That’s some nerve! Ocular drug delivery and dry eye
There’s more to dry eye treatment than eye drops.
Image credit: AdobeStock/krissikunterbunt
Eye care’s earliest stabs at treating ocular surface disease (OSD; also referred to as dysfunctional tear film, dry eye disease [DED] or syndrome, lacrimal keratoconjunctivitis, keratitis sicca, meibomian gland [MG] dysfunction, etc) primarily aimed to add eye elements that were lacking in the tear film to the surface of the eye or to reduce tear film instability. The tear film was supplemented via solutions, gels, suspensions, ointments, emulsions, and/or dissolving conjunctival cul-de-sac inserts. As we became sophisticated in our experience and knowledge of the eye surface and tear production, we learned that tempering inflammation was paramount to managing disease signs and symptoms. The molecules that modulate inflammation are also added to a variety of vehicles that are dripped onto the eye surface. Autologous serum and, more recently, recombinant human nerve growth factors are also instilled topically in the eye. Additionally, more than a dozen dry eye pipeline drugs are stated to be delivered via local, topical application.
Although topical eye drops are the most accepted and widely used formulations in ocular drug delivery for DED and other eye diseases, they are not without limitations, including a generally low bioavailability that can be difficult to instill.1 Commonly available eye drops are formulated with excipients and/or preservatives that may be deleterious to the ocular surface and exacerbate or compound the clinical spectrum of DED. More importantly, these ophthalmic preparations modulate the tears’ or eye’s response to poor-quality tears in some way. They are not a replacement for the exquisitely complex natural tear film.
Of course, the integrity of the lipid barrier seal of the tears to the surface of the eye is paramount to tear quality and preservation. Unique to Rx topical formulations is the single-ingredient perfluorohexyloctane ophthalmic solution (Miebo, Bausch + Lomb) that, once instilled, forms a protective surface layer to the tears. Tactics to enhance MG lipid production and delivery, apart from oils added to topical preparations, include MG warming and mechanical expression (pumping, massaging, squeezing, etc) and nutraceuticals. For instance, γ-linolenic acid, a unique ω-6 fatty acid, may positively modify the turbidity and density of the lipid of MG secretion.2
Ideally, our goal would be to prompt the secretion of the very complex natural tear. Stimulation of the trigeminal nerve pathway to meet this outcome may be the answer.
The parasympathetic nervous system via the trigeminal parasympathetic pathway (TPP) controls tear film homeostasis by innervating the lacrimal functional unit, which includes the cornea, conjunctiva, lacrimal glands, MGs, and goblet cells.3 The TPP, or nasolacrimal reflex, accounts for approximately 33% of basal tear film production from stimulation of the anterior ethmoidal nerve in the nose.4 Increasing endogenous tear film production via neuroactivation of the nasolacrimal reflex is a therapeutic approach to treating DED. Stimulation of the lacrimal functional unit produces tears with natural proportions of oil, mucin, aqueous, proteins, and other beneficial components. Normal tear film consists of aqueous fluid, electrolytes, and an array of mucin glycoproteins, lipids, and proteins (including wound-healing, innate defense/antimicrobial, and anti-inflammatory/antioxidant factors) that enable it to perform its basic functions of lubricating and protecting the ocular surface.5
Multiple mechanisms to stimulate the TPP have been explored. For example, TrueTear (Allergan; now off the market)6 was an intranasal neurostimulator that used randomly generated microelectrical impulses to drive the reaction. The iTEAR device (Olympic Ophthalmics) stimulates the nasal nerve externally via a sonic frequency applied to the soft tissue fold on the outside of the nose to increase tear production.7 Varenicline (Tyrvaya; Oyster Point Pharma) is a nasal spray believed to bind to trigeminal nerve endings in the nasal cavity to activate the TPP, resulting in increased production of basal tear film.8
Of interest, ophthalmologist Barry Linder, MD, MS, has developed an instrument for the management of OSD. This facial masklike device, which is under investigation but currently not approved or cleared by the FDA, is designed for both in-office use and at-home, patient on-demand use.9 Built to comfortably conform to the ocular adnexa, this unit (Eye Lipid Mobilizer; ELM; Eyedetec Medical) includes the integration of novel mechanisms, such as heat and vibration, to induce shear thinning of oils in the eyelid glands, thereby safeguarding the tear film and preventing evaporation.9 Additionally, the ELM incorporates neuromodulation (via specific amplitude and frequency of external device vibration that extends nasally to the bridge of the nose) to stimulate active expression of liquefied meibum offering a comprehensive treatment approach.9
Remember that we have access to alternative and additive treatment modalities in our management of DED. Think outside the drop!
References
1. Agarwal P, Craig JP, Rupenthal ID. Formulation considerations for the management of dry eye disease. Pharmaceutics. 2021;13(2):207. doi:10.3390/pharmaceutics13020207
2. Pinna A, Piccinini P, Carta F. Effect of oral linoleic and gamma-linoleic acid on meibomian gland dysfunction. Cornea. 2007;26(3):260-264. doi:10.1097/ICO.0b013e318033d79b
3. Stern ME, Gao J, Siemasko KF, Beuerman RW, Pflugfelder SC. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. 2004;78(3):409-416. doi:10.1016/j.exer.2003.09.003
4. Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. Cornea. 1997;16(6):645-648.
5. Pflugfelder SC, Stern ME. Biological functions of tear film. Exp Eye Res. 2020;197:108115. doi:10.1016/j.exer.2020.108115
6. Crabbe J. Allergan, now integrated with AbbVie, discontinues sales of TrueTear device for dry eye. Market Scope. July 17, 2020. Accessed September 12, 2024. https://www.market-scope.com/pages/news/4658/allergan-now-integrated-with-abbvie-discontinues-sales-of-truetear-device-for-dry-eye
7. Announcing FDA clearance and availability of the next generation iTEAR 100. Olympic Ophthalmics. Accessed September 12, 2024. https://olympicophthalmics.com/itear-100/
8. It’s not another drop with the only nasal spray for dry eye, real tears are my relief. Tyrvaya. Accessed September 12, 2024. https://www.tyrvaya.com/
9. Eye news media. News release. Eyedetec. April 22, 2024. Accessed July 12, 2024.https://www.eyedetec.com/eye-news-media/
