Current Trends in Pharmaceutical Treatment of Dry Eye Disease A Review - 2023

European Journal of Pharmaceutical Sciences 175 (2022) 106206
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps
Current trends in pharmaceutical treatment of dry eye disease: A review

Hebatallah B. Mohamed a, *, Basma N. Abd El-Hamid b, Dina Fathalla b, Ehab A Fouad b
a
Department of Pharmaceutics, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
b
Department of Pharmaceutics Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt
A R T I C L E I N F O A B S T R A C T
Keywords: Dry eye disease (DED), keratoconjunctivitis sicca or dysfunctional tear syndrome, is the most prevalent
Dry eye disease ophthalmic disease which affects a substantial segment of people worldwide with increasing frequency. It is
Nanomedicine considered a multifactorial disease of the ocular surface and tear film, characterized by a variation of signs and
Ocular delivery system
symptoms. The symptoms range from mild to severe itching, burning, irritation, eye fatigue, and ocular
New treatment
Ocular devices
inflammation that may lead to potential damage to the cornea, conjunctiva and even vision loss. Correspond
New diagnostic techniques ingly, depending on the different manifestations and pathophysiology, the treatment must be tailored specifically
to each patient by targeting the specific mechanisms implicated in their disease. Currently, there are several
medical products and techniques available or under investigation for the treatment of DED. The present article
focused on the pathophysiology of DED, the new diagnostic approach and the recently developed drug delivery
systems or devices reducing the progress of the disease and treating the causes.
1. Introduction Sjögren syndrome. In 1946 Eugene Wolff proposed that the tear film is
composed of three layers: outer lipid layer, middle aqueous layer, and
When the eye is unable to produce an adequate amount of tear with inner mucin layer, covering corneal epithelial cells. In 1995 National
good quality, "there is a disturbance between tear production, absorp Eye Institute stated the first overall definition of DED as a "disorder of the
tion, and drainage". Or when the eye produces an acceptable amount of tear film due to tear deficiency or excessive evaporation” (Dunn et al.,
tear, but this tear is unable to provide good lubrication, protection 2021). In 2017 the International Dry Eye Workshop (DEWS II) refined
against infection, and assess wound healing of the eye surface, this the definition of DED to include a loss of homeostasis and neurosensory
medical condition is known as dry eye disease (DED) (Craig et al., 2017; abnormalities. The treatment strategy of DED was based on the
Messmer, 2015; Módis and Szalai, 2011; Perry, 2008; Pflugfelder and de compensation for loss of tear, so artificial tears containing buffer and
Paiva, 2017). DED is a very common ocular condition characterized by viscolizer were used. Nowadays, with the development of DED diag
loss of the tear film homeostasis with an increase in its osmolarity nosing techniques, tear structure is found to contain proteins and fatty
(Messmer, 2015; Pflugfelder and de Paiva, 2017). It is defined by In materials. So, the treatment policy is changed not only to compensate for
ternational Dry Eye Workshop in 2017, as “Dry eye is a multifactorial the decreased part in tear composition but also to stimulate the secretion
disease of the ocular surface characterized by a loss of homeostasis of the tear of this part and treat the underline causes of DED. This review highlights
film, and accompanied by ocular symptoms, in which tear film instability and the etiologies, the pathophysiology of DED, and the role of diagnostic
hyperosmolarity, ocular surface inflammation and damage, and neurosen techniques in the policy of treatment.
sory abnormalities play etiological roles.” (Craig et al., 2017). Approxi
mately 5–30% of the population have been diagnosed with DED, and the 2. Anatomical and physiological overview
prevalence increases significantly with age (Módis and Szalai, 2011).
Historically, in 1933 DED was reported as a sign related to Sjögren The tear film is a complex structure produced by the lacrimal func
syndrome, an autoimmune disease that attacks the glands that secrete tional unit (LFU). LFU is an integrated system that includes the lacrimal
tears and saliva. Then, excessive studies occurred on the ocular surface glands, ocular surface (cornea and conjunctiva), meibomian glands,
to recognize the real causes of DED since the reported signs of DED were eyelids, and net of nerves connect them (Aragona et al., 2013; Craig
detected in a large number of patients who were not suffering from et al., 2017). The normal tear film forms a layer, approximately three μm
* Corresponding author.
