Contact Lens & Anterior Eye 33 (2010) 76–82
`
`Contents lists available at ScienceDirect
`
`Contact Lens & Anterior Eye
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c l a e
`
`Effect of castor oil emulsion eyedrops on tear film composition and stability§
`Ce´ cile Maı¨ssa a,*, Michel Guillon a, Peter Simmons b, Joseph Vehige b
`a OTG Research & Consultancy, London, UK
`b Allergan, Irvine, CA, USA
`
`A R T I C L E I N F O
`
`A B S T R A C T
`
`Keywords:
`Dry eye
`Eyedrops
`Castor oil
`Tear film stability
`Tear lipids
`Triglycerides
`
`Purpose: An emulsion eyedrop containing castor oil has been shown to modify the tear film lipid layer
`and increase tear film stability. The primary objectives of this investigation were to measure the
`prevalence of castor oil in the tear fluid over time and quantify the effects on the lipid layer. A secondary
`objective was to quantify the initial effects on ocular symptomatology.
`Methods: The investigation was an open label pilot study on 5 normal and 10 dry eye subjects. A single
`eyedrop (Castor oil emulsion, Allergan) was instilled in each eye; the tear film appearance and
`composition were monitored for 4 h via in vivo visualisation using the TearscopeTM and post in vivo tear
`samples analysis by HPLC.
`Results: Combined results for both normal and dry eye subjects showed that castor oil was detected up
`to 4 h after a single eyedrop instillation and associated with an increase in the level of tear film lipid. The
`relative amount of various lipid families was also changed. An increase in tear lipid layer thickness was
`significant up to one hour post-instillation for the symptomatic sub-population. The changes in tear film
`characteristics were associated with significantly lower symptoms up to four hours post-instillation for
`the symptomatic sub-population.
`Conclusion: This pilot investigation showed that castor oil eyedrops achieved a residence time of at least
`four hours post-instillation, producing a more stable tear film and an associated significant decrease in
`ocular symptoms over the entire follow-up period for the symptomatic subjects.
`ß 2009 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
`
`1. Introduction
`
`Dry eye is defined as a disorder of the tear film due to a
`deficiency in aqueous tear production and/or increased evapora-
`tive loss that leads to irritation of the ocular surface and is
`associated with symptoms of discomfort [1].
`The prevalence rates reported in the literature are highly
`dependent upon the selection criteria used to diagnose dry eye
`subjects. Estimates in the prevalence of dry eye syndrome ranged
`from 14.4% to 34.0% [2–9] depending upon population biases and
`selection criteria. Additionally, an increased prevalence of dry eye
`with age [3,6], in women [3,6,10] and in contact lens wearers with
`estimates from 43% to 50.1% [2,3,11] has also been observed.
`Treatments have been formulated to either restore tear volume
`or to increase tear film stability hence reducing tear evaporation.
`The most commonly used treatment for dry eyes consists of
`
`§ The investigation was sponsored via a grant from Allergan Inc..
`* Corresponding author at: OTG Research & Consultancy, Optometric Technology
`Group, 66 Buckingham Gate, London SW1E 6AU, UK. Tel.: +44 2072224224;
`fax: +44 2072224246.
`E-mail address: cmaissa@otg.co.uk (C. Maı¨ssa).
`
`topically applied artificial tears and lubricants in the forms of
`eyedrops, gel or ointments. In a 2000 study by Nelson et al. [12],
`87% of dry eye patients were reported to have used medications for
`dry eye in the previous 3 months, 56% reported using lubricant
`drops and 40% using lubricant ointments. The main active agents in
`traditional artificial tears products are viscosity enhancing agents
`used in a range of concentrations, in preserved or unpreserved
`formulations. Such products have been used in practice to help in
`the relief of the symptoms present in mild dry eye conditions, with
`more viscous products dedicated to more pronounced symptoms
`[13,14].
`In the last few years, as a result of a better understanding of the
`complex aetiology of dry eye syndrome, more targeted, specialised
`treatments have emerged, either pharmacological compounds
`aimed at decreasing inflammation, improving lipid production
`and/or stimulating mucin and aqueous secretions from the ocular
`surface or treatments formulated to mimic the structure and
`function of natural tears.
