Managing patients with dry eye symptoms remains a well-known challenge despite the wide array of topical, mechanical and oral therapies available today. To put it another way, there would be no need for palliative artificial tears if we could truly conquer the underlying processes that lead to dry eye symptoms. Although treatment options abound, they are fraught with compromises and shortcomings.

Technological advances like LipiFlow (TearScience), BlephEx (Scope Ophthalmics) and intense pulsed light (IPL) devices have been used to treat meibomian gland dysfunction (MGD)—the most common form of dry eye—and Demodex; however, equipment costs and space requirements often limit widespread use in practice.¹ Practitioners can also prescribe less expensive options like hot compresses and lid soaks to loosen debris and instigate meibum flow, but some critics say heat from these treatments does not penetrate deep enough or last long enough to have a positive effect on MGD. 

Other therapies like lid disinfectants (e.g., Cliradex and Avenova) or lid scrubs (e.g., Ocusoft, TheraTears and Systane) have also been used to treat blepharitis; these have shown a clinical benefit when used regularly.² Long-term effects with respect to more chronic cases remain unknown, however. Other research has suggested omega-3 and omega-6 fatty acids taken orally may have a positive but limited effect on meibomian gland inflammation and oil quality. Autologous serum and amniotic membranes (e.g., Prokera, AmbioDisc and BioDOptix) may be used to enhance epithelial repair, but remain expensive and hard to procure. 

In light of these controversial options, many practitioners would agree the first-line treatment for dry eye remains over-the-counter (OTC) artificial tears. OTC tears are simple enough to use, with a variety of well-known indications, including dryness, irritation and discomfort relief. However, despite their simple indications, these drops are complex formulations with a host of active and inactive ingredients that can be difficult to evaluate. Why is this?

FDA Follies
Last year, Dr. Christensen received a call from a friend looking for information on studies used for approval of OTC tears, as he had been having difficulty locating any. What he didn’t realize was that none currently exist. Though numerous well-controlled industry-sponsored, randomized clinical studies that support product package claims are available, no FDA trials for drop efficacy have been instituted. 

Why are some ingredients labeled as active and others inactive, and why do the companies seemingly only expound on what is special about the inactive ingredients? What differentiates one company’s product from that of a competitor with the same active ingredients?  

In 1988, the FDA finalized a monograph to help expedite artificial tears, coded “lubricant eye drops,” to the market.² Its primary purpose was to reduce the costs and barriers associated with new product development, thus easing manufacturing and marketing efforts. Under the new document, the company must notify the FDA of its intention to release an artificial tear to the public. To approve the drop, the agency evaluates its safety via toxicology testing and checks to ensure good manufacturing procedures. The monograph contains specific details on the indications for use; namely, one of the following:

• Temporary relief of burning and irritation due to dryness of the eye.

• Temporary relief of discomfort due to minor irritation of the eye or to exposure to wind or sun.

• As a protectant against further irritation or to relieve ocular dryness.

• As a lubricant to prevent further irritation or to relieve ocular dryness.

The FDA also requires manufactures to include the following box statement on the box: “Stop use and ask your doctor if you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the aforementioned condition worsens or persists for more than 72 hours.” 

The active ingredients in the monograph comprise a list of demulcents or emollients (Tables 1 and 2).^3-7 A demulcent is a high molecular weight polymer substance that relieves irritation of the mucous membranes by forming a protective mucous-mimicking film that acts to lubricate, protect and increase the viscosity of the eye drop. Emollients, in contrast, are oleaginous substances that include fats and oils, which work to reduce evaporation. As part of the monograph’s development, the FDA deemed a specific range of concentrations as safe and effective for these drugs; it was also decided that extra or repetitive testing was unnecessary for future products. 

Table 1. Approved Active Demulcents
Demulcents			Concentration Range	Function
Carboxymethylcellulose			0.2% to 2.5%	Increases viscosity (thickener) and stabilizes emulsions.
Dextran 70			0.1% (when used with another demulcent)	Increases mechanical strength of tear film. Requires thickener due to low viscosity of compound.
Gelatin			0.01%	Gelling agent that is seldom included.
Glycerin			0.2% to 1%	Lubricant and humectant. Blunts the damaging effects of high osmolarity on the ocular surface. Promotes epithelial cell growth.
Hydroxethyl cellulose Hydroxpropyl-methyl-cellulose Methylcellulose			0.2% to 2.5%	Crosslinks upon contact with tear film due to pH difference to increase viscosity. Too viscous to instill easily alone.
Polyethylene glycol 300 Polyethylene glycol 400			0.2% to 1%	Increases viscosity and forms protective layer over mucous membrane to relieve irritation.
Polysorbate 80			0.2% to 1%	Stabilizes oil emulsions.
Polyvinyl alcohol			0.1% to 4%	Lowers tear viscosity.
Povidone			0.1% to 2%	Lubricates and soothes. Lipid that integrates with existing oil layer, thickening it and reducing evaporation.
Propylene glycol			0.2% to 1%	Forms a protective layer over mucous membranes, relieving inflammation. Increases viscosity. Holds up to three times its own weight in water.

