Low-concentration Homogenized Castor Oil
`Eye Drops for Noninflamed Obstructive
`Meibomian Gland Dysfunction
`
`Eiki Goto MD12 Jun Shimazaki MD1 Yu Monden MD3 Yoji Takano MD12 Yukiko Yagi1
`Shigeto Shimmura MD12 Kazuo Tsubota MD12
`
`Objective
`
`trial
`
`We developed low-concentration
`homogenized castor oil eye drops for the treatment of patients
`with noninflamed obstructive meibomian gland dysfunction MGD major cause of lipid-deficiency dry eye and
`assessed the safety stability and efficacy of the eye drops
`Design Randomized double-masked placebo-control
`led crossover clinical
`Forty eyes of 20 patients with noninflamed MGD
`Participants
`preliminary study of eye drops containing castor oil 2% castor oil and 5% polyoxyethylene
`Methods After
`castor oil emulsifier were mixed to formulate homogenized oil eye drops The patients were assigned randomly
`weeks each
`to receive oil eye drops or placebo six times daily for
`periods of
`Main Outcome Measures At the end of each treatment period we assessed symptoms tear interference
`grade tear evaporation fluorescein and rose bengal scores tear break-up time BUT and meibomian gland
`orifice obstruction Safety and stability tests were also performed
`Results Symptom scores tear
`interference grade tear evaporation test results rose bengal scores tear
`BUT and orifice obstruction scores after the oil eye drop period showed significant
`improvement compared with
`the results after the placebo period No complications attributable to the eye drops were observed The oil eye
`drops were stable when stored at 4C
`The results indicate that castor oil eye drops are effective and safe in the treatment of MGD
`Conclusions
`The possible mechanisms of this treatment are improvement of tear stability as
`lipid spreading ease
`of meibum expression
`evaporation and
`the
`effect
`of
`the oil
`of
`tear
`eye
`lubricating
`prevention
`
`drops Ophthalmology2002 2002 by the American Academy of Ophthalmology Inc
`
`result of
`
`lipids into tears and the lipids
`Meibomian glands secrete
`expand to form the oily preocular
`film layer that
`tear
`excessive evaporation of
`isponsible for preventing
`tears
`barrier function at
`while also providing
`the lid margin
`lubrication during blinking and producing
`smooth optical
`1-5 Noninflamed obstructive meibomian gland dys
`surface
`function MGD is the major cause of lipid tear deficiency
`or evaporative dry eye and recently has attracted attention as
`
`is
`
`Originally received October 29 2001
`Accepted March 22 2002
`
`Manuscript no 210908
`
`Department of Ophthalmology Tokyo Dental College Chiba Japan
`
`Department of Ophthalmology Keio University School of Medicine
`Tokyo Japan
`
`Department of Ophthalmology Kurume University School of Medicine
`Kurume Japan
`
`and Science
`Supported by grants from the Japanese Ministry of Education
`Tokyo Japan Medical School Faculty and Alumni Grants of Keio Uni
`versity Medical Science Fund Tokyo Japan Hightech Research Center at
`Tokyo Dental College Chiba Japan and Nihon Tenganyaku
`Kenkyusho
`Co Ltd Nagoya Japan
`Authors Eiki Goto MD Kazuo Tsubota MD and Nihon Tenganyaku
`Kenkyusho Co Ltd are in the process of obtaining
`Japanese patent on
`herein and their clinical application
`the eye drops described
`requests to Kazuo Tsubota MD Department
`and reprint
`Correspondence
`of Ophthalmology
`Tokyo Dental College 5-1 1-13 Sugano
`Chiba Japan 272-8513 E-mail eikigoto@nifty.com
`
`Ichikawa-shi
`
`cause of ocular discomfort.68 Meibomian gland dysfunc
`decreased lipid supply which in turn leads to
`tion causes
`increased tear evaporation decreased tear stability loss of
`lubrication and damage to ocular surface epithelium result
`ing in symptoms ilated to dry eye.79 The conventional
`for blepharitis and MGD includes warm com
`treatment