`A new emulsion eyedrop developed by Allergan, containing
`1.25% castor oil stabilised within an aqueous demulcent formula,
`was initially used as a vehicle for cyclosporine ophthalmic
`emulsion 0.05% (Restasis1, Allergan), a pharmaceutical compound
`used to modulate inflammatory components in KCS and severe dry
`
`1367-0484/$ – see front matter ß 2009 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
`doi:10.1016/j.clae.2009.10.005
`
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`77
`
`eye cases. It is available in the US in slightly modified form as an
`artificial tear emulsion (Refresh Endura1, Allergan). This artificial
`tear solution falls into the category of eyedrops with targeted
`efficacy, aiming at treating all three layers of the tear film. Upon
`release the oil is thought to interact with the superficial lipid layer
`stabilising the tear film and reducing tear film evaporation, while
`the aqueous demulcent enhances the aqueous and mucin layers
`[15].
`in clinical studies of Restasis1 cyclosporine
`Interestingly,
`ophthalmic emulsion, the castor oil vehicle alone was reported
`to reduce some signs and symptoms of dry eye [16,17] and a pre-
`market study on the emulsion itself as an artificial tear on 73 mild
`to moderate dry eye subjects reported a significant increase in tear
`break-up time compared to baseline together with some improve-
`ments in signs and symptoms of dry eye after 90 days of usage [18].
`Di Pascuale et al. [19] in a study on 5 normals and 10 aqueous
`tear deficient subjects reported a significant increase in tear lipid
`layer thickness and improved tear film spread time following the
`use of 1.25% castor oil emulsion eyedrop. Khanal et al. [20]
`measured reduced tear film evaporation with use of the 1.25%
`castor oil emulsion eyedrop, greater than that with a conventional
`aqueous drop. Further, Goto et al.
`[21] reported improved
`symptoms scores, increased tear break-up time and decreased
`tear evaporation after 2 weeks of six times daily treatment of
`homogenised castor oil compared to placebo for patients with non-
`inflamed obstructive meibomian gland dysfunction.
`Castor oil eyedrops are lipid eyedrops which beneficial effects
`are thought to be associated with a modification of the lipid layer
`properties. The objectives of this pilot study were primarily to
`measure the prevalence of castor oil in the tear fluid over time and
`quantify the effects of the castor oil eyedrops on the tear film lipid
`layer of normal and dry eye subjects. A secondary objective was to
`quantify the initial effects of the emulsion eyedrop on ocular
`symptomatology.
`
`2. Materials and methods
`
`2.1. Test products
`
`The test product was an investigative formula of a new
`emulsion eyedrop containing a polar oil (castor oil) within a
`aqueous demulcent formula. The castor oil primarily consists of
`the triglyceride of ricinoleic acid. The demulcent aqueous phase
`consists of polysorbate 80 (demulcent and emulsifier), carbomer
`1342 (gelling agent and emulsifier) and glycerin (demulcent and
`tonicity agent). The non-preserved formula was dispensed in unit-
`dose plastic ampoules. The modality of use of the test product was
`a single instillation by the investigator. The test product, which
`was an investigational product, was used under a clinical trial
`exemption (CTX) from the Medicines and Healthcare products
`Regulatory Agency.
`
`2.2. Subjects
`
`Non-contact lens wearers were randomly enrolled in this
`research study. The test population included both normal subjects
`(n = 5) and subjects who complained of dry eye (n = 10). The
`McMonnies questionnaire was used to assess the symptomatology
`of the subjects at the enrolment visit [22]. The dry eye group
`(Symptomatic group) was defined as those subjects with a
`score  40 and the remainder were classified as normal (Asympto-
`matic group).
`Subjects were excluded if they showed signs of ocular infection
`or anomaly and if ocular medication was currently being used.
`Systemic diseases, general medications and systemic allergy with
`possible ocular components were also grounds for exclusion. All
`
`subjects signed an informed consent and experimental procedures
`were reviewed and approved by an ICH-GCP independent ethics
`committee.
