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Assessing artificial tears

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The molecular structure of hyaluronic acid

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Dr Nicholas Young
BSc(Hons) BOptom PhD(Med) PGCertOcTher
Dry Eye Centre, Heathmont VIC

 

What makes a good artificial tear (AT)? It’s hard to answer this question as most of us who treat dry eye are aware that no single AT is effective for all patients. Many patients appear refractory to all ATs. In some cases, ATs worsen dry eye symptoms.

Comparative studies of ATs are somewhat futile in this context too, as it is difficult to predict how a patient will respond to a given product with variations in their disease severity over time. Successive meta-analyses are also inconclusive on this point,1,2 as is DEWS II (2017 international dry eye workshop) which acknowledged that no two dry eye patients are alike and that no single treatment plan can be effective for all patients.3

Historically, artificial tears (ATs) act as a first-line topical treatment in dry eye. ATs mainly comprise three classes of pharmaceutical: natural cellulose derivatives, (such as carboxymethylcellulose), synthetic polymers (such as PVA and HP-guar)and hyaluronic acid. In their own way, ATs can have a role to play in reducing ocular surface inflammation.

Carboxymethylcellulose (CMC) and hyaluronic acid (HA) are two of the most commonly prescribed and used artificial tears.4 CMC’s anionic cellulose polymer with substituted carboxyl group makes it ‘sticky’ to the ocular surface, enabling greater bio-adhesion and increased tear retention time. In comparison, HA is a glycosaminoglycan with repeating alternating N-acetylglucosamine and glucuronate sequences in linear chains. This structure is viscoelastic and binds water molecules,5 helping to reduce surface dehydration and shear forces during blinking,6,7 effects that indirectly help lessen surface inflammation.

What is hyaluronic acid?

Sodium hyaluronate is a naturally-occurring molecule of the human body, but sodium hyaluronate and hyaluronic acid are different chemicals; the former is a water-soluble salt form of the latter. Although about half the HA in our bodies is found in skin, it was first discovered by Karl Meyer and John Palmer in human vitreous.8 Synthetic HA was patented in 1942 by Endre Balazs for commercial use in baking products, and was originally intended for use as a substitute for egg white.9

The name ‘Healon’ (a highly purified form of HA) was trademarked in 1970 and first used medically in ophthalmic surgery. Today HA has become widely used in ophthalmic surgery, dry eye care and cosmetic medicine to improve skin texture and hydration.10

HA is one of several viscosity enhancers used in ATs. Its ability to retain a significant volume of water11 and its visco-elasticity helps it to maintain corneal surface wettability, reduce tear osmolarity and reduce shear forces associated with blinking and air flow. HA has been shown to improve corneal density of all five layers,12 and suppress specific inflammatory mediators, while up-regulating other protective mediators.13 It is also associated with protection of goblet cell density and a reduction of dry eye associated squamous metaplasia, two characteristics of dry eye.14 Collectively, these properties appear to have stabilising effects on the ocular surface, preventing disease and enhancing epithelial repair processes.15,16

BENEFITS OF HYALURONIC ACID

Tear osmolarity

Excessive tear evaporation and reduced aqueous volume can lead to hyperosmolar tears. These changes cause stress on the ocular surface with resultant corneal and conjunctival cell death, tissue inflammation and a destructive cycle of events.17

Tear osmolarity’s predictive value for dry eye disease was conceptualised from indecision regarding diagnostic criteria for Sjögren’s syndrome, but its experimental origins date from almost 50 years ago. In animal studies, hypo-osmolar electrolyte solutions appear best suited to reducing the effects of dry eye,18 while hypotonic HA is effective in human trials2,19 and may be more effective in lowering tear film osmolarity than carboxymethylcellulose and HP-guar.20

pH balance and phosphate free

The pH of normal tears is 7.4 (tolerance: 6.6–7.8). AT complexity revolves around buffer maintenance of this criterion while ensuring good wettability, lubricity and retention time on the ocular surface. While some ATs use phosphate as a buffer, the use of citrate has been found to be desirable.

Although phosphate buffers in eye-drops are effective, innate corneal calcium can react with phosphate to form calcium phosphate crystals. These have been shown to cause corneal calcification: an accumulation of the insoluble crystals, particularly in severe dry eye and already compromised corneas. In one study, 26 of 59 eye-drops tested had phosphate levels above physiological levels, with very high concentrations being found in three products.21 In some reported cases, affected patients have required corneal transplants.22 Fortunately, the incidence of this adverse response is low; however, given a choice, phosphate-free is more prudent.

Preservative free

Many eye-drops contain the preservative benzalkonium chloride (BAK), a cationic surfactant which disrupts the lipid layer on contact with the eye. It also penetrates the epithelial cell microvilli and goblet cells with consequential cell death. Without clearance of the BAK, cell death allows release of the BAK to affect neighbouring cells;23,24 a single drop of 0.01% BAK is detectable in the epithelial cell layer for up to seven days.25 In addition to cell toxicity, the use of preserved ATs is also associated with allergies in some patients.26 Newer ATs contain neutralising or less-invasive preservatives; however, some of these are also associated with adverse ocular surface effects.27

There are many unpreserved ATs on the market, but only two main delivery systems. Individual-use vials are most common. These are typically used once, prior to disposal.

The alternative is a multi-dose system such as the one used by AFT pharmaceuticals for Hylo-Forte. The ‘COMOD’ (COntinuous MOno Dose multidose) system comprises a pump in a bottle; the solution is contained within the bottle in a sterile flexible bag. By pressing the pump, a drop is expelled from the bag onto the eye. When the pump is released, air pressure is restored in the bottle via a ventilation duct, but not into the bag. The contents of the bag therefore remain sterile.

The active ingredient in Hylo-Forte may also prove useful in patients who use BAK-containing medications for other purposes such as glaucoma treatment, as HA may reduce the toxic effect of benzalkonium chloride.28

Conclusion

Hylo-Forte is one of a number of dry eye products that contribute some significant features and benefits to the choice of AT for our dry eye patients. Apart from the active ingredient 0.2% sodium hyaluronate, the other Hylo-Forte components are citric acid, sodium citrate dehydrate and sorbitol. While we cannot entirely predict the outcome of a treatment, informed choice can help to prevent prescribing errors.

Disclosure

This article was written with the financial support of AFT Pharmaceuticals. 

 

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