`lid hygiene and topical or systemic medica
`presses
`tion.52 Nevertheless
`long-term compliance with con
`is often insufficient and thus results in
`ventional
`therapy
`only limited relief of symptoms Another possible approach
`is direct supplementation with oil as the deficient compo
`nent Lipid-containing eye drops designed to simulate nat
`ural tears previously have been reported to be an effective
`they have not been accepted
`treatment
`for dry eye but
`generally.34 Because high-concentration
`oil eye drops and
`ointments are viscous and cause blurred vision resulting in
`decreased patient satisfaction we conducted
`preliminary
`low-concentration
`assessment of the efficacy of
`castor oil
`mixture and in this study assessed the efficacy safety and
`stability of low-concentration
`and homogenized oil eye drops
`
`Materials and Methods
`
`Preliminary Study to Choose Oil
`We used seven oil
`ingredients permitted as additives for eye drops
`low-concentration mixture
`and ointments in Japan to fomrnlate
`
`2030
`
`2002 by the American Academy of Ophthalmology
`Inc
`
`Published by Elsevier Science
`
`Inc
`
`ISSN 0161-6420/02/Ssee front matter
`
`PIT S0161-64200201262-9
`
`FAMY CARE - EXHIBIT 1017-0001
`
`

`
`Goto et
`
`Castor Oil Eye Drops for MOD
`
`Results of Preliminary Study using Castor Oil Mixture
`Table
`for Noninflamed Obstructive Meibomian Gland Dysfunction
`Mean
`Standard Deviation
`
`Examination
`
`Before
`
`Aftert
`
`Value
`
`Pace score 19
`
`Tear evaporation rates
`X107 g/second
`score 09
`Pluorescein
`Rose bengal score 09
`
`time
`
`Tear break-up
`sec
`Schirmers test value mm
`
`7.5
`
`1.6
`
`309.0
`
`1.6
`
`1.2
`
`1.5
`
`1.4
`
`3.4
`
`2.4
`
`5.3
`
`14
`2211
`
`0.20
`
`o.so
`
`9.0
`
`060
`0.76
`
`36
`
`1814
`
`1612
`
`0.01
`
`0.02
`
`0.005
`
`0.2
`
`0.002
`
`0.6
`
`by Wilcoxons
`signed rank test
`Data were analyzed
`value of 005 was accepted
`paired data
`Result before use of castor oil mixture
`Result after
`weeks of application of castor oil mixture
`Statistically significant
`
`for nonparametric
`
`as statistically significant
`
`artificial
`
`tears Soft Santear Santen Phar
`with preservative-free
`maceutical Co Ltd Osaka Japan and tested them on normal and
`dry eye volunteers.15 Because the subjects reported that
`the castor
`oil Astra Japan Osaka Japan mixture eye drops were the most
`comfortable this mixture was formulated for use in
`preliminary
`trial and applied to MGD patients
`weeks The
`times daily for
`surface and tear
`function were examined and compared
`before and after application The examinations are described in
`later section As shown in Table
`score tear break-up time BUT and tear evaporation
`fluorescein
`rates improved significantly The mixture was simple to formulate
`but being made from only hydrophobic oil
`it may not spread
`the ocular surface We therefore decided to formulate
`readily over
`oil eye drops with castor oil
`
`ocular
`
`detail
`
`in
`
`the face score
`
`homogenized
`
`Formulation Safety and Stability of Low-
`concentration Homogenized Oil Eye Drops
`
`tion of castor oil
`
`To formulate low-concentration and homogenized oil eye drops
`oil eye drops 2% castor oil
`lubricant castor oil Yoshida Phar
`maceutical Co Tokyo Japan 5% polyoxyethylene castor oil
`Sigma St Louis MO 0.3% sodium
`POE castor oil
`chloride 0.15% potassium chloride and 0.5% boric acid were
`stirred into distilled water under sterile conditions The concentra
`in the preliminary study was changed to formulate
`of the eye drops were lucent
`an emulsion The characteristics
`odorless and low viscosity The pH of the eye drops was 7.0 and
`their osmolarity was 260 mOsmlkg H20 Bacterial and fungal
`cultures of the remaining unused eye drops were performed at the
`the usual conditions at room temperature.16
`end of therapy under
