DED can be classified into two main types: Aqueous-deficient, characterised by reduced tear production, and evaporative, marked by increased tear film.^1,2

DED can be classified into two main types: Aqueous-deficient, characterised by reduced tear production, and evaporative, marked by increased tear film.^1,2

As the disease progresses, the two types often overlap - referred to as mixed mechanism disease or hybrid DED. Evaporative DED is more common than aqueous-deficient DED. This mixed aetiology affects between 30% and 70% of patients.^2,3,4

Meibomian gland dysfunction (MGD) is widely recognised as a leading cause of DED. Symptoms of DED include redness, burning, stinging, a sensation of a foreign body, itching, and sensitivity to light. Some patients also present with neuropathic pain. DED can significantly impair functional vision, particularly during activities like reading, using a computer, or driving.^1,2,3

Factors driving DED

Tear hyperosmolarity and instability are the primary factors driving DED. Tear hyperosmolarity, where the tear fluid has a higher concentration of solutes compared to the surrounding epithelial cells, leads to reduced cell volume and increased solute concentrations.⁴

In aqueous-deficient DED, hyperosmolarity is caused by a decrease in lacrimal gland secretion. For instance, reduced tear production due to age-related lacrimal gland dysfunction is a common example of this condition. In contrast, in evaporative DED, hyperosmolarity results from excessive evaporation of the tear film.⁴

As DED worsens, it may involve a gradual loss of corneal sensitivity, leading to reduced compensatory responses, which further exacerbate the condition. In advancing aqueous-deficient DED, the tear film's lipid layer spreads less effectively, a process worsened by diminished reflex tearing.⁴

Research suggests that this reduced lipid layer spreading may increase evaporation, transforming aqueous-deficient DED into mixed DED. Similarly, in evaporative DED, corneal damage and reduced sensory drive to the lacrimal gland can lead to increased tear hyperosmolarity, evolving the condition into mixed DED.⁴

How is DED treated?

Treating DED is complex due to its multifactorial nature and the time required for effective treatment. Each patient's management plan will vary based on the underlying causes, disease severity, and external factors such as environmental conditions or medications.⁴

After diagnosing DED and distinguishing between aqueous-deficient, evaporative, or mixed DED, the clinician's first responsibility is to educate the patient about the condition, including treatment expectations and timelines.⁴

For aqueous-deficient cases, treatment often begins with artificial tears, progressing to non-preservative solutions or higher-viscosity gels. Artificial tears are a cornerstone in managing dry eye disease and play a role in treating corneal abrasions, promoting wound healing, managing pain and inflammation, addressing conjunctivitis and keratitis, rewetting and removing contact lenses, and aiding in foreign body removal.^4,5

Punctal occlusion may be considered for tear retention, especially in specific cases, though it remains debated in inflammatory conditions. For evaporative cases, lid hygiene, warm compresses, and targeted therapies like antibiotics or anti-inflammatory treatments are also recommended.⁴

Punctal occlusion can help retain tears and is especially useful for DED resulting from refractive surgery, contact lens wear, systemic diseases, or a rapid tear film break-up time. It is debated whether punctal plugs are suitable for patients with an inflammatory component, as they may prolong inflammation.⁴

For those in adverse environments, moisture chamber goggles and humidifiers can reduce tear evaporation. In severe cases or when other treatments fail, autologous or allogeneic serums may be considered. Oral secretagogues might also be an option for patients with aqueous-deficient or mixed DED, particularly if associated with Sjögren’s syndrome.⁴

What about mixed DED?

Artificial tears are available in both single-use and multi-dose formulations. Single-use units are preservative-free, while multi-dose packages typically contain preservatives to extend shelf life and prevent microbial growth. Newer formulations come in specially designed bottles that prevent micro-organism entry.^5,6

Preservatives like benzalkonium chloride (BAK) are associated with potential toxicity to the ocular surface, particularly with long-term use. BAK can cause damage to corneal and conjunctival cells, delay corneal healing, and destabilise the tear film, leading to worsening symptoms.⁶

Preservative-containing artificial tears are generally suitable for patients who require occasional use and do not have a history of ocular surface disease. Preservative-free artificial tears are recommended for patients with severe DED who need frequent application throughout the day.⁶

They are also preferred for individuals with known sensitivity to preservatives or existing ocular surface conditions, such as glaucoma or post-surgical recovery.⁶

Preservative-free options significantly reduce the risk of preservative-induced ocular toxicity. Advances in multi-dose dispensers with unidirectional valves allow for preservative-free formulations while minimising the risk of contamination.⁶

For patients with mixed DED, preservative-free propylene glycol-hydroxypropyl guar (PG-HPG) nano-emulsion lubricant eye drops is a viable option, according to Silverstein et al.⁷