`
`2.3. Clinical test procedures
`
`The in vivo evaluation of the tear film characteristics was carried
`out using a slit-lamp observation system with the TearscopeTM
`lighting system allowing the different layers of the tear film to be
`visualised non-invasively.
`The lipid layer was observed over the whole corneal surface; the
`mixing patterns observed within the lipid layer were classified
`upon their appearance. Lipid mixing patterns, that are transient or
`of the open meshwork type, are considered to be of poor efficacy
`and characteristics of a thin lipid layer (15 nm), close meshwork
`layer mixing patterns are viewed as average in efficacy and flow
`and subsequent layer mixing patterns, characteristics of a thick
`lipid layer (30–80 nm) are considered optimal [23].
`The Non-Invasive Break-Up Time (NIBUT) was taken as the
`quantification of the pre-ocular tear film stability. Three successive
`measurements of the NIBUT were recorded; the smallest value
`recorded (Minimum NIBUT), representing the worst case, and the
`median value (Median NIBUT) were used for statistical analysis.
`The tear prism height was measured as an indication of tear
`volume pre- and post-eyedrop instillation. The measurement was
`made immediately below the central part of the inferior cornea
`using the graduated slit opening on the biomicroscope.
`Subjective tolerance and satisfaction were evaluated in terms of
`ocular comfort, subjective vision and ocular symptomatology
`during four hours post-instillation. Ocular comfort and subjective
`vision were recorded on dedicated continuous 50-point scales with
`the following descriptive anchors (0 = Very poor; 8 = Poor;
`17 = Less than satisfactory (below average); 25 = Satisfactory;
`33 = Better than satisfactory; 42 = Good; 50 = Excellent). Ocular
`symptomatology was monitored in terms of ocular dryness,
`grittiness, burning sensation, scratchiness and itchiness. All
`symptoms were recorded on continuous 50-point scales with
`anchors (0 = Constantly; 8 = Very Often; 17 = Often; 25 = Some-
`times; 33 = Rarely; 42 = Very rarely; 50 = Never) [24,25].
`The other parameters recorded during the clinical examination
`were not efficacy parameters but were carried out for legal and
`safety purposes. Visual acuity measurement and safety slit-lamp
`biomicroscopy with sodium fluorescein and lissamine green vital
`stains instillation were carried out before eyedrop instillation and
`four hours post-eyedrops instillation.
`
`2.4. Laboratory procedures
`
`Tear samples were collected at the test visit at regular intervals
`before and after single eyedrop instillation (15 min, 1 h and 4 h)
`from both the right and left eyes. The tear samples were collected
`from the lower tear prism of each eye using sterile disposable
`surgical eye sponges for the overall
`lipid profiling and glass
`microcapillaries for the quantification of castor oil by the
`investigators, trained in the techniques and who paid particular
`attention not to stimulate reflex tearing. Sampling of tear in the left
`eye took place after sampling in the right eye. Approximately 2 ml
`of tears was collected from each eye.
`The tear samples from the right and left eyes were analysed by
`two different High Performance Liquid Chromatography (HPLC)
`methods. The amount of castor oil present in the tear film was
`quantified from the right eye tear samples which were analysed by
`HPLC, using a technique optimised for fatty acids/triglyceride
`separation with a reverse phase column and UV detection at
`205 nm. The height and area of the peak characteristic of castor oil
`were recorded. The presence of castor oil in the tear samples
`
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`collected at the various time points was used as an indicator of the
`emulsion eyedrop residency time. Quantification was carried out
`by calibration of the HPLC with castor oil samples of known
`concentrations.
`The endogenous lipid profile and its possible changes over time
`were analysed from the left eye tear samples by HPLC on a normal
`phase silica column (LiChrospher SI60) with UV and fluorescence
`detectors. Five main lipid classes, ranked in increasing retention
`times, were separated from the tear fluid: Cholesterol esters,
`Phospholipids/Triglycerides, Fatty acids, Monoglycerides, and
`Cholesterol. The data was reported for each tear sample in terms
`of the total amount of lipids detected and the individual amount
`for each of the lipid classes detected (in absolute amount and in
`percentage (%) of total lipids).