`The stability of the eye drops was assessed by testing for
`weeks
`at 60C and 4C Stress testing testing at 60C for weeks was
`testing at 40C for
`performed instead of accelerated
`testing
`months for the eye drops.17 In these tests the pH of the eye drops
`was measured and the volunteers were checked for any irritation
`that might have been caused by administering the eye drops The
`samples stored at 4C remained stable at pH 7.0 for
`weeks and
`did not cause irritation whereas the pH value of the samples stored
`at 60C changed to 5.8 and caused irritation
`
`Subjects
`
`We examined
`series of 20 patients 40 eyes with
`MGD whose symptoms had not
`improved sufficiently despite
`
`consecutive
`
`conventional
`
`treatment such as by lid hygiene and topical therapy
`with artificial
`and corticosteroids or systemic
`tears antibiotics
`antibiotics Both eyes of patients were included The participants
`males and 13 females 52.1
`11.0 years with
`consisted of
`MGD Nine patients had Schirmers test value of less than mm
`indicating aqueous tear deficiency.918 Four patients of the aqueous
`group were diagnosed with Sjogrens syndrome
`tear deficiency
`according to aqueous tear deficiency.19 Eyes with anterior bleph
`antis of more than moderate
`severity infectious conjunctivitis
`MGD with acute inflammation and eyes with excessive expression
`of meibum seborrheic MGD were excluded
`from the study No
`patients used contact
`
`lenses
`
`Criteria for Meibomian Gland Dysfunction
`Criteria for the diagnosis of MGD were presence of meibomian
`gland dropout poor meibum expression and lack of active inflam
`mation.79 Transillumination examination meibography with
`fiber-optic device L-3920 Inami Co Tokyo Japan was per
`formed.20 Visible loss of meibomian gland structure gland drop
`out was observed during meibography and was considered evi
`dence of MGD because this finding was reported to be
`good
`The
`for MGD-associated ocular surface
`changes.79
`parameter
`degree of meibomian gland dropout was
`scored as described
`no gland dropout grade
`previously7-9 grade
`less than half of the inferior
`tarsus and grade
`more than half of the inferior
`tarsus
`To assess meibum expression
`and meibomian gland orifice
`obstruction digital pressure was applied on the upper
`tarsus and
`of meibomian secretions
`ease of expression
`the degree
`of
`meibum was evaluated semiquantitatively as follows grade
`clear meibum easily expressed grade
`cloudy meibum expressed
`cloudy meibum expressed with more
`with mild pressure grade
`meibum could not be ex
`than moderate pressure and grade
`pressed even with strong pressure.79 Patients with meibography
`score of grade
`and meibomian gland orifice obstruction
`or
`or were diagnosed as having MGD in this study
`score of
`
`gland dropout
`
`in
`
`gland dropout in
`
`Assessment of Symptoms Tears Ocular Surface
`and Meibomian Glands
`
`on overall comfort complaints and complications
`questionnaire
`face score card that showed nine
`was administered by using
`different expression.16 For example the saddest
`faces each with
`described severe symptoms and irritation of the
`face scored as
`ocular surface and the happiest
`represented no
`face scored as
`irritation of the ocular surface This face score was used to assess
`patient sensation of lubrication and smoothness during blinking in
`
`this study
`images were assessed using DR-i camera
`Tear
`interference
`Kowa Ltd Nagoya Japan at
`12 magnification based on the
`gray color uni
`somewhat
`grading previously reported grade
`form distribution grade
`somewhat gray color nonuniform dis
`few colors nonuniform distribution grade
`tribution grade
`many colors nonuniform distribution
`grade
`corneal
`surface
`partially exposed.2122 Tear evaporation
`during normal blinking
`was measured by the method previously reported.23 The evapora