PG-HPG features propylene glycol as the primary demulcent and employs a higher concentration of HPG gelling technology compared to previous formulations. This updated formulation includes a lipid excipient in nano-sized droplets that improves lipid coverage and provides a more translucent appearance.⁷

Upon application, the HPG/borate meshwork forms a protective, viscoelastic barrier on the ocular surface. As the pH normalises and sorbitol dilutes, this meshwork cross-links to maintain the barrier and slowly release lipids into the tear film.⁷

The inclusion of anionic phospholipid dimyristoyl phosphatidylglycerol enhances lipid stability by merging with existing lipids to address gaps caused by MGD. This nano-emulsion helps restore the tear film structure, prevent dry eye exacerbations, and support a healthier ocular surface.⁷

How effective are PG-HPG nano-emulsion lubricant eye drops?

In their phase IV study, Silverstein et al, evaluated the effectiveness of a single drop of PG-HPG nano-emulsion in relieving symptoms of DED. This formulation is now also available in preserved and multi-dose preservative-free options.⁷

Results showed significant symptom relief, with median score reductions of -1.0 at zero hours, -2 at four hours, and -2 at eight hours post-application. Both aqueous-deficient and evaporative subtypes experienced a median symptom reduction of -2 at eight hours, while the mixed subtype had a reduction of -1.7

Median soothing sensation scores were 3 at zero hours, 4 at four hours, and 3.5 at eight hours. Tolerability was high across all DED subtypes, with most patients reporting low scores for burning, stinging, and foreign body sensations.⁷

The team concluded that PG-HPG nano-emulsion provides immediate and sustained symptom relief for up to eight hours in DED patients, with excellent tolerability.⁷

Rangarajan and Ketelson evaluated the effects of PG-HPG nano-emulsion on corneal epithelium models. Results demonstrated that PG-HPG nano-emulsion significantly improved moisture retention and hydration protection compared to a polyethylene glycol/propylene glycol formulation and a vehicle control, with a hydration protection of 39.5% and surface hydration retention of 32.6% after desiccation.⁸

Additionally, cell recovery from BAK damage was faster with PG-HPG nano-emulsion, and corneal permeability was reduced, indicating enhanced barrier function. The formulation also exhibited superior lubricity and elastic filament strength. PG-HPG nano-emulsion outperformed the other formulation and vehicle in all assessments.⁸

Springs conducted a review of the safety and efficacy of PG-HPG nano-emulsion in treating DED. Results indicated that PG-HPG nano-emulsion exhibited viscoelastic properties optimised for ocular pH, mimicking the tear film elasticity and viscosity found in individuals without DED.⁹

Additionally, the formulation effectively reduced corneal and conjunctival staining, improved tear film stability, and maintained best-corrected visual acuity over time, with a low coefficient of friction in vitro.⁹

Conclusion

The PG-HPG nano-emulsion has shown significant efficacy in treating mixed DED. Studies have demonstrated its ability to provide immediate and sustained symptom relief for both aqueous-deficient and evaporative subtypes, with notable improvements in moisture retention, hydration protection, and barrier function. The formulation also reduced corneal and conjunctival staining, improved tear film stability, and maintained visual acuity. Overall, PG-HPG nano-emulsion stands out as an effective treatment option for mixed DED, offering enhanced protection and sustained relief with excellent tolerability.

References

1. Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int, 2015.
2. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II Definition and Classification Report. Ocul Surf, 2017.
3. McCann P, Kruoch Z, Qureshi R, et al. Effectiveness of interventions for dry eye: a protocol for an overview of systematic reviews. BMJ Open, 2022.
4. Kwak DH. Mixed DED: A Chimera in Your Chair What is it and how can you diagnose and manage patients who have it? Review of Optometry, 2019.
5. Semp DA, Beeson D, Sheppard AL, Dutta D, Wolffsohn JS. Artificial Tears: A Systematic Review. Clin Optom (Auckl), 2023.
6. Barabino S, Benitez-Del-Castillo JM, Fuchsluger T, et al. Dry eye disease treatment: the role of tear substitutes, their future, and an updated classification. European Review for Medical and Pharmacological Sciences, 2020.
7. Silverstein S, Yeu E, Tauber J, et al. Symptom Relief Following a Single Dose of Propylene Glycol-Hydroxypropyl Guar Nanoemulsionin Patients with Dry Eye Disease: A Phase IV, Multicenter Trial. Clin Ophthalmol, 2020.
8. Rangarajan R, Ketelson H. Preclinical evaluation of a new hydroxypropyl-guar phospholipid nano emulsion-based artificial tear formulation in models of corneal epithelium. J Oculi Pharmacol Ther, 2019.
9. Springs CL. Novel hydroxypropyl-guar gellable lubricant eye drops for treatment of dry eye. Adv Ther, 2010.

Document Number : ZA-VC-2400008

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