lID ft
`
`1110
`
`5981607
`Nov
`1999
`
`IIM Iii
`
`ii DII IM IID
`ii
`IMI
`US005981607A
`Patent Number
`
`Date of Patent
`
`United States Patent
`
`Ding et at
`
`III
`
`Iii
`
`EMULSION EYE DROP FOR ALLEVIATION
`OF DRY EYE RELATED SYMPTOMS
`IN DRY
`EYE PATIENTS AND/OR CONTACT LENS
`WEARERS
`
`5411952
`5474979
`
`5/1995
`
`12/1995
`
`Kaswao
`
`Ding et
`
`514/11
`
`514/11
`
`FOREIGN PATENT DOCUMENTS
`
`Inventors Shulin Ding Irvine Orest Olejnik
`Trabuco Canyon Brenda
`Reis
`Costa Mesa all of Calif
`
`Assignee Allergan Irvine Calif
`
`Appl No 09/008924
`
`Filed
`
`Jan 20 1998
`
`Int Cl.6
`
`U.S Cl
`
`A61K 47/12 A61K 47/14
`A61K 47/34
`514/785 514/786 514/912
`514/915 514/941 514/943 514/975
`514/9 11 178
`Field of Search
`514/179 180 181 420 625 627 784
`785 786 912 913 914 915 941 943
`975
`
`References Cited
`
`U.S PATENT DOCUMENTS
`
`2228198
`
`8/1990
`
`95/31211
`
`11/1995
`
`Uoited Kingdom
`WIPO
`
`OTHER PUBLICATIONS
`
`Stultng
`
`Diagnosis
`
`and Management of Tear Film Dysfunction
`Waring pp 445468 not dated
`Diagnosis and Management of Dry Eye and Ucular Surface
`No
`Disorders OPH Clinic of N.A vol
`pp 575594
`Dec 1990
`
`Primary ExaminerJeffrey
`Russel
`Attorney Agent or FirmWalter
`ABSTRACT
`
`Hackler
`
`An eye drop composition for alleviation of dry eye related
`symptoms in dry eye patients and contact
`lens wearers
`includes an emulsion of
`fatty acid glyceride
`higher
`polysorbate 80 and an emulsion stabilizing
`amount of
`Pemulen in water suitable for topical application to ocular
`tissue
`
`4839342
`
`6/1989
`
`Kaswan
`
`514/11
`
`Claims Drawing Sheets
`
`WEEK
`
`WEE/C
`
`WEEK 12
`
`POST-TX W1
`
`DST- lx Wfl
`
`0.1
`
`0.0
`
`-0.1
`
`-0.2
`
`-0.3
`
`/7
`
`/7 /f
`
`/7 10
`
`/7
`
`/7
`
`/3
`
`FAMY CARE - EXHIBIT 1010-0001
`
`

`

`U.S Patent
`
`Nov
`
`1999
`
`Sheet
`
`of
`
`5981607
`
`PhRTZ Ci77DiE
`c/L
`
`PhRrff 41/EO 116
`57Vtt 5OLL/T/ON
`cDNrg/N/N1 WTEie
`PdL YJO5i If 80
`4A/B GLYCERIN
`
`STERILE
`FIL TRflTION
`
`51e/L
`TfL TRI7TION
`
`F/L TA4TE
`IER/L
`0/- Pge7
`
`IEf/LE FIL T4rE
`Of P14R117
`
`45E107C
`
`ac-5
`
`45EPTIC MIX/f Vô
`
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`
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`
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`PEM/ILEN TR-2
`S7VK D/5PEA/LW
`CON TI//N/NO
`PEM/JLEiV 1k-f
`gvz kV1QTER
`
`pI/krIv DILL/IF
`Va2//fOLIT/ON
`
`5/iL
`
`EM/IL 5/N
`
`üOL To Rc2i2iW
`
`7L Ti4 I/O/i
`EPTiC FIL iiii
`
`FAMY CARE - EXHIBIT 1010-0002
`
`

`

`_P.2
`
`Pull-TAW/
`
`PD-TAWK
`
`WEEK
`
`WEE/C
`
`WEEK
`
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`
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`
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`
`7J5
`
`Y.0
`
`.5
`
`92
`
`FAMY CARE - EXHIBIT 1010-0003
`
`

