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?
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|
|0.2% to 2.5%|
|0.1% (when used with another demulcent)|
|0.2% to 1%|
|0.2% to 2.5%|
|0.2% to 1%|
|Polysorbate 80||0.2% to 1%|
|Polyvinyl alcohol||0.1% to 4%|
|Povidone||0.1% to 2%|
|Propylene glycol||0.2% to 1%|
|Table 2. Approved Active Emollients|
|1% to 10% in combination with one or more listed oleaginous emollient.|
|Up to 50% in combination with one or more listed emollient.|
|Up to 5% in combination with one or more listed emollient.|
|Up to 100%.|
|Up to 5% in combination with one or more listed emollient.|
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.
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|
|Table 4. Approved Preservatives|
|Preservative||Concentration Range||Additional Effects (+/-)|
|Benzalkonium chloride (BAK)||0.004% to 0.02%|
|Stabilized oxychloro complex||0.005%|
|Polyhexamethylene biguanide (PHMB)||0.02%|
|EDTA (edetate disodium or ethylene diamene tetra acetic acid)||1%|
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.
1. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction: executive summary. Invest Opthalmol Vis Sci, 2011;52:1922-9.
2. Duncan K, Jeng BH. Medical management of blepharitis. Curr Opin Ophthalmol, 2015 Jul;26(4):289-94.
3. Rules and Regulations. Food and Drug Administration 21 CRF Parts 349 and 369. Federal Register 53(43)March 1988:7076-83.
4. Brafman S, Eiden BS. Finding the balance for contact lens-associated dry eye. Review of Cornea and Contact Lenses. Jan 2012.
5. Elder DP, Crowley PJ. Antimicrobial preservatives part one: choosing a preservative system. American Pharmaceutical Review. Jan. 2012. Available: www.americanpharmaceuticalreview.com/Featured-Articles/38886-Antimicrobial-Preservatives-Part-One-Choosing-a-Preservative-System/.
6. Freeman PD, Kahook MY. Preservatives in topical ophthalmic medications: historical and clinical perspectives. Expert Rev Ophthalmol. 2009:4(1):59-64.
7. Bartlet JP, Jaanus SD. Clinical ocular pharmacology. 5th ed. Stoneham: Butterworth-Heinemann; 2007.
8. Zheng LL, Myung D, Yu CQ, Ta CN. Comparative in-vitro cytotoxicity of artificial tears. JSM Ophthalmology. 2015 Jan;3(1):1026.
9. Montani G. Intrasubject tear osmolarity changes with two different types of eyedrops. Optom Vis Sci. 2013 Apr:90(4):372-7.
10. Corrales RM, Luo L, Chang EY, Pflugfelder SC. Effects of osmoprotectants on hyperosmolar stress in cultured human corneal epithelial cells. Cornea. 2008. Jun;27(5):574-9.