc sulfate, silver sulfate, plant tan-
`nins, oak bark extract, pentagalloyl glucose, alum, burow’s
`solution, black thorn extract, bird cherry extract and natural
`flavanoids. Preferably, the astringent agent is witch hazel
`and/or zinc sulfate and the effective amount is in the range of
`about 0.001% to about 10% w/v, preferably about 0.01% to
`about 5% w/v, more preferably about 0.1% to about 1% w/v,
`even more preferably about 0.2% to about 0.75% w/v.
`[0016]
`In a certain embodiment, the compositions of the
`invention comprise a combination of an