`
`2.5. Study design
`
`The study was a prospective, open label, interventional study
`introducing a single eyedrop in each eye. Each subject was required
`to attend for one enrolment visit and one test visit. The test visit
`involved the use of the investigational eyedrop in both eyes and a
`four hours follow-up post-instillation. The eyedrops were instilled
`by the investigator. The primary end points were the objective
`measurement of tear lipid biochemical and biophysical character-
`istics 15 min, one hour and four hours post-eyedrop instillation.
`
`2.6. Data analysis
`
`The relative performance over time of the eyedrop was
`compared to baseline for each time point using paired statistics,
`for the overall population and both the symptomatic and normal
`asymptomatic sub-populations. Non-parametric data was com-
`pared by Wilcoxon Signed Rank Exact Test and parametric data
`was compared using Paired Samples T-test or Repeated Measures
`ANOVA with Time post-instillation & eye as factors.
`
`3. Results
`
`Fifteen subjects completed the study with no observed adverse
`events. The demographics of the population are presented in
`Table 1. Out of the fifteen subjects, ten subjects were classified as
`symptomatic according to the McMonnies questionnaire with an
`average score of 58.2 ranging from 40 to 88; the remaining five
`subjects were representative of normal asymptomatic patients
`with an average McMonnies score of 24.4 ranging from 16 to 34.
`Conjunctival hyperaemia, rated using a 5-point scale, was low;
`on average over the bulbar and limbal areas, hyperaemia was
`graded as slight or less in 30–100% of cases prior to eyedrop
`instillation and in 55–100% of cases four hours post-instillation.
`Hyperaemia was never worse than Mild (Grade 2.5). Corneal
`staining, recorded on a 0–5-point scale, and conjunctival staining,
`recorded on a 0–4 point scale, were most commonly rated as
`Absent (Grade 0) or Slight (Grade 1), both prior and following the
`use of the eyedrops. The safety data gathered revealed an overall
`good tolerance of the test eyedrop by the ocular tissues.
`
`Fig. 1. POTF lipid layer distribution for the overall population and each sub-
`population at various time point (*p  0.05).
`
`The lipid mixing patterns of the POTF lipid layer were most
`commonly meshwork or wave patterns at all time points pre- and
`post-eyedrop instillation (Meshwork: 20–43%, Wave 40–53%)
`(Fig. 1). For the overall population the effect of the eyedrops on the
`lipid pattern was statistically significant and limited to the first
`hour post-instillation (15 min, p = 0.050; 1 h, p = 0.035) (Fig. 1).
`The effect was, however, more marked for the symptomatic sub-
`population; the eyedrops significantly modified the patterns
`observed for the symptomatic sub-population, producing a thicker
`lipid layer both 15 min (p = 0.013), and one hour (p = 0.006) post-
`instillation. The changes were characterised by less open mesh-
`work patterns (Thinnest layers) and more wave patterns (Thick
`layers) post-instillation compared to pre-instillation (Fig. 1) (Pre:
`Open Meshwork = 20%, Wave = 40%; 15 min: Open Mesh-
`work = 0%, Wave = 55%; One hour: Open Meshwork = 0%,
`Wave = 65%; Four hours: Open Meshwork = 10%, Wave = 40%).
`Neither a change in patterns distribution over
`time, nor
`statistically significant changes were observed in the asympto-
`matic population (Fig. 1).
`The POTF NIBUTs (Median and Minimum) tended to increase
`post-eyedrop instillation compared to baseline. The increase was
`initially slow and only observed from one hour post-instillation
`when the NIBUT was longest (Fig. 2). One and four hours post-
`instillation, the differences in average response observed in the
`symptomatic subpopulation were always superior to 2 s and
`considered to be clinically significant (average increase >15% of
`the mean value) for both the Minimum and Median NIBUTs
`(Minimum NIBUT Pre: 8.2 s, One hour: 10.5 s, Four hours: 10.4 s;
`Median NIBUT Pre: 12.6 s, One hour: 16.8 s, Four hours: 15.3 s).