`tion rate at 40% ambient humidity was used as
`representative
`value
`
`the double
`
`The ocular
`surface was examined
`by
`method
`2-jtl volume of preservative-free
`solution consisting of
`and 1% rose bengal dye was applied to the con
`1% fluorescein
`sac The intensity of the rose bengal
`the
`staining of
`junctival
`cornea and conjunctiva was recorded with maximum score of
`Tear
`Fluorescein staining of the cornea was also rated from to
`BUT was measured three times and the measurements were av
`
`staining
`
`2031
`
`FAMY CARE - EXHIBIT 1017-0002
`
`

`
`Ophthalmology
`
`Volume 109 Number 11 November 2002
`
`Table
`
`Schedule of Examinations in Crossover Study of Castor Oil Eye Drops for Noninflamed Obstructive Meibomian Gland
`Dysfunction
`
`Week
`
`Group
`Group
`
`Wash-out Period Began
`AT
`AT
`
`Beginning of Study
`Oil eye drop usage began
`Placebot
`usage began
`
`Patients Switched Eye Drops
`Switched to placebot
`to oil eye drops
`Switched
`
`Completion of Study
`Completed
`Completed
`
`AT
`preservative-free
`Low-concentration homogenized
`Placebo eye drops
`controller YY Participants used AT for
`and
`weeks during the washout period used oil eye drops or placebo
`were divided randomly by
`weeks Examinations were performed at
`the end of each 2-week period of treatment
`and then switched
`eye drops for the next
`
`artificial
`
`tear
`
`castor oil eye drops
`
`Groups
`weeks
`
`for
`
`eraged.24 Schirmers test was performed to measure tear secre
`tion.1825 Assessment of meibum expression and meibomian gland
`orifice obstruction was recorded as described above in the inclu
`
`sion criteria section.79
`
`Study Design
`
`artificial
`
`double-blind
`prospective
`randomized
`placebo-controlled
`2-week wash-out
`crossover clinical study was performed after
`tears Soft Santear.26 Dur
`period with preservative-free
`periods of
`weeks each
`the patients were assigned
`ing the
`randomly to receive oil eye drops or placebo eye drops six times
`We used normal saline solution as the placebo eye
`daily Table
`drops At the end of each treatment period i.e the oil eye drop
`period and the placebo period the following examinations de
`scribed below were performed
`The examinations were carried out
`in the following order to
`avoid the influence of one procedure
`on another subjective
`grading DR-i 22 tear
`tear
`interference
`evaporation
`scores16
`test23 fluorescein and rose bengal vital staining BUT measurement
`and assessment of meibomian gland orifice obstruction.79162425
`When the results of the oil eye drop period were better
`than those
`of the placebo period the use of the oil eye drops was judged an
`test was not performed during the study
`improvement Schirmer
`period to avoid any influence on the tear evaporation test which is
`sensitive to ocular surface damage Informed consent was obtained
`from all subjects Institutional Review Board or Ethics Committee
`approval was not required for this study
`
`face
`
`Statistical Analysis
`
`standard deviation Both eyes of
`All data are presented as means
`each patient were studied separately Symptoms and findings at the
`end of each
`treatment period the oil eye drop period and the
`and analyzed
`by Wilcoxons
`placebo period were
`compared
`signed rank test
`paired data
`for nonparametric
`value of less
`than 0.05 was accepted as statistically
`
`significant
`
`Results
`
`Figures
`
`show results
`and
`case with tear
`from representative
`images tear break-up and rose bengal staining at the
`interference
`end of the placebo period Fig
`and at
`the end of oil eye drop
`period Fig
`Each result shows improvement
`from the oil eye
`drop period compared with the placebo period
`The results at the end of placebo period and oil eye drop period
`Compared with the placebo period the
`are shown in Table
`
`2032
`
