With all the hyaluronic acid eyedrops available, it can become a daunting task trying to determine which of these specific products are the right fit for your patient’s dry eye needs. Here is an overview of what hyaluronic acid eyedrops are all about and what is currently offered over-the-counter.
First, a quick reminder of the basics. TFOS DEWS II defines dry eye disease (DED) as a multi-factorial disease characterized by the loss of homeostasis of the tear film by tear film instability, hyperosmolarity, and ocular surface inflammation. In order to supplement and replace our natural tear film, preservative-free artificial tears are the most common initial topical therapy for DED.
Why are preservative free eyedrops strongly recommended over preservative containing eyedrops?
For dry eye relief, eyedrops are prescribed to be used regularly for comfort and to enhance visual performance. Some of the preservatives in these eyedrops can become intolerable after long term use because they cause damage to cell tissues and destroy the natural tear film. Most preservative containing eyedrops recommend discarding the bottle after only 30 days from opening, while preservative free eyedrops can last up to 3, 6 and even 12 months from opening due to the bottle keeping the drops clean by using a separate compartment to prevent back-flow. This function significantly makes the drops last longer while simultaneously providing less irritating and safer drops for the eyes. Overall, choosing a preservative free eyedrop will help with your patients’ visual comfort, especially with increasing computer strain as we work from home.
Why are buffers important in eyedrops?
Buffer systems mimic the natural tear film and help maintain the pH of the eyedrop to help maintain the composition of the solution in order to extend the shelf life. The average physiological pH of the tear film is 7.4. Phosphate buffers are considered safe buffers and are the most widely used since it has excellent capabilities at keeping pH levels neutral and exists naturally on the surface of the eye. Newer eye drops are starting to implement citrate or borate to maintain a safe pH solution for the eyes because these buffer systems are the least cytotoxic to cellular tissues and also show high cell viability.1
What is the deal with Hyaluronic acid (HA)?
HA is a natural occurring glycosaminoglycan and sodium hyaluronate is the salt form of HA, which is a more stable compound for topical application. It is commonly found in dry eyedrops because it prevents dehydration by binding to water molecules, and is highly biocompatible as it is naturally found in high concentrations in the eye. Clinical studies have shown that HA protects corneal epithelial damage via promoting corneal epithelial wound healing by stimulating epithelial migration, thus improving overall optical quality.1
How does HA compare to other common artificial tear ingredients that are known to help alleviate DED?
Carboxymethylcellulose (CMC) and hydroxypropyl methylcellulose (HPMC) are common polymers that are used to mimic mucins to protect inflamed tissues and increase viscosity, and emollients are common agents used to protect evaporation by sealing in existing moisture. In vitro studies have showed that HA preformed slightly better than CMC, HPMC, and emollients at retaining water and protecting corneal epithelial cells. HA can not only retain water but also slowly releases it to help maintain hydration overtime when compared to CMC, HPMC, and emollients.2
Which HA concentration is better? HA 0.1%, 0.18% or 0.3%?
The more HA, the better! A 2018 study revealed that all concentrations helped improve overall DED symptoms. The details of the study show that the group with 0.3% HA showed the longest Tear Break Up Time (TBUT) over the 0.18% and 0.1% groups after 21 days. Remember that TBUT measures tear film instability by measuring the time it takes for the tears to first break up on the surface of the eye from the first complete blink. The study concluded that 0.3% HA is more effective than 0.18% and 0.1% in improving tear film stability, increasing conjunctival goblet cell density, and in protecting corneal epithelial cell damage.3
Keep in mind that eyedrops with HA can have different viscosities due to the different concentrations of hyaluronate. The higher the concentration of HA, the more viscous the eyedrop will be. The viscosity of eyedrops is important to consider because eyedrops have a limited time in contact with the eye before it gets washed away, this means the time of direct contact is short for absorption. Patients will need to constantly reapply and the number of drops to apply becomes difficult to recommend for the severity of the dry eye causing overall compliance issues. Ocular contact time can be enhanced by increasing the viscosity of the eyedrops and that is why higher viscosity drops are important because they tend to allow for higher bioavailability of the drug.3
Other factors that should be considered when HA% alone may not be enough
Molecular weight: Long vs short chain HA:
High quality HA depends on the molecular weight, which is related to the length of the chain of each molecule. The concentration of HA does not always reflect the molecular weight. It is possible to have a high molecular weight HA at a lower concentration in a formulation, which can outperform one with a higher concentration of HA. High molecular weight HA is more cohesive since it will take more time to breakdown than lower molecular weight HA. It can sit on the ocular surface longer to draw in moisture and continually hydrate the cornea and promote regenerative healing. Low molecular weight HA is more dispersive due to its light weight, which can bind with other molecules and encourage an inflammatory response.4 Examples of high molecular weight HA (>1000 kDa) eyedrops include Hylo, Hylo Gel, and Hylo Dual.
