Propylene Glycol and Hydroxypropyl Guar Nanoemulsion - Safe and Effective in Management of Dry Eye Disease

DED can be classified as aqueous deficient dry eye (ADDE), evaporative dry eye (EDE), and mixed DED. ADDE is due to tear underproduction by the lacrimal glands. EDE can occur due to causes related to either lid (meibomian gland dysfunction [MGD] or blink-related) or ocular surface (mucin deficiency and contact lens wear), resulting in abnormal lipid secretion, tear film instability, and excessive evaporation of tears. Although EDE is considered a leading cause of DED, ADDE can occur without obvious signs of EDE and vice versa.

Further, iatrogenic DED could be caused by topical or systemic drugs, contact lens wear, and ophthalmic surgical/non-surgical procedures. Goblet cells, which produce mucins and contribute to the stability of the tear film and immune defenses, are extremely sensitive to toxic/inflammatory stress and are reduced in density after exposure to iatrogenic factors. Owing to the multifactorial nature of DED, medications that can target multiple underlying pathologies simultaneously are desirable.

Treatment goal for DED is to restore ocular surface and tear film homeostasis. Current treatment options in the management of DED include artificial tears or ocular lubricants, nutraceuticals, anti-inflammatory agents, tear stimulants, autologous serum, antibiotics, and other therapies (eg, physical treatments such as warm compresses, complementary medicines such as herbal products, punctal occlusion, and surgical approaches).

Artificial Tears

Artificial tears, which substitute or supplement the natural tear film, are the first line option in the management of DED. Artificial tears improve symptoms (burning, irritation, and/or discomfort), and provide temporary relief of dryness of the eye, but have not been shown to treat pathophysiology of DED. Ideal artificial tears should spread uniformly and evenly, minimize friction during blinks, have minimal visual disturbance upon instillation, be safe/ convenient to use, and effectively improve the signs/symptoms of DED.

Artificial tears are formulated with polymeric lubricants, demulcents, buffering agents (compatible with ocular pH of approximately 7.5), electrolytes, osmolality adjusting excipients, and surfactants, with/without preservatives. Most of artificial tears are formulated to supplement either lipid layer or aqueous layer of the tear film. However, some eye drops are formulated as emulsions, which contain aqueous lubricants (such as hydroxypropyl guar [HPG], polyethylene glycol [PEG], and propylene glycol [PG]) and lipid ingredients (such as phospholipid and mineral oil). Lipid-based artificial tears have been shown to stabilize the tear film lipid layer, reduce tear evaporation, and improve the signs of MGD and EDE.

One of the major challenges with eye drops is low retention time. To increase the retention time, viscosity enhancing agents such as hyaluronic acid (HA) and carboxymethyl cellulose (CMC) are incorporated in eye drops; these agents also exhibit muco-mimetic properties and reduce desiccation by forming a protective layer on the ocular surface. However, eye drops with high viscosity may cause transient visual disturbances (blurred vision) and also result in debris, leading to intolerance and non-compliance. Thus, to overcome low ocular retention, in situ gelling chemistry is used; this is achieved through HPG, a natural polysaccharide, that forms a viscoelastic gel at ocular pH through cross-linking.

HPG forms the backbone in artificial tears of the SystaneTM family (Alcon Laboratories, Inc., Fort Worth, TX, USA), which are indicated for the temporary relief of dry eye symptoms (such as burning and irritation) and ocular surface protection in patients with DED. Artificial tears of the SystaneTM family include nonlipid-based (PEG/PG-HPG lubricant eye drop [SystaneTM Original], PEG/PG-HPG-sorbitol lubricant eye drop [SystaneTM Ultra] and PEG/PG-HPG/sodium hyaluronate (HA)-sorbitol lubricant eye drop [SystaneTM Hydration]) as well as lipid-based (PG-HPG microemulsion lubricant eye drop [SystaneTM Balance] and PG-HPG nanoemulsion lubricant eye drop [SystaneTM Complete]) formulations.

In this review, Srinivasan and Williams presented the formulation components, mechanisms of action, and the summary of literature evidence of PG-HPG nanoemulsion lubricant eye drop (SystaneTM Complete, Alcon Laboratories, Inc., Fort Worth, TX, USA) that is indicated for temporary relief of symptoms of burning and irritation in DED.

PG-HPG Nanoemulsion Lubricant Eye Drops

Craig et al demonstrated the treatment of DED according to disease subtype and severity. In a multicenter, double-masked, parallel group, randomized controlled trial, 99 participants (mean age, 44±16 years; 64% female) with DED were enrolled. Participants instilled either lipid-based PG-HPG nanoemulsion drops (SystaneTM Complete) or nonlipid-based aqueous drops (SystaneTM Ultra) ≥4 times daily for 6 months; dry eye symptomology, and tear film and ocular surface characteristics were assessed.49 Both treatments demonstrated sustained reduction in DED symptoms (Ocular Surface Disease Index [OSDI], Dry Eye Questionnaire-5 [DEQ-5], and Symptom Assessment Questionnaire iN Dry Eye [SANDE] scores) from Day 30 onwards (all p≤0.01) and decreased superior lid wiper epitheliopathy grades from Day 60 onwards (all p≤0.01).

