La dry eye syndrome (DES-Dry Eye Syndrome) is one of the most widespread ocular surface disorders, afflicting tens of millions of individuals worldwide. The first-line treatment is the administration of artificial tears.
DES is a multifactorial disease of the ocular surface, characterised by a loss of tear film homeostasis, accompanied by ocular symptoms, in which instability and hyperosmolarity of the tear film, inflammation and damage of the ocular surface and neurosensory abnormalities play an aetiological role.
Pathology
Dry eye syndrome or 'dry eye', referred to in medical parlance as 'dry keratoconjunctivitis', is a multifactorial disorder that affects the tear film and ocular surface and results in symptoms of discomfort, visual disturbances, tear film instability and potential damage to the ocular surface. It is accompanied by an increased osmolarity of the tear film and inflammation of the ocular surface.
The tear film
The tear film is a film that covers the corneo-conjunctival surface and forms the interface between the eye and the external environment. It consists of three layers, respectively: lipidic, aqueous and mucous.
The aqueous part of the tear film is the most abundant and contains electrolytes and numerous proteins, including lysozyme with antibacterial properties. It is produced by the main and accessory lacrimal glands.
The tear film performs numerous functions:
- lubricates the eye, creating a smooth surface on the cornea on which the eyelids can slide easily.
- nourishes the cornea, which, being devoid of blood vessels (avascular), receives nutrients and oxygen precisely through the tear film.
- protects the eye from bacterial and viral infections and removes its waste substances
Forms of dry eye
Depending on the causes, two main forms of dry eye can be distinguished: 1) from hyposecretion; 2) from evaporation.
Dry eye from hyposecretion
Hyposecretory forms, in which there is a reduced functioning of the lacrimal glands, include forms related to autoimmune diseases, such as primarily Sjögren's syndrome, but also rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, Wegener's granulomatosis, systemic sclerosis and other connective tissue diseases.
Then there are the hyposecretive 'non-Sjögren' forms of dry eye, the most important of which is age-related.
Dry eye from excess evaporation
Dry eye due to excess evaporation can be classified according to the conditions that cause it, into 'intrinsic' (e.g. in case of Meibomian gland dysfunction or eyelid and orbital abnormalities) and 'extrinsic' (due to contact lens use or topical drugs with preservatives; eye diseases such as allergy and conjunctivitis; vitamin A deficiency).
The main risk factors can be summarised as follows:
1. Age: ageing causes progressive atrophy of the lacrimal glands.
2. Gender: women between 40 and 60 are more affected by dry eye, probably due to the new hormonal balance following the menopause.
3. Use of certain drugs: hormones, immunosuppressants, antihypertensives, antihistamines, antidepressants and others.
4. Climatic-environmental factors: air conditioning, dry climate, cigarette smoke, wind, smog.
5. Prolonged use of computers and television.
6. Nutritional deficiencies: insufficient vitamin A intake.
7. Contact lens wear. The use of all types of contact lenses has been found to result in changes to the ocular surface and tear film. The magnitude of these effects varies depending on the lens material, how they are worn and the characteristics of the wearer. Silicone hydrogel lenses generally cause fewer harmful effects. However, the risk of corneal infection and inflammation remains high, especially in the case of recurrent night-time lens wear. In the case of predominantly daytime use, damage to the ocular surface may also result from the use of certain solutions for daily lens cleaning, to which the eye can be or become particularly sensitive.
In recent years, dry eye, like other eye diseases such as glaucoma and keratoconus, has been associated with oxidative stress. The surface of the eye is also particularly exposed to environmental agents (wind, temperature variations, ultraviolet radiation) and irritants that make it vulnerable to oxidative stress. Mechanical factors such as contact lens wear or eye surgery can also be causes of oxidative stress on the ocular surface.