`

`j/6w/rIcg/JTcIIgNEi2MBg34EL/NE
`
`rj
`
`12JI
`
`-4
`
`-O.g
`
`P.T-TXW/t
`
`WEEKIt
`
`WEEK
`
`WEEK
`
`FAMY CARE - EXHIBIT 1010-0004
`
`

`

`P1zG4
`
`//WVOEIAOM55E//NE
`
`/o/V/i/CPWT
`
`rj
`
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`
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`-0.9
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`2.J
`
`PO5T-TXP1Ik
`
`Oi75fTXfl/K
`
`WEE/If
`
`WEEK
`
`WEEK
`
`FAMY CARE - EXHIBIT 1010-0005
`
`

`

`5981607
`
`of
`
`Sheet
`
`1999
`
`Nov
`
`Patent
`
`U.S
`
`vS
`
`cs
`
`ME4iV
`
`C//7WGE
`
`F047
`
`845E1/VE
`
`FAMY CARE - EXHIBIT 1010-0006
`
`

`

`5981607
`
`of
`
`Sheet
`
`1999
`
`Nov
`
`Patent
`
`U.S
`
`vz
`
`tzi
`
`tM
`
`vs
`
`vs
`
`s_I
`
`c$
`
`ME4iV
`
`747/V6E
`
`TAOM
`
`SR5EL/A/E
`
`FAMY CARE - EXHIBIT 1010-0007
`
`

`

`U.S Patent
`
`Nov
`
`1999
`
`Sheet
`
`of
`
`5981607
`
`25
`175
`C7M OIL COVCEVT4T/N IN YE/I/CL
`
`/w
`
`FAMY CARE - EXHIBIT 1010-0008
`
`