`subjective
`
`6.7
`
`of the other
`
`0.7i
`
`to 2.0
`
`0.77
`
`face score improved during the oil eye drop period from
`0.004 along with the improvement
`i.6 to 5.5
`i.8
`grade decreased
`tear examinations Tear interference
`0.000i
`from 3.i
`rates
`tear evaporation
`during normal blinking decreased from
`g/second
`6.2
`7.5 i07 g/second
`0.Oi and tear BUT was
`to ii
`2.8 seconds to i2
`seconds
`prolonged from 4.6
`3.5
`score also was ac
`0.000
`The improvement of the subjective
`by improvements of the rose bengal
`companied
`score
`staining
`from 2.2
`0.007 and the meibomian
`i.3
`0.85 to i.4
`gland orifice obstruction score from 2.2
`0.63
`0.38 to i.6
`0.002 but not accompanied
`by the improvement of the fluo
`rescein staining score from 0.4
`0.06
`0.33
`0.8i
`to 0.i3
`the MGD without
`Results of these improvements between
`ii and the MGD with aqueous
`aqueous tear deficiency
`showed no statistically
`group
`tear deficiency
`significant
`difference Administration of the oil eye drops was well tolerated and
`none of the subjects reported initation or severe bluning None of the
`samples tested positive
`for bacteria or
`collected
`ilingi Blinding
`persons perfomuing the intervention outcome
`among participants
`assessors and data analyses were perfomied entirely by protocol
`
`group
`
`Discussion
`
`clear benefit of using low-con
`This study demonstrated
`centration homogenized
`oil eye drops for the treatment of
`MGD Because MGD is major cause of ocular
`irritation
`symptomatic relief is an essential aspect of treatment The
`improvement in symptoms was accompanied by improve
`findings including tear interference im
`ment of objective
`age tear evaporation tear BUT rose bengal staining and
`meibomian gland orifice obstruction The improvements
`were attributed to the effects of the oil eye drops because all
`double-blind protocol The eye
`patients used eye drops in
`drops were stable and well tolerated and they did not cause
`irritation or blurred vision at room temperature By using
`oil we succeeded
`in avoiding the usual
`low-concentration
`of oil administration such as blurred vision
`complications
`and
`viscous sensation
`the missing tear lipid in MGD we used
`To supplement
`POE castor oil
`to solubilize the castor oil
`in distilled water
`low concentration.27 It has been reported that
`hydro
`in
`philic lipid is requiitd to enable oil
`to spread over
`the
`human tear aqueous layer and that polar phospholipids exist
`hydrophilic lipid in tears.2427 The POE castor oil
`as
`derivative of castor oil
`polar lipid having
`hydrophilic
`
`is
`
`FAMY CARE - EXHIBIT 1017-0003
`
`

`
`Cow et
`
`Castor Oil Eye Drops for MCD
`
`Figure
`
`of the representatsve
`interference smage shows
`
`Tear interference image tear break.up and rose bengal staining
`The tear
`the end of the placebo period
`few colors and
`nonunsform pattern
`
`case at
`
`stained by fluoresceiss and rose bengal were taken
`Slit-lamp photographs
`immediately afrer eye opening Note tlse remarkable tear break-up
`and
`bssure Cl
`rose bengal staining of the ocular surface between the palpebral
`
`and
`
`hydrophobic group which is considered to be au ideal
`tears Because the castor oil cau spread over
`oil for artificial
`is expected to make the tear more
`the ocular
`surface it
`stable to decrease tear evaporation and to decrease
`between the lid and ocular surface.28
`
`friction
`
`Tear inrerference image rear brcak up and rose bengal srairilng
`Figure
`The rear
`of rhe same case as in Figure
`at rhe end of oil eyedrop period
`somewhar
`
`Interference
`
`shows
`
`gray color and more uniform distribution
`
`and rose bengal were
`srained by fluorescein
`Slsr.lamp phorographs
`he seen and
`raken immediarely afrer eye opening Tear breale.up cannot
`lB and 2B were enhanccd
`rose bengal staining was decreascd