Further, non-invasive tear film breakup time (NITBUT), and sodium fluorescein and lissamine green staining scores consistently improved from Day 120 onwards in both groups (all p<0.05).49 Tear film lipid layer grades increased only with PG-HPG nanoemulsion eye drops (from Day 90 onwards); with significantly greater improvement in patients with low lipid layer thickness at baseline (lipid layer grade ≤3; p=0.01).49 Hence, both lipid-based and non-lipid-based artificial tears provided symptom relief within a month.49 Improvements in the tear film stability and ocular surface characteristics were slower than the symptomatic improvements.49 Further, both formulations showed long-term efficacy and a good tolerability profile across DED subtypes; however, improvement in tear film lipid layer grade was observed only with PG-HPG nanoemulsion drops; particularly in subgroup of patients with evaporative DED due to tear lipid insufficiency (with baseline lipid layer grade ><0.05).

Tear film lipid layer grades increased only with PG-HPG nanoemulsion eye drops (from Day 90 onwards); with significantly greater improvement in patients with low lipid layer thickness at baseline (lipid layer grade ≤3; p=0.01). Hence, both lipid-based and non-lipid-based artificial tears provided symptom relief within a month. Improvements in the tear film stability and ocular surface characteristics were slower than the symptomatic improvements. Further, both formulations showed long-term efficacy and a good tolerability profile across DED subtypes; however, improvement in tear film lipid layer grade was observed only with PG-HPG nanoemulsion drops; particularly in subgroup of patients with evaporative DED due to tear lipid insufficiency (with baseline lipid layer grade ≤3).

In a Phase IV, openlabel, single-arm, multicenter trial, patients with DED (N=134; 56.6±14.8 years; 75.4% female) instilled one drop of PGHPG nanoemulsion in each eye, twice daily for 28 days. The instillation of PG-HPG nanoemulsion eye drops increased tear film break-up time (TFBUT) by 1.5±2.8 seconds at 14 days; and the improvement remained consistent through 28 days. It also improved (decreased) ocular discomfort at 14 days (mean±SD change in visual analog scale [VAS] score, −17.3±24.80). Moreover, subgroup analysis of patients with ADDE, EDE, and mixed DED indicated that PG-HPG nanoemulsion was effective and well tolerated in all three types of DED. PG-HPG nanoemulsion improved tear film stability, and signs and symptoms of DED

DED is a multifactorial condition with ADDE, EDE, and mixed etiologies. Artificial tears are the backbone in the management of DED. Lipid-based lubricant eye drops with viscoelastic characteristics are beneficial in providing temporary relief of dry eye symptoms.

PG-HPG and borate components in PG-HPG nanoemulsion lubricant eye drops form a thin viscoelastic layer that prolongs retention of demulcent; thus, provides long-term surface hydration and moisture retention, and ocular surface protection by improving cell barrier functions and cell recovery, and temporary relief of symptoms in DED. Moreover, it provides tear film stability between and during blinks owing to viscoelastic properties of HPG. Further, PG-HPG nanoemulsion formulation helps to optimize ocular surface coverage of lipids that is beneficial in replenishing the tear film lipid layer. Additionally, PG-HPG nanoemulsion lubricant eye drops in the form of multidose preservative-free system (with Novelia® bottles) is effective, convenient, and well tolerated in DED patients who have intolerance to preservatives with long-term eye drop use.

Clinically, PG-HPG nanoemulsion lubricant eye drops have been shown to improve dry eye symptoms, enhance tear film stability, and lipid layer thickness; hence, they help to restore eye surface health and provide symptom relief in patients with DED, regardless of subtypes. Moreover, PG-HPG nanoemulsion relieves ocular dryness and discomfort associated with daily contact lens wear, and in prophylactic treatment of dry eye against adverse environmental conditions.

Conversely, other lipid-based and/or liposome-based lubricant eye drops, shown to mimic tear film composition, provide ocular surface benefits and improve signs of dry eye; however, large-scale controlled clinical studies are required to obtain more robust evidence on the efficacy. With over a demi-decade of usage, PG-HPG nanoemulsion lubricant eye drops are effective, convenient to use, and well tolerated in DED, regardless of its subtypes.

Source: Srinivasan and Williams; Clinical Ophthalmology 2022:16 https://doi.org/10.2147/OPTH.S377960