E-mail address: dochoba2014@svu.edu.eg (H.B. Mohamed).
https://doi.org/10.1016/j.ejps.2022.106206
Received 7 March 2022; Received in revised form 5 May 2022; Accepted 9 May 2022
Available online 11 May 2022
0928-0987/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
H.B. Mohamed et al. European Journal of Pharmaceutical Sciences 175 (2022) 106206
Table 1
The composition of the tear film′ s layers.
Type of layer Origin Major components Function References
The outermost - Meibomian glands on Combination of low polarity lipids (e.g., wax and - Preventing evaporation of the tear film (Craig et al., 2017)
(lipid layer) the eyelid. cholesterol esters) and high polarity lipids (e.g., between blinks.
- Zeis and Moll glands. triglycerides, free fatty acids, and phospholipids). - Enhancing tear film spreading.
- Providing a smooth optical surface.
The middle - Lacrimal gland (above Represents the bulk of the precorneal tear film. - Wettability to the ocular surface. (Akpek et al., 2019;
(aqueous the lateral end of the - Water and electrolytes. - Carrying oxygen and nutrients to the Módis and Szalai,
layer) eye). - Antibacterial proteins (e.g., lysozyme, lactoferrin, and cornea. 2011)
immunoglobulins). - Protecting against infections.
- Vitamins (vitamin A). - Promoting wound healing.
- Growth factors.
The innermost - Conjunctival goblet - High molecular weight glycoproteins are called mucins. - Lubricating the ocular surface. (Dunn et al., 2021)
(mucin layer) cells. - Providing an adsorbent interface between
- Ocular surface the aqueous layer and the hydrophobic
epithelium. ocular epithelium surface.
Table 2
Some factors lead to dysfunction in the lacrimal fluid unit.
Medical condition Examples
Aging Older age and female gender (McCarty et al., 1998;
Pflugfelder, 2004).
Decrease in supportive Decrease androgen hormone (Azcarate et al., 2014).
factors
Ocular disease Keratitis, blepharitis, and allergic eye disease (Akpek
et al., 2019; Leonardi et al., 2017).
Systemic condition - Rheumatoid arthritis (McCarty et al., 1998; Moss et al.,
2000).
- Autoimmune thyroid disease (Bacman et al., 2001).
- Sjӧgren syndrome (Akpek et al., 2019).
Medications Antihistamines, antidepressants, antianxiety,
anticholinergics, diuretics, oral corticosteroids (Bacman
et al., 2001; Moss et al., 2000; Rolando et al., 2018), and
hormonal replacement therapy (ex. estrogen) (Rolando
et al., 2018; Schaumberg et al., 2001).
Loss in corneal nerve - Contact lens use (Craig et al., 2017).
Fig. 1. Tear film structure: lipid (oil), aqueous (water), and mucous layers. sensitivity - Chronic diabetes causes nerve damage (Zhang et al.,
Each layer owns a different content which dictates its function. These layers 2016).
work together to maintain the health of our eyes and prevent infection. - Laser eye surgery may cause nerve damage (Bacman
et al., 2001).
Other conditions - Extensive desk work (Uchino et al., 2008).
thick and a three µl volume, located on the anterior conjunctival surface. - Prolonged use of eye drops containing preservatives (
The main three components of this film are: the outermost lipid layer Leung et al., 2008; Rossi et al., 2009).
secreted by the meibomian glands, the intermediate aqueous layer - Smoking (Bacman et al., 2001).