`

`5981607
`
`EMULSION EYE DROP FOR ALLEVIATION
`OF DRY EYE RELATED SYMPTOMS IN DRY
`EYE PATIENTS AND/OR CONTACT LENS
`WEARERS
`
`It
`
`10
`
`continuous tear
`The presence of
`film is important
`for
`the corneal and conjunctival epithelium
`the well-being of
`and provides the cornea with an optically
`high quality
`surface In addition the aqueous part of the tear film acts as
`to the eyelids during blinking
`lubricant
`of
`the lids
`Furthermore certain enzymes contained
`in the tear fluid for
`lysozyme and beta lysin are
`example immunoglobulin
`known to have bacteriostatic properties
`is believed that
`is responsible for
`the lipid layer
`retarding evaporation of water from the eye If
`the lipid layer
`of the tear film is disturbed by for example trauma disease
`lens wear excessive evapo
`irritation of the eye or contact
`ration of water from the eye may occur
`leaving the surface
`of the eye dry see e.g Cedarstaff and Tomlinson Am
`Physiol Optics 60167174 1983
`film
`15 Optometry
`sicca or dry
`disruption in patients with keratoconjunctivitis
`eye
`
`The present application is related to pending Interna
`tional Patent Application Ser No PCT/US95/06302
`filed
`May 17 1995 designating the United States which is
`application 5cr No
`of U.S patent
`continuation-in-part
`08/243279 filed May 17 1994 now U.S Pat No 5474
`979 The referenced
`are to he incorpo
`applications/patent
`rated herein by this specific reference thereto
`pharmaceutical com
`The present
`invention relates to
`dry eye related symptoms for
`position for alleviating
`example as in patients having immune mediated keratocon
`sicca KCS or dry eye disease or other autoim
`junctivitis
`mune dysfunction of the lacrimal gland as well as dry eye
`symptoms of contact
`lens wearers
`film abnormality
`Dry eye generally refers to any tear
`usually with epithelial abnormalities
`specific deficiency
`film is known as
`of
`the tear
`component of
`the aqueous
`sicca KCS which affects about
`30
`keratoconjunctivitis
`is usually included as part of
`million people worldwide It
`inflamma
`syndrome Literally the term denotes
`Sjogrens
`tion of the cornea and conjunctiva secondary
`to drying
`When
`the tear
`film fails to perform its functions of
`lubrication oxygenation and removal of debris symptoms
`of
`sensation grittiness scratchiness
`foreign body
`sandiness fatigue and dryness result
`patient may expe
`rience severe pain especially in the presence of filamentary
`keratopathy Loss of the smooth refractive surface of the tear
`film causes blurred vision which can vary from blink to
`variable manifest refraction and for
`for
`blink accounting
`the day Surface
`complaints of variable vision throughout
`drying may produce reflex tearing and the misleading com
`plaint of excess tears Typically symptoms of tear deficiency
`are worse late in the day with prolonged use of the eyes as
`when the patient
`television and in con
`reads or watches
`ditions of heat wind and low humidity as on the beach or
`ski slopes Symptoms that are worse in the morning suggest
`an associated chronic blepharitis recurrent corneal epitbelial
`erosion or exposure keratopathy Further symptoms include
`corneal
`erosions
`filaments coarse
`punctate
`superficial
`mucus plaques and epithelial defects
`As hereinabove
`noted most of these symptoms result
`from the unstable tear film and abnormal ocular surface that
`diminish the ability of
`to respond
`the ocular
`surface
`challenges Dry eye syndrome if
`environmental
`left
`untreated can cause progressive pathological changes in the
`and corneal epithelium
`conjunctival
`The etiologies of dry eye are varied The disease gener
`ally referred to as dry eye may be the result of age-related 50
`decreases in systemic androgen support to the lacrimal gland