`Figures
`using Adobe Photoshop Adobe Systems
`digitally to show tear break.up
`lssc San Jose CA from original photographs
`at brightness 40 and
`70 The reflex from the central cornea is the result of rhe digital
`
`contrast
`
`enhancensent
`
`2033
`
`FAMY CARE - EXHIBIT 1017-0004
`
`

`
`Ophthalmology
`
`Volume 109 Number 11 November 2002
`
`Table
`Results of Crossover Study during Placebo and Oil Eye
`Drop Periods for the Treatment of Noninflamed Obstructive
`Meibomian Gland Dysfunction Mean
`Standard Deviation
`
`Examination
`
`Pace score 19
`grading 15
`
`interference
`
`Tear
`
`Tear evaporation
`rates X107
`g/second
`
`Placebo
`Period
`
`6.7
`
`3.1
`
`1.6
`
`0.71
`
`Oil Eye
`Drop Periodt
`
`Valuet
`
`077
`
`13
`
`6.2
`
`11
`
`o.oi
`
`oil
`
`the ideal
`
`considered more for
`eye drops should be
`patients with aqueous tear
`tears Theoretically
`artificial
`from the application of these artificial
`deficiency can benefit
`tears because MGD needs
`to be supplemented by oil or
`some other
`ingredient that can stabilize the ocular surface
`decrease tear evaporation and decrease
`friction between the
`lid and ocular surface Based on study it
`is necessary to
`means of maintaining the stability of artificial
`in rooms with higher temperatures
`tears with castor oil
`however this randomized double-blind study clearly shows
`the benefit of the addition of castor oil
`tears
`to artificial
`
`develop
`
`Rose bengal
`
`Pluorescein
`
`score
`
`09
`score 09
`BUT sec
`
`Orifice
`
`obstruction
`
`03
`
`0.40
`
`0.81
`
`0.13
`
`0.33
`
`0.06
`
`2.2
`
`0.85
`
`1.4
`
`1.3
`
`0.007
`
`References
`
`4.6
`
`2.8
`
`2.2
`
`0.38
`
`12
`
`1.6
`
`3.9
`0.63
`
`0.0001
`
`0.002
`
`Mishima
`
`evaporation
`
`Maurice DM The oily layer of the tear film and
`surface Exp Eye Res 1961
`from the comeal
`
`film physiology Am Optom Physiol Opt
`
`time
`
`BUT tear break-up
`Placebo eye drops
`Low-concentration homogenized
`castor oil eye drops
`by Wilcoxons
`signed rank test
`Data were analyzed
`paired data
`value was determined between
`placebo
`value of 005 was statistically significant
`
`period
`
`Statistically significant
`Meibomian gland orifice obstruction score
`
`for nonparametric
`and oil eye drop
`
`3945
`Holly FJ Tear
`980572527
`Tiffany SM The role of meibomian secretion in the tears
`1985104396401
`Trans Ophthalmol Soc
`Tiffany JIM The lipid secretion of the meibomian glands Adv
`Lipid Res 198722162
`Driver PJ Lemp MA Meibomian gland dysfunction Surv
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`Ophthalmol
`Lemp MA Report of
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`Workshop
`22 132
`Shimazaki
`Sakata
`Tsubota
`Ocular surface changes
`and discomfort in patients with meibomian gland dysfunction
`Arch Ophthalmol 1995113126670
`Lee SH Tseng SCG Rose bengal
`and cytologic
`associated with lipid tear deficiency Am
`997124736 50
`Ophthalmol
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`et al Meibomian gland dys
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`Goto
`function in patients with Sjogren syndrome Ophthalmology
`199810514858
`10 Key JE
`study of eyelid cleaning regimens in
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`19962220912
`11 Korb DR Greiner JV Increase in tear film lipid layer thick
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`Syndromes New York Plenum Press 19942938
`12 Smith RE Flowers CW Jr Chronic blepharitis
`CLAO
`1995212007
`13 Rieger
`Lipid-containing eye drops
`step closer
`99020 120612
`tears Ophthalmologica
`14 Tiffany JIM Lipid-containing eye drops
`logica 1991203479
`15 Japanese Pharmaceutical
`Nippo 1994 109
`16 Tsubota
`Goto
`et al Treatment of dry eye by
`Fujita
`serum application in Sjogrens syndrome Br
`autologous
`Ophthalmol 1999833905
`17 Awata
`Stability of The Eye Drops In Ohashi