`However, due to the small sample size in this pilot study, even
`though the improvement in mean amplitude was large (2.2–4.2 s),
`it failed to reach statistical significance (p = 0.061–0.100). No
`statistically significant differences were observed for the asympto-
`matic population (p = 0.117–0.450; Minimum NIBUT Pre: 12.6 s,
`
`43.7 19.4 [18–72] years
`3:12
`47.4 20.8 [18–72] years
`3:7
`36.2 15.3 [25–62] years
`0:5
`
`Overall (n = 15)
`
`Table 1
`Demographics of cohort population (n = 15).
`Age (mean SD) [range]
`Sex (male:female)
`Age (mean SD) [range]
`Sex (male:female)
`Age (mean SD) [range]
`Sex (male:female)
`
`Symptomatic (n = 10)
`
`Asymptomatic (n = 5)
`
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`79
`
`Fig. 2. POTF Median NIBUT over time—overall and for each population subgroups
`(*p < 0.05, +p < 0.1).
`
`One hour: 13.2 s, Four hours: 10.6 s; Median NIBUT Pre: 16.9 s, One
`hour: 23.0 s, Four hours: 19.3 s). In the overall population, the
`differences in average response observed were more variable (0.8–
`4.9 s) and statistically significant for the median NIBUT after 1 h
`(p = 0.020).
`The tear film volume, which was evaluated in terms of Tear
`Prism Height, was statistically and clinically similar at all times
`post-instillation and unchanged (p = 0.157–0.484)
`from pre-
`instillation (Pre-instillation Asympt = 0.28 mm, Sympt = 0.22 mm,
`Overall = 0.24 mm;
`Post-instillation
`Asympt = 0.22–0.27 mm,
`Sympt = 0.22–0.24 mm, Overall = 0.23–0.24 mm) with the excep-
`tion of one hour (p = 0.010) and four hours (p = 0.060) post-
`instillation when the tear prism height measured for the
`asymptomatic sub-population was smaller than baseline mea-
`surements (Fig. 3).
`
`Table 2
`Comfort scores overtime.
`
`Asymptomatic (n = 5)
`
`p (vs. Baseline)
`
`Symptomatic (n = 10)
`
`p (vs. Baseline)
`
`Overall (n = 15)
`
`p (vs. Baseline)
`
`Baseline
`43.6 8.2
`(30! 50)
`–
`36.0 6.7
`(30! 50)
`–
`38.5 8.0
`(30! 50)
`–
`
`T 15 min
`45.8 4.0
`(40! 50)
`p = 0.121
`33.8 11.5
`(20! 50)
`p = 0.232
`37.8 11.2
`(20! 50)
`p = 0.368
`
`T 1 h
`43.0 6.3
`(35! 50)
`p = 0.404
`41.6 5.6
`(30! 50)
`p = 0.003
`42.1 5.8
`(30! 50)
`p = 0.012
`
`T 4 h
`45.2 3.7
`(40! 50)
`p = 0.208
`41.0 10.8
`(10! 50)
`p = 0.063
`42.4 9.4
`(10! 50)
`p = 0.041
`
`Fig. 3. Tear prism height over time—overall and for each population subgroups.
`
`The ocular comfort recorded on the 50-point continuous scale
`was on average reported as ‘‘better
`than satisfactory’’
`to
`‘‘excellent’’ prior to eyedrop instillation. Clinically significantly
`higher mean scores were achieved prior to the eyedrop instillation
`by the asymptomatic than the symptomatic sub-population
`(Table 2). Post-instillation the increase in comfort scores from
`the pre-instillation baseline was statistically significant one hour
`(p = 0.012) and four hours (p = 0.041) post-eyedrop instillation for
`the overall population (Fig. 4). Similarly, a statistically and
`clinically significant improvement in comfort scores was observed
`for
`the symptomatic population one hour post-instillation
`(p = 0.003); after four hours the improvement was at the limit
`of statistical significance (p = 0.063). No statistically significant
`changes in comfort were observed at any time for the asympto-
`matic population (p = 0.121–0.404) (Table 2).