`such as Sjogrens Syn
`or systemic autoimmune diseases
`drome
`growing body of research suggests that dry eye is
`the result of an underlying cytokine and receptor-mediated
`inflammatory process
`such
`Palliative agents
`replacement
`as
`tear
`tear
`and autonomic tear stimulation may provide
`preservation
`complete or partial relief of symptoms However
`therapeu
`the underlying inflammatory pro
`tic treatments directed at
`cess may prove beneficial
`in correcting the underlying
`disorder
`
`at
`
`25
`
`35
`
`40
`
`partial
`
`to 45
`
`to of
`
`normal eye consists of
`The tear film in
`thin about
`645 um in thickness
`film composed
`of mucous layer
`epithelium and an aqueous
`lying over
`the corneal
`layer
`covering the mucous layer and epithelium which is in turn
`covered by an extremely thin 0.010.22 um layer of lipid
`molecules
`
`65
`
`relief
`
`tear solution
`
`normal
`lacrimal system functions to form and maintain
`film The lacrimal
`properly structured continuous tear
`the secretory system the source the
`20 system consists of
`distribution system and the excretory system the sink In
`the secretory system aqueous tears are supplied by the main
`and accessory
`lacrimal glands
`Excessive evaporation of water from the tear film results
`in ocular discomfort
`frequently experienced
`by the person
`as dryness or tired eyes or other less frequently reported
`discomfort symptoms and may eventually lead to physi
`ological and pathological
`in the tissue of the eye
`changes
`especially in the cornea For contact
`such
`lens wearers
`acute because the loss of water
`30 discomfort
`is particularly
`the interface between
`from the tear film occurs
`the tear
`hydrogel soft
`film and the lens Further if
`the lens is
`lens excessive evaporation of water from the tear film can
`also result in excessive evaporation of water from the lens
`Thus taking into account
`this evaporation the continuous
`production and drainage
`is important
`tear
`to
`of aqueous
`and conjunctival
`epithelium in
`maintaining the corneal
`moist state in providing nutrients for epithelian respiration
`in supplying bacteriostatic agents and in cleaning the ocular
`surface by the flushing action of tear movement
`Abnormalities
`film include an absolute or
`of
`the tear
`tear production
`in aqueous
`sicca or KCS
`keratoconjunctivitis
`In relatively mild cases the main symptom of KCS is
`or mild scratchiness
`This can
`foreign body sensation
`progress to become
`intense burning irritative
`constant
`sensation which can be debilitating to the patient
`More severe forms of KCS progress to the development
`painful condition characterized
`by
`of filamentary keratitis
`the appearance of numerous strands or filaments attached to
`surface Recent
`evidence
`that
`these
`the corneal
`suggests
`breaks in the continuity of the normal
`filaments represent
`corneal epithelial cells The shear created by lid motion pulls
`these filaments causing pain Management of
`this stage of
`55 KCS is very difficult
`frequent complication of KCS is secondary
`infection
`Several breakdowns in the eyes normal defense mechanism
`seem to occur presumably attributable to
`decrease in the
`concentration of antibacterial
`lysozyme in the aqueous tears
`patient suffering from KCS
`Normally aqueous-deficient dry eye states such as for
`example KCS are treated by supplementation of the tears
`tear substitutes However
`with artificial
`is limited by
`the retention time of the administered artificial
`tear solution
`in the eye Typically the effect of an artificial
`administered to the eye dissipates within about
`thirty to
`forty-five minutes The effect of such products while sooth-
`
`deficiency
`
`FAMY CARE - EXHIBIT 1010-0009
`
`

