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Subspecialties Cornea / Ocular Surface

Multi-dose Preservative-free Lubricant Eye Drops for Dry Eye Disease


 According to the Tear Film and Ocular Surface Society Dry Eyes Workshop II (TFOS DEWS II), the global prevalence of DED is 5–50 percent, with a higher predisposition in women and elderly individuals (1).  Patients with DED can experience several symptoms, including ocular irritation, itching, redness, mucous discharge, foreign body sensation, photosensitivity, and visual blurring (2, 3), which can affect common daily activities and exert a substantial economic burden on patients and society (4, 5).

To delay DED progression, early intervention and management is recommended (6). DED management aims to minimize evaporative tear loss, stabilize the tear film, protect the ocular surface, repair ocular surface damage, increase lubrication, enhance glandular secretion, and curb inflammation. The TFOS DEWS II report recommends step-wise management and considers artificial tears as a mainstay of DED therapy (7).

First-line fakes – artificial tears

Artificial tears are generally considered the first-line treatment for DED (3, 8). Artificial tear supplements are buffered solutions that contain electrolytes, surfactants, one or more viscosity agents or lubricants, and may or may not contain preservatives (7). Artificial tears typically target one or more layers of the tear film and have shown to improve visual acuity, contrast sensitivity, corneal epithelial regularity, tear film stability, and reduce ocular surface stress (9, 10, 11). Artificial tears also minimize desiccation and cell death by providing moisture and lubrication to the ocular surface (7, 12). Reported side effects of some artificial tear products include blurred vision, foreign body sensation, and ocular discomfort (7, 13).

Preservatives used in artificial tear products protect the product from microbial growth during normal conditions of storage and repeated withdrawal of individual doses. Moreover, preservatives allow a margin of safety if the product is inadvertently contaminated.

Chronic exposure to preservatives has been associated with side effects, predominantly toxicity and adverse changes to the ocular surface, resulting in disease progression, conjunctival scarring, exacerbation of ocular inflammation, decrease in tear break-up time, ocular tissue irritation and destabilization of tear film, burning and stinging sensations, foreign body sensation, and deterioration of vision (7, 14, 15, 16, 17). To avoid side effects associated with long-term exposure, newer gentler preservative variants, such as sodium chlorite (Purite, OcuPure), sodium perborate (GenAqua), polyquaternium-1 (Polyquad) have shown lower consequences on the ocular surface (7). However, studies have reported negative effects on the ocular surface following the use of sodium chlorite and sodium perborate (18). And so we look towards preservative-free (PF) eye drops as an important alternative.

The pros of preservative-free formulations

Preservative-free formulations are necessary for patients with severe dry eye, ocular surface disease, and impaired lacrimal gland secretion or for patients on multiple preserved topical medications for chronic eye disease (7, 19). But other patient specific factors can make PF formulations a better alternative (3, 7, 15, 19, 20, 21, 22):

  • History of allergy to preservatives
  • Contact lens wearers
  • High frequency of eye drop instillation
  • Longer duration of treatment
  • Exposure to desiccated environment
  • Women and elderly individuals
  • Asian ethnicity
  • Exposure to electronic displays for both work and leisure.
  • Severe dry eyes
  • Receiving multiple preserved drugs

Preservative-free eye drops cause the least disruption to the ocular surface at both clinical and cellular levels (23, 24).  Additionally, PF formulations significantly improve tear ferning patterns, symptoms, and signs of DED after cataract surgery and may result in better adherence and persistence compared to preserved formulations (25, 26).

Previously published studies on switching to PF drops have shown ameliorated DED symptoms as well as improved clinical signs. In a large switch study including the majority of patients (81 percent) with severe DED and habitual users of preserved artificial tears, a minimum of three-weeks switching to PF eye drops reduced Ocular Surface Disease Index (OSDI) scores in 97 percent of the patients and reduced the prevalence of superficial punctate keratitis (27). Another case-controlled study reported significant improvements in symptoms, tear film break-up time, and Schirmer I scores in patients with severe DED when compared with preservative-containing eye drops (28). Moreover, tears from the PF group showed a significant decrease in inflammatory markers and significant increase in antioxidant activity compared with the group taking preserved eye drops.

Epidemiologic surveys carried out in patients with glaucoma reported that PF eye drops were less associated with ocular symptoms and signs of irritation than preserved eye drops (29). Another switch study reported an increase in tear film thickness, breakup time, and an improvement of Dry Eye–Related Quality-of-Life Score in patients with glaucoma or ocular hypertension who were taking preservative-containing eye drops for at least six months (20).

Commercially available PF eye drops include Systane (Alcon), Refresh (Allergan), Soothe (Bausch and Lomb), and Hylo-fresh (Scope Ophthalmics) – and their safety and efficacy is explained in detail elsewhere (23).

Unit-dose versus multi-dose

To deliver sterile drops without preservatives, packaging changes are necessary; PF preparations are typically supplied in a unit dose format (30). However, unit dose vials are not an ideal solution – less dexterous individuals (for example, elderly patients) may have difficulty opening the rigid plastic (17), inappropriate handling (or inadequate closure) can lead to contamination (31), the additional packaging makes them bulky to store, less convenient to carry, and also generates more plastic waste (32) – and all of these issues are exacerbated by the chronic nature of the condition and the high frequency of instillation. Multi-dose PF (MDPFs) could help with both functionality, storage, and transport, while ensuring a sterile formulation for long-term treatment (32). So far, a number of different technologies have been used in MPDF systems (see Table 1).

Table 1. Technologies used in multi-dose PF (MDPF) dispensation in lubricant eye drops. Abbreviations: FDA, Food and Drug Administration; OSD, ophthalmic squeeze dispenser; PF, preservative-free (33–39)

Artificial tears are considered the mainstay of dry eye therapy. However, chronic exposure to preservatives present in eye drops can result in exacerbation of dry eye symptoms. To mitigate these side effects, PF formulations in unit dose format are available to prevent the potential risk of contamination during instillation or usage. However, unit dose vials are also associated with several drawbacks. The latest addition of MDPF dosing of lubricant eye drops ensures easy instillation and storage convenience.However, adequate evidence is lacking in terms of the susceptibility to microbial ingress or contamination when used for a longer time period.


Medical writing support was provided by Sulekha Shafeeq, PharmD, and Ashwini Atre, PhD, from Indegene Pvt. Ltd. Bangalore, India.

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About the Author
Sruthi Srinivasan, Paul Shannon

Sruthi Srinivasan and Paul Shannon work for Alcon research

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