`For the overall population a clinically significant decrease in
`symptomatology was observed up to four hours post-instillation
`(Fig. 5). The improvement was across all the symptoms recorded:
`dryness (p < 0.001–0.003), grittiness (p = 0.002–0.010), itchiness
`(p < 0.001),
`burning
`(p < 0.001–0.006)
`and
`scratchiness
`(p = 0.002–0.003). For
`the symptomatic sub-population,
`the
`decrease in symptoms scores from the pre-instillation values
`were also very marked, with differences in average score ranging
`from 7 to 21 points. For all symptoms recorded, the scores at one
`hour
`(p < 0.001–0.003)
`and
`four
`hours
`post-instillation
`(p < 0.001–0.019) were statistically significantly different than
`those recorded at baseline. For the asymptomatic sub-population,
`the change in the average scores recorded post-eyedrop instillation
`were less marked and ranged from 0 to 9 points. Some statistical
`
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`
`Table 4
`Castor oil emulsion eyedrop—volume detected overtime (n = 15).
`
`Volume detected (in ml eyedrop equivalent) mean [SD]
`
`Asymptomatic
`Symptomatic
`Overall
`
`At 15 min
`
`0.12[0.12]
`0.21[0.26]
`0.18[0.22]
`
`At 1 h
`
`0.22[0.13]
`0.13[0.16]
`0.16[0.15]
`
`At 4 h
`
`0.09[0.10]
`0.12[0.19]
`0.11[0.16]
`
`Table 5
`Effect of castor oil presence on NIBUT.
`
`No castor oil detected
`NIBUT Minimum (mean SD) (s)
`NIBUT Median (mean SD) (s)
`
`Castor oil detected
`NIBUT Minimum (mean SD) (s)
`NIBUT Median (mean SD) (s)
`
`At 15 min
`
`At 1 h
`
`At 4 h
`
`9.3 6.1
`13.0 7.6
`
`7.7 3.3
`16.7 13.7
`
`10.9 6.9
`16.5 7.1
`
`11.4 8.0
`16.4 9.8
`
`13.7 8.8
`22.4 12.6
`
`11.9 9.7
`19.0 15.1
`
`with detectable levels of emulsion eyedrops in the tear film than
`for those without (Table 5). The differences were maximal one
`hour post-instillation (Mean NIBUT Increase: Minimum = 6.0 s
`(78.5%), Median = 5.7 s (34%)). The difference in tear film stability
`was still present four hours post-instillation but of
`limited
`amplitude (Mean NIBUT Increase: Minimum = 0.9 s (9%), Med-
`ian = 2.5s (15%)). Despite their amplitude, the differences above,
`failed to reach statistical significance (p = 0.084–0.417).
`A trend towards an increased volume of total lipids in the tear
`film post-instillation was observed for both sub-populations. The
`effect was noticeable from one hour post-instillation (p = 0.162)
`and most marked four hours (p = 0.086) post-instillation (5
`increase) but never reached statistical significance.
`Overall, no statistically significant differences were observed in
`the level of any individual lipid family. However, the following
`trends were observed (p < 0.1): a twofold increase in the level of
`fatty acids (p = 0.082) and a higher level of triglycerides compared
`to baseline (p = 0.085) four hours post-instillation. Similar results
`were obtained for the proportion of each lipid class in the tear film.
`A significantly lower proportion of cholesterol ester (18.9% vs.
`26.8%, p = 0.045) and higher proportion of triglycerides at the limit
`of statistical significance (28.5% vs. 16.1%, p = 0.061) compared to
`baseline were recorded four hours post-instillation.
`
`4. Discussion
`
`The primary laboratory objective of this investigation was to
`measure the residence time of castor oil emulsion eyedrops in the
`tear film. Castor oil presence was detected up to 4 h after a single
`eyedrop instillation. The use of the emulsion eyedrop was also
`associated in some cases with a significant increase in the total
`volume of lipids presents in the tear film. Such increase was most
`marked for the triglycerides family at one and four hours post-
`instillation. However, overall due to the small sample size in this
`pilot study, statistical significance was not achieved. The elevated
`level of lipids observed post-instillation could be due to the
`previously reported enhanced meibomian gland secretion with
`homogenized castor oil [13]. However, the level of triglycerides
`recorded was also significantly higher than average population
`levels (at least 10 times) suggesting that some of the triglycerides
`sampled were non-endogenous and most likely have originated
`from the eyedrop itself.