`

`5981607
`
`ing initially
`inconvenienced
`
`long enough The patient
`does not
`last
`by the necessity of repeated administration
`tear solution in the eye as needed to supple
`of the artificial
`ment the normal
`tears
`
`is
`
`tear preparations lens rewetting solu-
`Presently artificial
`and ointments utilizing
`tions and ophthalmic
`lubricants
`active components other than monolayer forming long chain
`fatty alcohols are extant in the art Such available artificial
`tear solutions commonly include carboxymethyl methyl or
`ethyl cellulose or polyvinyl alcohol as the principal active
`tend more toward
`Lubricants
`and ointments
`ingredient
`film and
`the tear
`in the lipid layer of
`replacement of oil
`commonly include petrolatum lanolin and/or mineral oil
`Contact
`lens rewetting products vary in composition to
`greater extent however
`the solutions are typically aqueous
`buffered solutions which frequently contain carboxymethyl
`methyl or ethyl cellulose polyvinyl alcohol and/or glycerin
`lecithin and phospholipid-based solu
`Recently several
`tions have been proposed
`as treatments to reduce evapora
`tion of water from the tear film U.S Pat No 4421748 to
`issued Dec 20 1983 discloses an artificial
`Trager
`tear
`composition comprising an aqueous hypotonic solution of
`lecithin and
`viscosity adjusting agent for the alleviation of
`dry eye conditions
`U.S Pat No 5474979 hereinabove
`teaches novel
`incorporated herein by reference
`thereto
`incorporating chemicals
`compositions
`pharmaceutical
`which are poorly soluble in water and is more particularly
`novel ophthalmic emulsion including
`related
`to
`cyclosporin in admixture with castor oil and polysorbate 80
`level and low irritation potential
`with high comfort
`The present
`invention is directed to an emulsion system
`in combina
`which utilizes higher fatty acid glycerides but
`tion with polysorbate 80 which results in an emulsion with
`level and low irritation potential suitable for
`high comfort
`delivery of medications to sensitive areas such as ocular
`tissues as well as being suitable itself
`for alleviating dry eye
`symptoms
`
`referenced
`
`and
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present
`invention
`non-irritating
`pharmaceutical composition with high comfort
`level and
`low irritation potential suitable for delivery to sensitive areas
`such as ocular tissues comprises an admixture of an emul
`sifying amount of
`higher fatty acid glycerol and polysor
`bate 80 The higher fatty acid glyceride may comprise for
`example castor oil corn oil sunflower oil or light mineral
`The emulsion may also be used
`oil
`for
`to advantage
`introducing an active agent such as cyclosporine as set forth
`in parent U.S Pat No 5474979 In one embodiment
`the
`such as for
`composition may comprise an active
`agent
`example cyclosporine
`
`to castor oil
`
`the weight
`Preferably
`ratio of
`the castor
`oil
`to the
`polysorbate 80 is between about 0.3 to about 30 and weight
`to the fatty acid glyceride is below
`ratio of the active agent
`0.16 More preferably
`the weight
`ratio of castor oil
`to
`polysorbate 80 is between 05 and 12.5 and the weight ratio
`is between about 0.001 to about
`of active agent
`0.7
`When
`is dissolved in the oil phase in
`an active agent
`invention the emulsion is found
`accordance with the present
`to be physically stable upon long term storage No demul
`sification or crystallization of active agent was noticed after
`up to one year at room temperature
`Most
`importantly the emulsion of the present
`provides for long retention of the higher fatty acid glyceride
`
`invention
`
`when the emulsion is instilled into an eye This in turn can
`retard water evaporation from the eye which alleviates dry
`eye symptoms
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`and features of the present
`The advantages
`invention will
`be better understood by the following description when
`10 considered
`in conjunction with the accompanying drawings
`in which
`
`FIG
`is manufacturing schematic
`for production of
`sterile emulsion in accordance with the present
`
`invention
`
`FIG is
`
`bar graph showing mean change from baseline
`time as clinically
`function of
`using the
`diagnosed
`following the instillation of the emulsion in
`accordance with the present
`invention
`
`as
`
`Schirmer
`
`test
`
`FIG is
`
`as
`
`function of
`
`bar graph showing mean change from baseline
`time as clinically
`diagnosed
`using the
`Temporal Rose Bengal Staining test following the instilla
`inven
`tion of the emulsion in accordance with the present
`
`15
`
`20
`
`25
`
`tion
`
`is
`
`FIG
`bar graph showing change
`in superficial
`func
`punctate Keratitis as measured with fluorescein as
`the emulsion in
`time following the instillation of
`tion of
`accordance with the present
`invention
`
`FIG is
`
`bar graph of subjective reports of Burning and
`function of time following instil
`Stinging by patients as
`lation of the emulsion in accordance with the present
`inven
`tion
`
`35
`
`is
`
`FIG
`bar graph of subjective reports of Ocular
`function of time following instillation of the
`dryness as
`invention
`40 emulsion in accordance with the present
`
`FIG
`
`is
`
`bar graph of mean ocular residue time in
`function of the amount of fatty acid glyceride in
`hours as
`invention
`an emulsion in accordance with the present
`
`45
`
`DETAILED DESCRIPTION
`
`An ocular monolayer with significant efficiency of water
`50 evaporation retardation should spread effectively and form
`film after spreading has occurred Furthermore
`compressed
`film should be sufficiently flexible so that
`the compressed
`when broken by wind the eye lids or
`lens it will
`re-form promptly and therefore reduce the tear film local
`dryup and breakup
`
`contact
`
`invention is founded
`
`The discovery on which the present
`relates to an emulsion of
`higher fatty acid glyceride such
`as for example castor oil corn oil sunflower oil or light
`60 mineral oil and an emulsifier and dispersing agent polysor
`bate 80 The selection of these components
`could not have
`been anticipated on the basis of conventional
`
`thinking
`
`Polysorbate 80 is mixture of oleate esters of sorbitol and
`the
`65 sorbitol anhydrides consisting
`predominantly of
`monoester condensed with approximately 20 moles of eth
`ylene oxide It conforms generally to the formula
`
`FAMY CARE - EXHIBIT 1010-0010
`
`