- Reduced humidity and increased wind (Bacman et al.,
secreted by lacrimal glands, and the innermost mucin layer secreted by 2001).
conjunctival goblet cells (Akpek et al., 2019; Módis and Szalai, 2011) - Deficiency of vitamin A or omega-3 (Aragona et al.,
(Table 1). Recently, this tear film is described as a complex blend of 2013).
two-layer structures: the outer lipid layer and a muco-aqueous layer
(Dunn et al., 2021) (Fig. 1).
forming the lipid layer of the tear film. Also, stimulating the nerve end
This film has different functions, including lubrication, maintenance
encourages the lachrymal gland to produce the watery part of the tear
of corneal transparency with the smooth optical surface, antimicrobial
film. Finally, the goblet cells in the conjunctiva and ocular surface are
protection, nutrition, wound healing of the ocular surface, and removal
accelerated to create a mucin layer (Dunn et al., 2021; Módis and Szalai,
of any foreign body (Akpek et al., 2019; Messmer, 2015; Perry, 2008).
2011). Ocular inflammation and hyperosmolarity of tear film are
Typically, the spontaneous blink (5–10 blinks/second) spreads the tear
considered the hallmarks of this disease. This hyperosmolarity triggers
film over the ocular surface and the excess fluid drains into the nose
the production of inflammatory mediators (e.g., interleukin 1, tumor
through the tear ducts. This process is regulated centrally by the brain to
necrosis factor-α) into the ocular surface that damage each of the ocular
maintain the good optical quality of the eye (Porola et al., 2007; Wilson,
epithelial and the goblet cells leading to disturbance in the tear film and
2003).
then DED exists (Dunn et al., 2021; Garrigue et al., 2017; Pflugfelder and
de Paiva, 2017). However, it is unclear whether this hyperosmolarity of
3. Pathophysiology
the tear film arises early in the course of the DED or if it is a manifes
tation of tear film dysfunction.
DED is a multifactorial disorder including several interacting
Usually, the osmolarity of the tear film is 296–302 mOsm/L; how
mechanisms. The LFU is worked as a tightly integrated unit (Azcarate
ever, in cases with DED, this rate rises to 316–360 mOsm/L. Several
et al., 2014). Any disease or environmental factors disrupt the function
studies performed in animal models and humans have found that the
of this unit, causing a disturbance in the tear film by changing its volume
application of hyperosmolar slain to the ocular surface initiates a sec
or composition will lead to loss of ocular surface homeostasis. Normally,
ondary immune response that can lead to a direct pro-inflammatory
the stimulation of nerve endings in the cornea and nasal passages sends
effect on the ocular surface epithelium. It has been shown to activate
impulses to the central nervous system that regulates tear-producing and
mitogen-activated protein kinases (MAPKs); stimulate the secretion of
blinking. Through blinking processes, gentle squeezing occurred to
pro-inflammatory cytokines (e.g., interleukin [IL]-1b, TNF-a, and IL-6),
meibomian glands to produce lipids that spread over the ocular surface,
2
Fig. 2. The classification of dry eye disease according to causes into two basic types: aqueous-deficiency and hyper-evaporative types. These two types result from
numerous pathways leading to a loss of the tear film homeostasis.
chemokines, and matrix metalloproteinases (MMP-3 and MMP-9); and ocular surface, meibomian glands, Lacrimal gland, autoimmune disease
induce apoptosis (Guzmán et al., 2020; Liu et al., 2009; Luo et al., 2005). or systemic inflammation, and dysfunction develop with age play a great
Several clinical researchers observed that the inflammation in the role in the pathogenesis of DED (Barabino et al., 2005; Ciprandi et al.,
1994; Rolando et al., 2018; Rolando et al., 1990; Stern et al., 1998; Wei
and Asbell, 2014). Other factors, Table 2, lead to the development of
Table 3 LFU dysfunction and then DED were reported (Pflugfelder et al., 2000;
Diagnostic tests for dry eye disease. Stern et al., 1998). Generally, if the case is left untreated, the corneal
Diagnostic tests Management ulcer may develop in this case and a loss of vision will exist (Dunn et al.,
Patient history - Symptom-oriented questionnaire. 2021).
Physical - Measurement of visual disturbance.
examination
4. Etiology and classification
Slit-lamp - The eyelid margins (Lid congruity and lid closure).
examination - Temporal lid-parallel conjunctival folds (LIPCOFs).
