CE Credit Article

Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Raymond M. Stein entitled Treating Dry Eye by Replicating All Three Layers of the Natural Tear Film with an Ophthalmic Gel. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 274 for complete instructions.

Treating Dry Eye by Replicating All Three Layers of the Natural Tear Film with an Ophthalmic Gel
Raymond M. Stein, MD, FRCSC

INTRODUCTION
In this article, Dr. Raymond Stein presents a review of the biomechanics of dry eye and his experience with Liposic ophthalmic gel, as an effective dry-eye treatment regimen designed to replicate the natural tear film. Although artificial tear solutions should duplicate the composition of human tear fluid, many artificial tears do not adequately respond to disorders of the lipid phase (the most frequently encountered tear film deficiency). Liposic successfully replicates all three phases of the tear film, providing relief to dry-eye sufferers.

The Aqueous Layer This layer comprises the largest part of the precorneal tear film, and is 99% water (secreted by the main lacrimal gland and the Krause and Wolfring accessory glands). The remainder consists of proteins, enzymes, and antibodies. This layer ensures corneal oxygen supply, lubricates the eye surface, helps remove foreign bodies, and serves an antibacterial function. The Lipid Layer This outermost layer acts as a tear film stabilizer and prevents aqueous tear evaporation. It also protects the ocular surface from microbial contamination and irritants. The lipid layer is comprised of several fatty substances secreted mainly from the meibomian glands. As well, the glands of Zeiss and Moll are also thought to produce a portion of these secretions.

TEAR PHYSIOLOGY
Eye comfort and correct function are dependent upon normal tear secretion and drainage. Precorneal tear film is essential for keeping the cornea smooth and free of irritation due to drying, as well as proficiently clearing foreign bodies from the eye. Tear film is comprised of three layers: the inner mucous (or mucin) layer, the middle aqueous layer, and the outer lipid layer (Fig.1). The Mucous (Mucin) Layer This is the innermost layer found immediately on the eye surface. The cornea and conjunctival epithelia are naturally hydrophobic; by keeping the cornea smooth, the mucin layer converts these two processes to hydrophilic states, allowing the aqueous layer to adhere to them. It is mainly the conjunctival goblet cells that secrete the mucin, with lesser secretions produced by the corneal and conjunctival cells. It was previously thought that the mucin layer was completely separate from the aqueous layer, but it is now proven to be present throughout the entire tear film in a gradient.
R.M. Stein Medical Director, Bochner Eye Institute; Chief of Ophthalmology, Scarborough General Hospital, Toronto, Ontario Correspondence to: Dr. Raymond Stein, Bochner Eye Institute, 40 Prince Arthur Avenue, Toronto, Ontario M5R 1A9 e-mail: rstein@bochner.com

PREVALENCE OF TEAR COMPONENT DISORDERS

Reliable diagnosis of the cause(s) behind dry eyes hinges upon accurately determining which of the three tear-film phases is deficient. Occasionally, a patient may have an insufficiency in more than one of the phases; in a study by Heiligenhaus et al, approximately one-quarter of the patients studied had a disorder of more than one tear-film phase (Fig. 2). Tear-film deficiency symptoms vary depending upon which tear-film phase is affected. Whereas patients with mucin phase disruption tend to have symptoms throughout the entire day, those with aqueous phase deficiencies typically report symptoms upon awakening and in the evenings, while patients with lipid phase defects primarily notice their symptoms in the mornings. Once the deficient tear-film phase is determined, the appropriate treatment can be administered (even if the cause cannot be eliminated, as is often the case). In the previously mentioned study, an exclusively aqueous phase disorder was found in only 8% of patients tested, and 26% of patients had a disorder of at least two of the tear phases. Conversely, 78% of patients were found to suffer solely from lipid phase disorders (Fig. 2). If these findings can be extrapolated to the general population, this has a significant impact on choice of dry eye treatment.

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Fig. 1 Model of tear-film structure

Fig. 2 Distribution of tear-film deficiencies

TESTING
No one test can sufficiently measure tear-film function. Rather, a combination of several tests is necessary to more accurately pinpoint the reason(s) behind a given patients dry eyes. First, therapy discontinuation can be a simple way to determine if irritants in their topical medication, such as benzalkonium, are causing a patients dry eyes. Measurement of tear break-up time (TBUT) helps in determining tear-film stability, with the most marked reductions in TBUT seen in mucin phase disorders, followed by aqueous phase disorders. Lipid phase disorders generally do not show TBUT reductions. Rose bengal staining can also prove valuable as a sensitive detector of even the tiniest epithelial cell lesions, and is particularly valuable for identifying combined tear film disorders. Aqueous phase disorders are discernable via pathological basal secretion values, and reliable detection of mucin phase disorders is possible with impression cytology, while lipid phase disorders can be diagnosed biometrically by lid-margin transillumination. In addition to the above tests, examination should also include medical history, slit lamp examination, visual acuity, and fluorescein dilution.

substitutes are geared to aqueous deficiencies, and as such are apt to evaporate with blinking. Also, many of the available products come in a more aqueous gel form that tends to liquefy, which renders them ineffective. Since artificial tear therapy is frequently long-term, a products viscosity plays an important role in its effectiveness. Both the type and concentration of polymer used as a thickening agent determine viscosity. Generally the more highly viscous the tear substitute, the better it resists wash-out, thereby prolonging the amount of time that the product resides in the eye and providing extended dry-eye symptom relief; typically, the viscosity of tear substitutes ranges from 2 to 6000 mPa.s. There is increasing acceptance of the importance of lipid layer deficiencies and their role in dry-eye conditions, and it is in this area where manufacturers of newer products are focusing their attention. Because it is now known that lipid deficiencies occur far more often than previously thought, dry-eye treatment with aqueous artificial tears is frequently unsuccessful.