`

`5981607
`
`EXAMPLE
`
`OCH2CH2OH
`
`OCH2CH2OH
`
`CH0CH2CFI20FI
`
`CH2OCH2CH2O CCH27CH
`
`CH3CH27CH
`
`where wxyz has an average value of 20 Polysorbate 80
`is available from ICI Americas Inc Wilmington Del
`is well known that castor oil
`For example it
`is irritating
`such as the eye Thus
`conventional
`to sensitive tissues
`teaching in the art is away from formulation which utilizes
`higher fatty acid glyceride such as castor oil by itself or
`in combination with an active agent
`Other than U.S Pat No 5474979 hereinabove
`refer
`enced and incorporated herein by reference thereto there are
`no examples of polysorbate 80 in combination with castor
`oil which produces
`an emulsion with
`high comfort
`level
`and low irritation
`potential suitable for
`the delivery of
`medication to sensitive areas such as ocular tissues
`
`Castor oil
`Polysorbate 80
`Pemulen
`
`Glycerine
`NaOH
`Purified water
`pH
`
`5.00%
`1.00%
`
`0.05%
`
`2.20%
`
`2.50%
`1.00%
`
`0.05%
`
`2.20%
`
`1.25%
`1.00%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`
`qs
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`qs
`7.27.6
`
`0.625%
`1.00%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`7.27.6
`
`EXAMPLE
`
`Castor oil
`
`Polysorbate 80
`Carbomer 1382
`
`Glycerine
`NaOH
`Purified water
`
`p1-I
`
`2.50%
`
`0.75%
`
`0.05%
`
`2.20%
`
`qs
`
`qs
`7.27.6
`
`10
`
`15
`
`20
`
`25
`
`the emulsions
`In accordance with the present
`invention
`polyelectrolyte or poly
`can be further stabilized using
`electrolytes if more than one from the family of cross-linked 30
`such as carbomers and Pemulen
`polyacrylates
`Pemulen is
`polymeric emulsifier having CTFA name
`of Acrylates/C10-30 Alkyl Acrylate Cross-Polymer and is
`described in the Carbomer 1342 monograph in the
`USPXXII/NFXVII
`
`The formulations set forth in Examples 12 were used for
`treatment of keratoconjunctivitis
`sicca dry eye syndrome
`Carbomer 1382 replacing the Pemulen
`with Example
`It should be appreciated
`that while specific examples
`hereinabove
`are presented
`for
`illustration
`the
`purposes
`range of the fatty acid glyceride which may be castor oil
`corn oil sunflower oil or light mineral oil may vary between
`about 0.5 and about 10 percent by weight The range of
`about
`0.2 and about
`Polysorbate 80 may be between
`percent by weight and the range of Pemulen may be
`35 between
`about 0.05 and about
`percent by weight
`double
`tests were performed in
`The following clinical
`marked randomized study to measure aqueous deficiency in
`sicca These clinical
`tests include the
`keratoconjunctivitis
`Schirmer Rose Bengal Staining and Fluorescein used to
`tests here
`40 determine punctate Keratitis In addition subject
`show
`relative assessment
`based
`on
`inafter presented
`reports of stinging/burning
`tearing discharge
`patient
`itching foreign body sensation blurred vision dryness
`and pain
`
`Carbomer 1342 is
`high molecular weight copolymer of
`acrylic acid and
`long chain alkyl methacrylate cross-linked
`with allyl ethers of pentaerythritol Carbomer 1342 previ
`ously dried in vacuum at 800
`hour contains
`for
`not
`less
`and not more than 62.0 percent of car
`than 52.0 percent
`boxylic acid COOH groups The viscosity of
`neutral
`aqueous dispersion of Carbomer 1342 is
`ized 1.0 percent
`between 9500 and 26500 centipoises
`Goodrich Car-
`Carbomer 1342 is available from
`bomer 1382 is also available from
`Goodrich in
`high
`long chain
`molecular weight copolymer of acrylic acid and
`alkyl methacrylate cross-linked with allyl ethers of pen
`taerythritol
`
`In addition the tonicity of the emulsions can be further
`if desired
`adjusted using glycerine mannitol or sorbitol
`The pH of the emulsions can be adjusted in
`conventional
`manner using sodium hydroxide to
`near physiological pFI
`level and while buffering agents are not
`required suitable
`buffers may include phosphates
`and
`citrates
`borates
`
`acetates
`
`inven
`While medication in accordance with the present
`other chemicals which are
`tion may include cyclosporine
`poorly soluble in water such as indomethacin and steroids
`such
`as androgens prednisolone
`prednisolone
`acetate
`and dexamethasones may be emulsified
`fluorometholone
`with castor oil and polysorbate 80 resulting in
`composition
`with similar low irritation potential
`
`photophobia
`
`CLINICAL TESTS
`
`Schirmer
`
`45
`
`50
`
`flow rates
`Clinical measures of tear film volume and tear
`the severity of aqueous deficiency in kera
`sicca
`
`help quantitate
`
`toconjunctivitis
`The Schirmer test measures the volume of tears produced
`fixed time period It
`is performed by placing the
`during
`folded 5-mm end of
`standard size number 41 Whatman
`the lower lid between its middle third
`filter paper strip over
`and lateral third After minutes the strip is removed and
`from the fold
`the amount of wetting is measured
`time
`The relative amount of wetting as
`function of
`following instillation of the emulsion of Example lB into an
`is shown in FIG
`the number of patients
`60 eye of
`patient
`As
`being indicated on the bar graph by the character
`the mea
`shown the instillation of
`the emulsion increases
`sured tear volume
`
`The
`invention
`is further
`illustrated by the following
`examples with all parts and percentages
`expressed
`by 65
`to the manu
`weight Emulsions were prepared
`according
`shown in FIG
`facturers schematic
`
`Rose Bengal Staining
`
`As hereinabove
`discussed patients with tear
`film dys
`function may become symptomatic because of dry spots on
`
`FAMY CARE - EXHIBIT 1010-0011
`
`