Symptoms
Patients with dry eye can present a wide variety of symptoms, such as: burning, foreign body sensation, difficulty in opening the eyelids, especially upon waking, blurred vision, photophobia (discomfort from light), pain (in severe cases). These symptoms are often accompanied by clinical signs such as: redness, mucous hypersecretion, suffering of the corneo-conjunctival epithelium.
Diagnosis
Dry eye syndrome is a very common condition, the diagnosis of which can be made using numerous tests, some of which are used to diagnose qualitative changes in the tear film (such as the tear film rupture test), while others measure quantitative tear deficits (such as the Schirmer test).
There is also a test to diagnose dry eye by measuring tear osmolarity: an increase in this parameter indicates dry eye.
Treatment
Although DES does not pose a threat to vision in most patients, visual disturbances associated with low spatial frequency and reduced contrast sensitivity, increased glare, blurred vision and eye fatigue have been frequently reported. In addition to these direct pathological manifestations, DES also tends to impair the physical efficiency, social interaction, health and general well-being of patients, leading to a significant deterioration in quality of life.
First-line treatment
Several therapeutic strategies are often employed simultaneously for the treatment of DES, with artificial tears representing the first line of intervention.
Topically applied aqueous and/or lipid-based artificial tears, together with eyelid hygiene, are, in fact, the mainstay of therapy for DES. The next line of treatment generally involves the administration of medicated topical eye drops containing antibiotics and anti-inflammatory agents, corticosteroids, omega-3 fatty acids or tear secretagogues.
Drug administration
Topical application, being simple and painless, is the preferred route of drug administration for the treatment of ocular surface pathological conditions, as it reduces systemic side effects by localising the drug close to the target site. Moreover, for a number of molecules, it is the only means of achieving effective therapeutic concentrations in the eye, as the blood-aqueous barrier prevents systemically administered drugs from reaching anterior segment tissues. It is therefore not surprising that more than 90% of the ophthalmic formulations currently on the market are topical. However, the efficacy of topically applied formulations is limited by the various protective mechanisms of the eye that reduce the bioavailability of the drug or active ingredient, thus necessitating frequent administration of eye drops for prolonged periods. This dosage is often associated with reduced patient adherence to the treatment protocol, which further limits the effectiveness of the treatment. The concomitant administration of several ophthalmic preparations, as is often necessary to manage DES, can further complicate the treatment regimen and further reduce patient cooperation.
Water- and lipid-based artificial tears
Aqueous-based artificial tears, which are often the first line of treatment for DES, are aqueous, isotonic or hypotonic therapeutic devices that typically work by increasing the aqueous layer and temporarily reducing the osmolarity of the tear fluid. To prolong symptomatic relief, artificial tears are often formulated with macromolecules that create viscosity, such as sodium hyaluronate, polyethylene glycol, carboxymethyl cellulose, polyvinyl alcohol, carbomers and natural gums. In addition to prolonging the pre-corneal residence time, viscosity-enhancing polymers also exhibit muco-mimetic properties and form a protective layer on the ocular surface, reducing surface dryness, friction and epithelial cell death.
Innovative Tears
Among the newer artificial tear formulations currently available on the market, those containing sodium hyaluronate (hyaluronic acid, HA) and/or xanthan gum (xanthan gum, XG) have also shown a synergistic effect on corneal abrasions, which are often characterised by acute ocular pain, and other symptoms of discomfort that negatively affect the quality of life of patients with DES.
DES is often characterised by excessive tear evaporation due to a compromised or absent lipid layer, which is why lipoidal artificial tears are sometimes used to replenish the lipid layer of the tear film, improving its stability and reducing evaporation of the underlying aqueous phase. In some conditions, a significant improvement in tear volume has been reported after the administration of lipoidal artificial tears compared to the use of water-based ones, however, the concomitant use of both formulations leads to an even more rapid improvement in the clinical signs of DES.