It is already known that hyperosmolarity of the tear film contributes to DED, thus clinical studies have shown that hypotonic solutions offer greater improvements over isotonic solutions. A 2008 study showed that by reducing the osmolarity of the tear film, the hypotonic solution not only improved the characteristics of the tear film and the vitality of the epithelial cells of the cornea and conjunctiva but also proved to be efficacious in reducing dry eye symptoms. The study compared preservative free 0.4% HA drops at 300 mOsm/L and another at 150 mOsm/L in dry eye patients. At the end of the study, 60.7% of the patients declared that they preferred the hypotonic solution, only 10.7% preferred the isotonic solution, and the remaining 28.6% did not notice any difference between the two treatments. Examples of hypotonic HA formulations includes Hyabak and Thealoz Duo eyedrops. Hylo eyedrops are approximately 280 mOsm/L, making them slightly hypotonic.5
Trehalose (TH) and its association with HA:
TH is a natural disaccharide that is a bioprotectant and an osmoprotectant. It is thought to protect corneal and conjunctival cells from desiccation through a number of theories that includes encasing and protecting proteins, keeping water out of proteins by becoming more compact, or replacing water, and thus increasing its stability. TFOS DEWS II recognizes trehalose as an effective ingredient with HA in moderate to severe dry eye. A study from 2016 found that HA-TH eyedrops are safe and offers greater patient satisfaction than existing HA only eyedrops, particularly for the first month of treatment, in patients with moderate to severe dry eye disease. The phase III, multicenter study included 105 adults with moderate to severe dry eye disease receiving either HA-TH or HA only eyedrops three to six times per day for 84 days. Researchers utilized a questionnaire on dry eye symptoms, Schirmer’s test, TBUT, and conjunctival hyperemia on day 35 and day 84. It was found that there was a greater effect in the HA-TH group at days 35 and 84. The results for HA-TH were favorable in stinging, itching and blurred vision, as well.6
Through numerous clinical studies, choosing preservative free HA eyedrops has been shown to be beneficial for the treatment of many patients’ moderate to severe dry eye symptoms. Hopefully, by considering other factors such as HA concentration, molecular weight, osmolarity, and other added ingredients, you can better clinically determine which specific preservative free HA eyedrop products will best fit your patients individualized dry eye treatment plan.
|Preservative-Free Eye Drops||Key Ingredients||Bottle Size||Number of Eyedrops||Expiry After Opening|
|Hyabak||0.15% sodium hyaluronate: natural hypotonic solution, actinoquinol (agent with anti-UVB properties)||10 mL||300||3 months|
|Thealoz DUO||0.15% sodium hyaluronate: natural hypotonic solution, 3% trehalose: natural osmoprotection||10 mL||300||3 months|
|HYLO||0.10% sodium hyaluronate||10 mL||300||6 months|
|HYLO DUAL||0.05% sodium hyaluronate, 2% ectoine (acts as an osmolyte), a borate buffer, and water||10 mL||300||6 months|
|HYLO GEL||0.20% sodium hyaluronate, a citrate buffer, sorbitol, and water||10 mL||300||6 months|
|iDROP PUR||0.18% viscoadaptive hyaluronan (hyaluronic acid and glycerin)||10 mL||240||12 months|
|iDROP GEL||0.30% hyaluronic acid with added glycerin||10 mL||240||12 months|
|iDROP MGD||0.20% hyaluronic acid with added glycerin, osmoprotectants||10 mL||240||12 months|
|Systane Hydration PF||0.15% hyaluronic acid, 0.4% polyethylene glycol 400, 0.3% propylene glycol||Single use vials: 30 x 0.7mL = 21mL||315||30 days if recapped|
|HydraSense||0.15% hyaluronic acid, sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water||10 mL||200||12 months|
|HydraSense Advanced||0.15% hyaluronic acid, Provitamin B5, sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water||10 mL||200||12 months|
|HydraSense Night Therapy||0.30% hyaluronic acid, sodium chloride, sodium citrate dihydrate, citric acid anhydrous, water||10 mL||200||12 months|
- HA: No Laughing Matter (2018): https://www.reviewofoptometry.com/article/ha-no-laughing-matter
- Comparison of HA & CMC (2018): https://www.healio.com/ophthalmology/cornea-external-disease/news/online/%7Beac8107e-2636-45fc-b2bb-295b9b2471ae%7D/two-dry-eye-drop-formulations-compared
- Comparison of 0.1%, 0.18%, and 0.3% Hyaluronic Acid Eye Drops in the Treatment of Dry Eye (2018): https://www.liebertpub.com/doi/full/10.1089/jop.2018.0032
- Hyaluronic Acid Yes Size Does Matter (2015): http://barefacedtruth.com/2015/03/31/hyaluronic-acid-yes-size-does-matter/
- Optimization of hyaluronan-based eye drop formulations (2016): https://www.sciencedirect.com/science/article/pii/S0144861716309043
- A Randomized, Controlled Study of the Efficacy and Safety of a New Eyedrop Formulation for Moderate to Severe Dry Eye Syndrome (2016): https://journals.sagepub.com/doi/full/10.5301/ejo.5000836