`

`the cornea Identification of dry areas with topically applied
`the diagnosis Patients who complain of
`stains substantiates
`nonspecific itching burning and stinging without
`identifi
`more difficult
`able corneal
`surface
`pathology
`present
`diagnostic problem The two commonly used dyes are rose
`bengal and fluorescein
`Rose bengal
`red aniline dye related to fiuorescein that
`corneal and conjunctival
`stains devitalized and degenerating
`1% solution may
`cells mucus and filaments
`full drop of
`drop on the wooden end of
`elicit pain Placing
`cotton tip
`applicator and then touching it
`reduce the
`to the eye will
`drop
`volume delivered to approximately
`one third of
`micropipette Pipetteman Ranin Woburn Mass may be
`used to deliver 2.5 uL to 5.0 uL into the inferior fornix This
`standardizes the amount
`to obtain adequate
`is sufficient
`staining and is not uncomfortable to the patient Using the
`score is given to each medial and lateral
`green
`filter
`interpalpebral zones
`As shown in FIG
`mean charge in score is shown as
`time using Temporal Rose Bengal Staining 20
`function of
`following instillation of the emulsion of Example lB These
`reduction in conjunctival dry
`changes
`represent significant
`areas
`
`5981607
`
`then
`
`at
`
`15
`
`assessment
`
`and 30 minutes post-instillation Subjective
`on several
`indices
`
`stinging/burning
`
`itching
`
`foreign body sensation blurred vision photophobia
`and other Assessment employed
`point Likert Scale
`where 0no discomfort 1mild 2moderate 3severe
`and 4very severe Duration of
`recorded
`symptoms will
`also be recorded in seconds only immediately after instilla
`tion of masked medication
`
`pain
`
`The grading of the symptoms of discomfort
`10 will be defined
`as follows
`
`for either eye
`
`15
`
`None
`
`Mild
`
`Moderate
`
`Severe
`
`very Severe
`
`No discomfort
`
`Awareness but no
`
`discomfort
`
`Discomfort
`
`that causes
`
`intermittent
`
`awareness
`
`Discomfort
`
`that causes
`
`continuous awareness
`
`Discomfort
`with normal daily activity
`
`that interferes
`
`The results shown in FIGS 56 reveal
`that reduction in
`follows
`and dryness occur
`subject ocular burning/stinging
`instillation of the emulsions of Example lB
`
`25
`
`30
`
`Retention Time
`
`the emulsion in the
`
`As can be appreciated retention of
`in achieving
`subjects eye is also important
`the objectives of
`invention In that regard emulsion in accordance
`the present
`invention can provide mean ocular residue
`with the present
`time of castor oil
`three hours
`in ocular tissue for up to about
`This has been established by an interferometric study in
`Beagle dog eyes as follows
`
`General Method
`
`is
`
`Superficial Punctuate Keratitis
`
`Fluorescein is used to determine punctate Keratitis Fluo
`rescein is also an aniline dye that differs from rose bengal
`in
`loss and not devitalized
`it stains areas of epitbelial cell
`that
`epithelium Fluorescein is available in sterile filter
`paper
`strips or as 2% solution alone or in combination with topic
`anesthetic One drop of 2% fluorescein provides an exces
`sive amount of fiuorescein
`sterile fiuorescein strip touches
`lake is preferred Patterns of conjunctival
`to tbe inferior
`tear
`and corneal staining similar in distribution to rose bengal
`staining are shown in FIG
`
`SUBJECTIVE TESTS
`
`Subjective
`
`Tests on patients
`reporting ocular burning/
`stinging and ocular dryness are shown in FIGS 56
`about symptoms of ocular discomfort
`Subjects
`responded
`recorded how
`for each eye and in weekly diary subjects
`both eyes felt on average for symptoms of ocular discomfort
`assessment
`on several
`indices stinging/
`Subjective
`burning tearing discharge not associated with infection
`itching foreign body sensation blurred vision dryness