Table 2. Approved Active Emollients
Emollients	Concentration Range	Function
Anhydrous lanolin Lanolin	1% to 10% in combination with one or more listed oleaginous emollient.	Lubricates and soothes. Contributes to oil layer.
Light mineral oil Mineral oil	Up to 50% in combination with one or more listed emollient.	Replaces or thickens lipid layer to increase tear stability and TBUT. Seals in existing moisture, but is non-moisturizing.
Paraffin	Up to 5% in combination with one or more listed emollient.	Seals in moisture. Waxy consistency.
Petrolatum White ointment White petrolatum	Up to 100%.	Lubricant that contributes to oil layer.
White wax Yellow wax	Up to 5% in combination with one or more listed emollient.	Contributes to oil layer.

In this sense, the ingredients listed in the monograph are “safe,” and overuse constitutes minimal risk to the patient. Only these ingredients can be considered for the fast track of FDA approval. Therefore, the result of the simplified monograph ruling had an unforeseen consequence: it has resulted in a plethora of products on the shelf but no new active ingredients in nearly 30 years. 

A new polymer requires a new drug application process to show that it is a pharmacologically active drug. Significant improvement in a sign and symptom must be shown; additionally, results using the new formula must be demonstrated. This is an exceedingly difficult task and sometimes not worth the investment of time and funding, since it can be added as a non-pharmacologically active polymer under the non-active ingredients.

Difference Makers
Other than the typical ingredients in artificial tears like boric acid, calcium chloride, magnesium chloride, potassium chloride, purified water and preservatives, inactives like hyaluronic acid along with hydroxypropyl guar, erythritol/levocarnitine and sodium provide the distinguishing factors that give each artificial tear its unique characteristics, improving their efficacy (Tables 3 and 4). 3-7 For example, BlinkTears (AMO) contains polyethylene glycol 400 0.25% as an active ingredient and sodium hyaluronate as an inactive ingredient. Sodium hyaluronate is a humectant that binds many times its weight in water, reduces mucous strands and is better at lowering tear osmolarity than glycerin.9 Refresh Optive Advanced (Allergan) incorporates carboxymethylcellulose sodium 0.5%, glycerin 1% and polysorbate 80 0.5% as actives with castor oil, erythritol, levocarntine and carbomer copolymer type A as inactives. Systane Ultra (Alcon) uses polyethylene glycol 400 0.4% and propylene glycol 0.3% in conjunction with HP-guar as an inactive. Retaine MGD (Ocusoft) contains light mineral oil 0.5% and mineral oil 0.5% as actives and a number of inactives (e.g., cetalkonium chloride, glycerol, poloxamer 188).

Table 3. Approved Inactive Ingredients
Inactive Ingredients	Function
Sorbitol	Lowers the viscosity of gelling agents. Dissipates quickly, optimizing viscosity.
Hyaluronic acid	Binds multiples of its weight in water. Lowers tear osmolarity. Adheres to the ocular surface. Stabilizes and evens out the tear film. Highly viscous until blinking thins it out. Improves cell-cell adhesion.
Sodium hyyaluronate	Protects and promotes healing of corneal epithelium.  Changes viscosity upon blinking (i.e., more viscous while the eye is open). Improves tear break-up time and helps spreading. Helps control localized inflammation. Reduces mucous strands. Lowers tear osmolarity. Retains water, increasing surface wettability.
Levocarnitine Erythritol	Blunts the damaging effects of high osmolarity by preventing stress activation. Absorbed by dehydrated cells to promote hydration. Prevents cell shrinkage and inflammation.
Hydroxpropyl guar	Increases viscosity. Mimics the mucin layer of the eye. Binds to the cornea and aqueous layer. Prolongs the efficacy of active-ingredients. Actively crosslinks/gels at pH above pH 7.
Polyacrylic acid	Increases viscosity/retention time of tears.
Tyloxapol	Surfactant and mucolytic agent.
Tromethamine	Organic amine proton acceptor. Emulsifying agent that thins waxy agents.
Boric acid Borate buffer Sodium-citrate Phosphate Phosphate-acetate Phosphase-cirtate Phosphate-cirtrate-bicarbonate Sodium hydroxide	Buffer systems used to obtain a pH for the artificial tear that is healthy and comfortable for the eye. A pH of 8.5 is most comfortable for dry eye patients (normal tear pH is about 7.5)
Calcium chloride Magnesium chloride Potassium chloride Zinc chloride Sodium chloride Sodium citrate Sodium lactate Sodium bicarbonate	Electrolytes are added to maintain or lower tear osmolarity, as high osmolarity products pull water from epithelial cells, interfering with metabolism. Some of the added electrolytes are also important for corneal epithelial metabolism. Some electrolytes are part of buffer systems.