Conclusions
Due to the multifactorial nature and tendency of DES to become chronic, the most desirable formulations are those that can simultaneously act on the underlying pathologies: combination formulas, which lubricate the ocular surface to provide symptomatic relief while delivering therapeutic agents to the eye, which do not contain preservatives, also reducing the washout effect and exposure to excipients.
Treatment
Although DES does not pose a threat to vision in most patients, visual disturbances associated with low spatial frequency and reduced contrast sensitivity, increased glare, blurred vision and eye fatigue have been frequently reported. In addition to these direct pathological manifestations, DES also tends to impair the physical efficiency, social interaction, health and general well-being of patients, leading to a significant deterioration in quality of life.
First-line treatment
Several therapeutic strategies are often employed simultaneously for the treatment of DES, with artificial tears representing the first line of intervention.
Artificial water- and/or lipid-based tears, applied topically, together with hygienic
and eyelids, are, in fact, the mainstay of therapy for DES. The next line of treatment generally involves the administration of medicated topical eye drops containing antibiotics and anti-inflammatory agents, corticosteroids, omega-3 fatty acids or tear secretagogues.
Drug administration
Topical application, being simple and painless, is the preferred route of drug administration for the treatment of ocular surface pathological conditions, as it reduces systemic side effects by localising the drug close to the target site. Moreover, for a number of molecules, it is the only means of achieving effective therapeutic concentrations in the eye, as the blood-aqueous barrier prevents systemically administered drugs from reaching anterior segment tissues. It is therefore not surprising that more than 90% of the ophthalmic formulations currently on the market are topical. However, the efficacy of topically applied formulations is limited by the various protective mechanisms of the eye that reduce the bioavailability of the drug or active ingredient, thus necessitating frequent administration of eye drops for prolonged periods. This dosage is often associated with reduced patient adherence to the treatment protocol, which further limits the effectiveness of the treatment. The concomitant administration of several ophthalmic preparations, as is often necessary to manage DES, can further complicate the treatment regimen and further reduce patient cooperation.
Water- and lipid-based artificial tearsca
Aqueous-based artificial tears, which are often the first line of treatment for DES, are aqueous, isotonic or hypotonic therapeutic devices that typically work by increasing the aqueous layer and temporarily reducing the osmolarity of the tear fluid. To prolong symptomatic relief, artificial tears are often formulated with macromolecules that create viscosity, such as sodium hyaluronate, polyethylene glycol, carboxymethyl cellulose, polyvinyl alcohol, carbomers and natural gums. In addition to prolonging the pre-corneal residence time, viscosity-enhancing polymers also exhibit muco-mimetic properties and form a protective layer on the ocular surface, reducing surface dryness, friction and epithelial cell death.
Innovative Tears
Among the newer artificial tear formulations currently available on the market, those containing sodium hyaluronate (hyaluronic acid, HA) and/or xanthan gum (xanthan gum, XG) have also shown a synergistic effect on corneal abrasions, which are often characterised by acute ocular pain, and other symptoms of discomfort that negatively affect the quality of life of patients with DES.
DES is often characterised by excessive tear evaporation due to a compromised or absent lipid layer, which is why lipoidal artificial tears are sometimes used to replenish the lipid layer of the tear film, improving its stability and reducing evaporation of the underlying aqueous phase. In some conditions, a significant improvement in tear volume has been reported after the administration of lipoidal artificial tears compared to the use of water-based ones, however, the concomitant use of both formulations leads to an even more rapid improvement in the clinical signs of DES.
Conclusions
Due to the multifactorial nature and tendency of DES to become chronic, the most desirable formulations are those that can simultaneously act on the underlying pathologies: combination formulas, which lubricate the ocular surface to provide symptomatic relief while delivering therapeutic agents to the eye, which do not contain preservatives, also reducing the washout effect and exposure to excipients.
Priyanka Agarwal et al. Formulation Considerations for the Management of Dry Eye Disease. Pharmaceutics. 2021 Feb 3;13(2):207. https://pubmed.ncbi.nlm.nih.gov/33546193/
English 
Italian