`Eye Drops Tokyo Medical View Co 19961523
`18 Xu KP Yagi
`Toda
`Tsubota
`Tear
`function index
`new measure of dry eye Arch Ophthalmol 1995113848
`19 Fox RI Robinson CA Curd JG et al Sjogrens syndrome
`Proposed criteria for classification Arthritis Rheum 98629
`577 85
`20 Robin JE Jester JV Nobe
`et al In vivo transillumination
`biomicroscopy and photography of meibomian gland dysfunc
`clinical study Ophthalmology 19859214236
`tion
`
`characteristics
`
`staining
`
`review
`
`to natural
`
`Ophthalmo
`
`Excipients
`
`1993 Tokyo Yakuji
`
`ed The
`
`interference
`
`great
`
`it
`
`Both castor oil and POE castor oil are commercially
`available are inexpensive and have been proven to have
`minimal topical toxicity for the eye.528
`It was surprising to us that only minimal amount of
`castor oil changed the ocular
`surface abnormality
`there was evidence
`deal Moreover
`tears over
`that
`the
`ocular surface were stabilized based on the improved tear
`tear BUT The tear
`image and increase of
`interference
`pattern significantly showed
`more uniform
`pattern of spreading of the lipid film layer after administra
`tion of the castor oil eye drops than with administration of
`Even though the amount of castor oil was
`the placebo.2122
`the oil eye drops were well homogenized
`minimal
`in the
`tear lipid layer and later spread to form more stable tear
`lipid layer and to improve the ocular surface condition
`Figs 1A and 2A.212229
`There is
`concern for the clinical application of castor
`oil eye drops because of their limited shelf life stability.7 It
`is expected that oil quality may change during storage room
`temperature and may be an obstacle for clinical application
`When we stored the castor oil at 4C for
`weeks
`the oil
`stability and was well preserved Moreover
`maintained
`did not cause any irritation to the volunteers However after
`storage of the castor oil eye drops at 60C for weeks
`the
`ph changed to 5.8 and caused slight irritation to the patients
`Castor oil
`treatment
`for ocular
`itself
`very effective
`the storage method should be consid
`surface diseases but
`ered before broad clinical application because of the insta
`bility of the oil at higher temperatums
`In conclusion we have documented
`castor oil for the treatment of ocular surface disorders with
`
`is
`
`MGD Although the concept of administering oily eye drops
`has not been considered seriously the application of castor
`
`beneficial effect of
`
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`
`FAMY CARE - EXHIBIT 1017-0005
`
`

`
`Goto et
`
`Castor Oil Eye Drops for MOD
`
`21 Yokoi
`
`layer interference
`
`Takehisa
`Kinoshita
`patterns with the diagnosis
`
`Correlation of tear
`
`lipid
`and severity of
`
`dry eye Am Ophthalmol 1996
`
`Tiffany JIIVI Bron AJ Assessment of
`Mossa
`22 Yokoi
`meibomian gland function in dry eye using meibometry Arch
`Ophthalmol 1999 177239
`23 Tsubota
`Yamada
`Tear evaporation
`
`from the ocular
`
`surface
`24 Toda
`
`Tsubota
`
`Practical
`
`double vital staining
`
`for ocular
`
`surface evaluation
`
`25 van Bijsterveld OP Diagnostic
`
`tests in the sicca syndrome
`
`Invest Ophthalmol Vis Sci 1992
`Cornea 1993
`Arch Ophthalmol 1969
`
`26 Rub AH Greve EL Geijssen HC Hoyng PFJ Reduction of
`intraocular pressure with treatment of latanoprost once daily in
`patients with normal-pressure glaucoma Ophthalmology
`1996 127682
`27 Mitsui
`Physiochemistry of the Cosmetics 1st ed Tokyo
`Nanzando 1993 12856
`28 Nagai
`Polyoxyethylene castor oil derivatives
`ed Handbook of Pharmaceutical Excipients
`Japanese
`The Pharmaceutical Society of Japan
`Edition Tokyo
`
`In Saito
`
`986
`29 Korb DR Baron DF Herman JP et al Tear film lipid layer
`function of blinking Cornea 1994
`
`thickness
`
`as
`
`2035
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`FAMY CARE - EXHIBIT 1017-0006