`The primary clinical objectives were to quantify the effect of the
`eyedrops on the tear film. Firstly it is important to note that the
`tear film volume, evaluated in terms of Tear Prism Height, was
`statistically and clinically unchanged pre- and post-instillation,
`
`Fig. 4. Comfort pre- and post-eyedrop instillation—overall population (*p < 0.05,
`+p < 0.1).
`
`Fig. 5. Ocular symptomatology pre- and post-eyedrop instillation—overall
`population (*p < 0.05 at all time points).
`
`differences were observed but were limited to the symptoms of
`burning at all
`time points
`(Mean score: Baseline = 39.0,
`15 min = 48.0, One hour = 46.0, Four hours = 47.4, p = 0.007–
`0.027) and to scratchiness symptoms at 15 min (p = 0.049) and
`four hours (p = 0.049) post-instillation (Mean score: Base-
`line = 40.0, 15 min = 48.0, One hour = 44.0, Four hours = 48.0).
`Post-instillation the subjective vision recorded on a 50 points
`continuous scale was on average reported as ‘‘good’’ to ‘‘excellent’’
`for the overall population. The eyedrops did not adversely affect
`vision for either of the sub-populations and on the contrary, at
`most time points post-instillation, the subjective vision scores
`recorded were statistically significantly higher, e.g. better vision
`than at baseline (Baseline Mean score: Overall = 37.2, Asympto-
`matic = 40.3, Symptomatic = 31.0; Mean score post-instillation:
`Overall = 43.4–45.4 (p < 0.001–0.011), Asymptomatic = 43.2–44.0
`(p = 0.014–0.021), Symptomatic = 43.5–46.1 (p = 0.009–0.133)).
`Castor oil was detected in 67% of tear samples up to one hour
`post-instillation and in 53% up to four hours (Table 3). On average
`the level of castor oil measured was similar 15 min and one hour
`post-instillation and equivalent to 0.17 ml of eyedrop on average;
`four hours post-instillation the level was on average equivalent to
`0.11 ml (Table 4). The presence of castor oil was associated with a
`more stable tear film as shown by the longer NIBUT for the subjects
`
`Table 3
`Castor oil emulsion eyedrop prevalence over time (n = 15).
`
`Incidence of cases with detectable amount of
`castor oil n[%]
`
`At 15 min
`
`3[60%]
`7[70%]
`10[67%]
`
`At 1 h
`
`5[100%]
`5[50%]
`10[67%]
`
`At 4 h
`
`3[60%]
`5[50%]
`8[53%]
`
`Asymptomatic
`Symptomatic
`Overall
`
`APOTEX 1059, pg. 5
`
`

`
`C. Maı¨ssa et al. / Contact Lens & Anterior Eye 33 (2010) 76–82
`
`81
`
`suggesting therefore that any observed effect of the eyedrop was
`not volume related. The results revealed a number of improve-
`ments for the overall population; more importantly, however, was
`the difference in interaction between the two sub-populations.
`Whereas, as expected little changes were recorded for the
`asymptomatic sub-population, improvements in tear film char-
`acteristics were recorded for the symptomatic sub-population. The
`lipid layer was significantly thicker over the first hour post-
`instillation. The effect on the stability of the tear film was delayed
`to the hour time point when the tear film break-up time was
`markedly longer than pre-eyedrop instillation; even though as
`reported above, due to the limited sample size the differences were
`only at the limit of statistical significance. This phenomenon
`supports the hypothesis that the potential benefit of the castor oil
`is achieved through its interaction with the native tear film lipids.
`It is also the cause of the longer residence time than that of
`conventional eyedrops, which rely on viscosity and their interac-
`tion with the tear aqueous layer. The aqueous turn around time
`being significantly shorter than the lipid turn around time, the
`dilution for aqueous interacting eyedrop is expected to be faster
`than lipid interacting eyedrops.