- The meibomian gland orifices. DED is classified according to the causes: "The aqueous-deficient
- Ocular surface (staining with fluorescein/lissamine green) ( type" with reduced tear production and "The hyper-evaporative type"
Macri et al., 2000). with increased tear film evaporation (Craig et al., 2017; Messmer, 2015;
- Tear film break-up time (Tear film stability) with
fluorescein drops (Less than ten seconds considered
Módis and Szalai, 2011; Pflugfelder and de Paiva, 2017; Rolando et al.,
abnormal). 2018). Mixed cases between the two types can be occurred e.g., in the
The Schirmer test - Aqueous tear production (ten mm on the test strip or less case of Sjögren syndrome, the autoimmune inflammation of lacrimal
considered abnormal)(Aaron et al., 2005). glands leads to a decrease in the secretion of the aqueous part, followed
laboratory - Tear film (osmolarity, lysozyme level, lactoferrin level,
by inflammation in the meibomian glands that leads to insufficient
measurements glycoprotein content, and immunoglobulin content) (Lemp
et al., 2011; Messmer et al., 2010). production of lipid in the tear film. This disturbance in the tear film
- The Oculus Keratograph (non-invasive tear-film break-up resulted from numerous factors (Módis and Szalai, 2011), including
time) (Gulati and Jain, 2017). androgen hormone changes, systemic autoimmune disease, inflamed
- LipiView uses interferometry to quantitatively evaluate meibomian glands, or allergic eye disease, Fig. 2. Both types make film
tear-film lipid layer thickness(Gulati and Jain, 2017).
composition hyper-osmotic due to an increase in the concentration of
3
Table 4 including ocular surgery, and past or current use of systemic and ocular
Differential diagnoses for types of dry eye disease. medications for conditions such as DED, blepharitis, and allergies. Then
Aqueous-deficient Hyper-evaporative dry eye Both forms preliminary assessments of the patient’s visual acuity are performed by a
dry eye physician through physical examination as a blurred or intermittent
- Reduced tear - Pathological changes to the - Tear film break-up time is distortion of vision is observed in patients with DED. After that, the tear
meniscus. lid margins. reduced.
film osmolarity and the ocular inflammation were estimated then the
- Reduced - Obstructed meibomian gland - Ocular surface damage.
LIPCOFs. orifices. - Elevated tear film tear volume was measured by a Schirmer strip test. Next to that, the
- Low Schirmer - Thickened meibomian gland osmolarity. primary assessments were occurred using a slit-lamp examination to
test. secretion. detect eyelids abnormalities, alteration or inflammation of the orifices of
the meibomian glands. Also, a slit-lamp can be used to visualized any
damage to the ocular surface after the application of dye and determined
solutes in the tear film, which stimulates the release of inflammatory
the tear break-up time (TBUT), the time required for the appearance of
mediators into the tears and damages the ocular surface over time. Also,
the first patch in the continuity tear film after the last blink of a patient,
this inflammation leads to the loss of goblet cells and reduces mucin
wherein the case of DED the patient has a rapid TBUT (<10 s). Addi
production, which finally contributes to the tearing film instability
tional diagnostic tests such as LipiView and the Oculus Keratograph are
(Perry, 2008; Pflugfelder and de Paiva, 2017; Wei and Asbell, 2014).
used to quantitatively evaluate tear-film lipid layer thickness and for
evaluating patients suffering from a distortion of vision respectively.