LIPOSIC PRODUCT DESCRIPTION

Liposic is a unique artificial tear gel that is the first to contain substitutes for all three tear-film phases (Table I) and is appropriate for treating mucin, aqueous, and lipid deficiencies. It is a dispersion of aqueous and viscous eye drops in gel form that contains incorporated oil droplets for better spreading and longer residence in the eye. The list of ingredients in Liposic includes purified water, the active ingredient carbomer, medium-chain triglycerides, and cetrimide. Plainly, the water content in Liposic addresses the aqueous tear-film phase, but an overview of the other ingredients in Liposic appears below. Carbomer Liposic uses carbomer in a concentration of 0.2% as its thickening agent, which makes it highly viscous (6000 mPa.s). Since carbomer possesses properties similar to those of mucin, it remains longer on the ocular surface and is wash-out resistant. Carbomer has a high

DEFICIENCIES IN CURRENT ARTIFICIAL TEAR PRODUCTS

Artificial tears ease eyelid movement by moistening the ocular surface, and aid in healing epithelial lesions as well as irritated and inflamed glands. The aim is to improve TBUT and basal secretion. Ideally, the artificial tears used to relieve and/or treat dry eyes should match the composition of human tear fluid. Essentially, this means recreating the naturally occurring tear-film phases with a corresponding surrogate: the mucin layer with a polymer, the aqueous layer with water, and the lipid layer with an oily component. However, current products have been chronically inadequate in addressing problems involving all of the three tear phases, particularly the lipid layer. This is mainly because the majority of tear

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Table I Liposic substitutes all three layers of tear film Liposic Carbomer (0.2%) Water (ca. 93%) Medium-chain triglycerides (1%) Natural Tear Film Mucin (0.1%) Water (90%) Lipids (ca. 1%)

Fig. 3 Liposics carbomer, medium-chain triglycerides and purified water components: mode of action

Fig. 4 TBUT values (in seconds) over time (mean STD)

binding power to water; this forms a fluid film on the ocular surface that distributes evenly with blinking (Fig. 3). Medium-chain Triglycerides What sets Liposic apart is its oily component in the form of medium-chain triglycerides; these fatty substances are invaluable for offsetting lipid layer deficiencies. The medium-chain triglyceride content in Liposic is in the same concentration as that found in the lipid phase of the natural tear film (1%). This oily substance disperses minute droplets into the hydrogel created by the combined carbomer and purified water (Fig. 3). Cetrimide Liposic contains cetrimide, a well tolerated preservative in a concentration of 0.01%. Owing to this effective preserving system, Liposic gels stability remains unchanged over a period of six weeks following the opening of the container.

Fig. 5 Schirmer-I values (mm) over time (mean STD)

TBUT is not greatly impacted unless there is also a reduction in the lipid layer. TBUT measures precorneal tear stability (the time from the last blink to the first tear-film break up). Studies with Liposic-treated patients show that TBUT increased steadily over the treatment phase. Over three months, TBUT increased from 4.9 seconds to 8.3 seconds (Fig. 4). Schirmer-I test The Schirmer-I chiefly evaluates the aqueous tear and reflex secretions and is one of the oldest tests for establishing dry-eye diagnoses. Studies with Liposictreated patients demonstrated that Schirmer-I test values increased from the average 4.8 mm at start of treatment to 8.2 mm after just three months of treatment (Fig. 5). Conjunctival injection This parameter is measured using the Draize scale and evaluation is based upon a 4-point scale, where assessment ranges from none (0) to severe (3). Studies with Liposic-treated patients have shown statistically significant decreases in the frequency and intensity of conjunctival injection. The number of eyes with moderate conjunctival injection (OD and OS) decreased from 18 at start of treatment to 5 after three months (Fig. 6).

LIPOSIC CLINICAL TESTING

Recent studies have been conducted to study the efficacy and tolerance of Liposic. Parameters measured included objective efficacy measures (TBUT, Schirmer-I, and conjunctival injection); subjective efficacy measures on a 1 to 4 scale; and tolerability measures on a 1 to 4 scale. Objective Efficacy Measures TBUT TBUT is shortened in dry-eye conditions involving the mucin or lipid layer. In aqueous phase disturbances,

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Fig. 6 Conjunctival injection over time (means) Table II Patients predominantly assessed tolerance to Liposic as good or very good Number of Patients Months Very Good Good Satisfactory Poor 1 2 3 5 6 6 4 4 6 5 4 2 1 1 1

Fig. 7 Sum score of subjective efficacy over time

Subjective Efficacy Measures Self-assessment This was a patient self-assessment (OD and OS) on such individual measures as dry-eye and foreign-body sensation, burning, itching, and pain. In studies, the Liposic-treated patients reported reductions from 8.9 at start of treatment to 4.4 after three months (Fig. 7). Tolerance of Liposic This patient-self-assessment was evaluated using a 4-point scale, where tolerability ranged from very good (1) to poor (4). The parameters evaluated included

blurred vision, burning, itching, and discomfort; from these, a sum score was calculated to evaluate the subjective tolerance of Liposic. Following one and two months of treatment the sum score of Liposic-treated patients was 2.8; after three months of treatment, the average score was further reduced to 2.6 (Table II).

CONCLUSION
Liposic was developed in response to the lack of products that address all three tear-film phases. As the first of its kind on the market, it is an effective artificial tear gel with an excellent tolerability profile that successfully responds to deficiencies in all of the tear film phases. Liposic has proven successful in improving dry-eye symptoms even in severe cases and is appropriate for long-term therapy of dry-eye syndrome.

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