`Previous studies evaluating at the effect of castor oil have
`demonstrated positive changes on the tear film characteristics, and
`principally for lipid related features [19–21]. Khanal et al. reported
`a statistically significant decrease in tear evaporation of mild to
`moderate dry eye subjects after 1 month of use [20]; similarly, after
`repeated use over a 2-week period in a population of 20 subjects
`with non-inflamed obstructive meibomian gland dysfunction,
`Goto et al. showed increased tear film stability, reduced tear
`evaporation, decreased symptoms and improved meibomian gland
`status [21]. Finally, Di Pascuale et al. reported improvement in lipid
`layer thickness and tear film spread time after a single instillation
`[19].
`The increase in the volume of total tear lipids measured as well
`as the changes in lipid patterns observed with the TearscopeTM
`from a majority of open meshwork patterns to wave patterns are in
`good agreement with the findings from Di Pascuale et al. The
`current pilot study, however, is the first to look at the functional
`effect of the eyedrop over time following a single instillation and to
`show its prolonged residence time. One further implication of the
`current study is its potential usefulness as a methodology for initial
`clinical screening during the development of new lipid eyedrops.
`The secondary clinical objectives were to quantify the effect of
`the eyedrops on subjective acceptance. The symptoms were
`reduced for the overall population over the 4-h period. The effects
`were again very prominent for the symptomatic sub-population:
`comfort was significantly better one hour post-instillation and
`symptomatology, in particular dryness, burning and itchiness were
`significantly reduced up to four hours post-instillation. The effects
`on the asymptomatic sub-population were never negative but due
`to the general lack of symptoms prior to instillation the differences
`recorded were limited. The clinical findings in this pilot study
`clearly showed that, whereas for an asymptomatic population the
`eyedrop does not have a clinical role, for a symptom-based
`targeted dry eye population, the castor oil emulsion eyedrop has
`significant beneficial effects. The reduction in symptoms and
`increase in comfort over the 4-h follow-up period confirm the long
`lasting effect of castor oil. The use of the castor oil emulsion
`eyedrops did not produce any significant change in ocular tissue
`characteristics or vision.
`A point that warrants further discussion is the pilot nature of
`the study achieving low statistical power, particularly for the small
`asymptomatic sub-population. Not withstanding this proviso, the
`results are remarkable in as much that the use of castor oil on
`symptomatic dry eye sufferers was shown to modify the tear lipid
`layer, increase the tear film stability, improve comfort and reduce
`
`symptoms. The absence of a change in the asymptomatic could be
`due to the insufficient sample size; however, observation of the
`data in this pilot sub-population strongly suggests, an absence of
`effect rather than an insufficient sample size for the parameters
`considered, with the exception of a trend for a clinically longer
`NIBUT at 1 h.
`
`5. Conclusion
`
`This pilot study primarily measured the prevalence of castor oil
`in the tear fluid over time and quantified its effects on the tear film
`lipid layer of normal and dry eye subjects. Combined results for
`both normal and dry eye subjects showed that castor oil was
`detected up to 4 h after a single eyedrop instillation.
`The volume of lipid present in the tear film, in particular
`triglycerides, increased significantly post-instillation suggesting
`that the castor oil eyedrop interacts with the tear film lipid layer.
`This interaction may be responsible for the long residence time, as
`tear film lipids have a relatively low turnover rate on the ocular
`surface. These findings were associated with significant clinical
`changes in particular for the symptomatic sub-population. For the
`symptomatic sub-population a significant decrease in ocular
`symptoms were recorded up to 4 h post a single eyedrop
`instillation. The effect on the tear film stability and tear film lipid
`layer thickness was, however, less marked but a significant trend
`was observed at least up to one hour post-instillation.
`In general conclusion, this pilot investigation showed that
`castor oil eyedrops achieved a residence time of at least four hours
`post-instillation and produced a more stable tear film and an
`associated significant decrease in ocular symptoms over the entire
`4 h follow-up period for the symptomatic subjects.
`
`References
`
`[1] Lemp MA. Report of the National Eye Institute/Industry Workshop on Clini