Table 4. Approved Preservatives
Preservative	Concentration Range	Additional Effects (+/-)
Benzalkonium chloride (BAK)	0.004% to 0.02%	Increases drug penetration Extends product shell life. Disrupts tight junctions. Accelerates epithelial desquamation. Promotes apoposis at low concentrations and necrosis at high concentrations. Stimulates production of inflammatory cytokines. Reduces aqueous production. Causes reversible and non-reversible neurotoxicity, reducing nerve fiber density.
Polyquaternium-1	0.001%	Causes superficial epithelial damage. Reduces the density of conjunctival goblet cells, which decreases aqueous tear film production.
Sodium perborate		Vanishing preservative: upon exposure to an aqueous environment, it is catalyzed into hydrogen peroxide, water and oxygen.
Stabilized oxychloro complex	0.005%	Degrades to water, oxygen, sodium and chlorine free radicals when exposed to light. Chlorine free radicals are thought to inhibit microorganism protein synthesis within cells by way of glutathione oxidation, which causes microbe cell death. Broad antimicrobial activity--includes antibacterial, antifungal and antiviral effects.
Sodium chlorite	0.005%	Mixture of 80% chlorite, 11% sodium chloride, water and trace electrolytes that breaks down into sodium and chloride ions, oxygen and water when exposed to light.
Polyhexamethylene biguanide (PHMB)	0.02%	Beneficial against bacteria and Acanthamoeba, however, its antifungal activity is limited. Lethally alters the transcription of bacterial DNA. Nonirritating to human corneal cells. Integrates into bacterial cell walls, disrupting the membrane.
Chlorobutanol		Alcohol that increases lipid solubility and is able to cross the bacterial lipid layer. Has extensive anti-bacterial action, causing cell lysis by disruption of microbial cell membrane lipid configuration. Causes significant keratitis and irritation to the ocular surface, but less than BAK.
EDTA (edetate disodium or ethylene diamene tetra acetic acid)	1%	Chelating agent that binds metals, which inactivates them. Enhances the activity of quaternary ammonium bases and sorbate.

There can also be differences in pH and osmolarity, depending on the characteristics the company wants to exhibit. Systane Gel Drops (Alcon) fall at pH 7.0, while Systane Ultra (Alcon) falls at 7.8. A pH that more closely matches that of the patient’s tears will result in less stinging on instillation and better overall comfort. Some tears are significantly hypoosmotic to the tear film, which is around 305 mOsmols (for example, TheraTears is at 181 mOsmols), while others are isosmotic or just slightly hypoosmotic. In general, a tear that is relatively hypoosmotic to the tears of the patient will blunt the damaging effects of high osmolarity.10 Lowering osmolarity generally improves OSDI scores, with an increased effect in younger patients and those with hyperosmotic tears.  

In addition to OTC eye drops, a number of companies have been diligently working on the development of new prescription drugs for dry eye, but none have thus far met the criteria for approval. Dry eye treatment trials include subjective accounts of patient comfort, and the FDA is typically wary of using subjective data as a factor in its approval process. For these and other reasons, Restasis (cyclosporine, Allergan) has remained the only prescriptive dry eye drug for over a decade. While others will eventually follow, until that time, it is important to understand the difference in the inactive ingredients contained in OTC eye drops and make specific recommendation to your patients. Even a savvy ingredient-reading patient may not be able to make sound choices in eyedrop use simply by reading the package labeling, so offer informational packets in-office, and discuss all potential complications with other medications the patient may be taking.    

Dr. Christensen is currently director of clinical research and an attending doctor in the cornea and contact lens and adult primary care services at Southern College of Optometry. 

Dr. Larson attended and completed a residency at Pennsylvania College of Optometry at Salus University following work as high school teacher for two years. After three years in private practice in northern Virginia, she joined the faculty at the University of Iowa as a contact lens and dry eye specialist.

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