`photophobia pain and other Assessment employed
`Liukert Scale where 0no discomfort 1mild
`2moderate 3severe and 4very severe
`The grading of symptoms of discomfort
`for either eye will
`be defined
`as follows
`
`point
`
`None
`
`Mild
`
`Moderate
`
`Severe
`
`very Severe
`
`Other
`
`No discomfort
`Awareness but on discomfort
`and
`no intervention
`
`required
`niscomfort that
`
`causes
`
`intecmittent
`
`awareness
`
`and
`
`requires intervention
`Discomfort
`
`that
`
`causes
`
`continuous awareness
`
`and
`
`that
`
`interferes
`
`requires intervention
`Discomfort
`with normal daily activity
`and
`requires intervention
`do not remember used only
`in Subject Diary
`
`Tolerability of the emulsion by the subject was evaluated
`immediately after instillation of masked study medication
`
`baseline
`
`35
`
`40
`
`ss
`
`slit
`
`as it
`
`is
`
`itself will abolish
`
`that
`
`film is docu
`After
`examination of the tear
`mented VHS recorder one drop of formulation B.C
`shown
`and
`formulation
`in Example
`having
`further
`0.125% w/w of castor oil was instilled superiorly onto the
`corneal surface of
`three minute
`dog eye and
`Beagle
`observation time point was carried out T03 mm Addi
`tional observation points are made at 20 60 120 and 240
`The results are shown in FIG
`minutes post
`instillation
`The results shown in FIG
`are based on the Guillon
`Technique The primary components for carrying out
`the
`Keeler Tearscope CCD camera and
`tear evaluations are
`remote color monitor VDR and cassettes
`and
`lamp
`bin-microscope For observing and recording the tear fringes
`important component
`is the most
`the tearscnpe
`50 highly specialized light source
`semi-quantitative determination Guillon Technique of
`the thickness of
`the lipid/nil
`component of the pre-ocular
`film POTF was carried nut with review of the video
`tear
`film footage of the experiments
`It should be appreciated
`that castor nil
`is unexpected
`the lipid layer completely Accordingly it
`invention can
`the emulsions in accordance with the present
`residence time for castor nil
`
`in the eye
`particu
`
`provide substantial
`described
`Although there has been hereinabove
`to lar pharmaceutical composition in the form of
`nonirritating
`emulsion for the purpose of illustrating the manner in which
`it should be
`the invention may be used
`to advantage
`invention
`is not
`limited thereto
`appreciated that
`the
`Accordingly any and al modifications
`variations or equiva
`lent arrangements which may occur
`to those skilled in the
`art should be considered to be within the scope of the
`invention as defined in the appended claims
`
`65
`
`present
`
`FAMY CARE - EXHIBIT 1010-0012
`
`

`

`5981607
`
`What
`
`is claimed is
`method for alleviation of dry eye related symptoms
`lens wearers said method
`in dry eye patients and contact
`comprising topically applying to ocular tissue an emulsion
`of
`polysorbate 80 and an
`higher
`fatty acid glyceride
`emulsion stabilizing
`amount of Pemulen in water
`said
`emulsion being characterized by an absence of cyclosporin
`The method according
`to claim wherein the weight
`ratio of the higher fatty acid glyceride to the polysorbate 80
`about 0.3 and about 30
`in the emulsion is between
`
`19
`
`The method accordiog
`whereio the higher
`to claim
`from the
`fatty acid glyceride in the emulsion is selected
`group consisting of castor oil and corn oil
`to claim wherein castor oil
`The method according
`is
`in the emulsion in an amount of between
`about
`present
`0.625% by weight and about 5.0% by weight the polysor
`in an amount of about 1.0% by weight the
`bate 80 is present
`in an amount of about 0.05% by weight
`Pemulen is present
`and the glycerine is present
`in an amount of about 2.2% by
`weight
`
`FAMY CARE - EXHIBIT 1010-0013
`
`