5. Diagnosis of DED using subjective and objective signs
The patient history, physical examination, and diagnostic tests
should be performed to assess DED in general, but the determination of
The two types of DED have the same symptoms. Patients typically
the type of DED is a very important step to choose the correct specialized
feel painful eyes, a grittiness or sandy sensation in both eyes, leading to
treatments for each case, Table 4 (Kojima et al., 2020). The aqueous
redness, itching, burning, and a scratchy sensation. Watery eyes develop
deficiency type of DED, that characterized by a decrease in the amount
as a body responds to the eyes’ irritation. These symptoms progress over
of the major aqueous component of the tear film through lowering in the
time to photophobia with corneal complications (ulceration and even
secretions of the lacrimal gland, can be diagnosed by a reduction in the
corneal perforation), and then, finally, loss of vision may occur (Craig
Schirmer score test to less than 10 mm on the test strip, a decreased tear
et al., 2017; Messmer, 2015; Módis and Szalai, 2011; Perry, 2008;
meniscus, and the ocular staining pattern showing a keratoconjunctivitis
Pflugfelder and de Paiva, 2017). Both types of DED appear similar in
sicca. Further, the hyper-evaporative type of DED, that characterized by
symptoms to infectious or allergic eye diseases (Akpek et al., 2019;
a deficiency in the outer lipid component of the tear film via meibomian
Kojima et al., 2020; Messmer, 2015; Perry, 2008). The diagnostic tests in
gland dysfunction, can be observed by interferometry and meibography,
addition to physical examination are necessary to differentiate between
assess any changes in the lipids component of the tear film, and also by
them (Table 3). If a patient with DED is incorrectly diagnosed and pre
an intensive investigation of the eye lid margins and meibomian glands.
scribed epitheliotoxic antibiotics or antiallergic drugs, DED may worsen
Otherwise, if there are any deficiencies in a goblet cell or mucin that
(Messmer, 2015).
affects the stability of the tear film that is detected through lowering in
Diagnosis of DED is mainly based on the review of symptoms and
TBUT (<10 s) and ocular surface damage that is evaluated by in-vivo
patient history. That summarized the medical and ocular history,
confocal microscopy.
Fig. 3. The management logarithm of dry eye disease; DED is a multi-factorial disease; therefore a proper diagnostic approach must decide the important factors
from the patient’s clinical standpoint. So a personalized, effective, and long-term treatment can be administered and altered if necessary.
4
Fig. 4. Symptoms development and treatment of DED: treatment recommended options according to the progress of the symptoms of the disease.
6. Management of DED to lubricate dry eyes and help in maintaining the moisture on the outer
surface of the eyes. They are used traditionally in all stages of DED
DED greatly impacts the patient′ s life through everyday activities treatment as a first-line therapy to improve symptoms. However, it is not
like driving, reading, and using devices containing monitors as the pa specifically designed to improve symptoms, but to prevent their build-
tient complains of uncomfortable and visual instability. Also, over time up. Artificial tears are classified according to US Food and Drug
the untreated DED undergoes serious complications (eye inflammation, Administration FDA into two categories:(Pucker et al., 2016) (1)
corneal ulcers, and vision loss) that become more difficult to get under demulcent agents which are water-soluble polymers applied directly to
control. The management of DED (Fig. 3) aims to reduce each of the the ocular surface, and (2) emollient agents which is a fat or oil applied
subjective and objective manifestations on the ocular surface to restore a externally on eyelids or oil in water emulsion eye drops. These two
good quality of life (Módis and Szalai, 2011). Scientists do all their best categories aim to protect and lubricate mucous membrane and prevent
to find a solution to this complicated situation of DED. Generally, the drying and cracking respectively.
DED is believed as a non-curable condition that needs chronic therapy to In addition to the above function, they replenish the deficiency of the
re-establish and maintain the ocular surface system homeostasis. Taking components of the tear film, wettability, and spreading. Also, artificial
into consideration that diseases such as diabetes, thyroid problems, tears reduce the osmolarity of the ocular surface through dilution of the
systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syn inflammatory cytokines and lower the susceptibility of the ocular sur
drome, and blepharitis usually aggravate symptoms of DED (Javadi and face to inflammation (Aragona et al., 2021). The approved components
Feizi, 2011). Patient education is an important step for the successful of artificial tears by the FDA and their function are depicted in Table 5.
management of DED. Ophthalmologists should educate the patients On the other hand, other classes of pharmaceutical excipients and
about the fact that DED is a chronic disease that needs long-term food additives were reported to provide therapeutic improvement in
treatment. The treatment of DED can be either “aqueous-deficient” or DED, but these items are not listed in the FDA monograph as active
“hyper-evaporative.” based on the severity of the disease, Fig 4 (Módis therapeutic ingredients for the treatment of DED as it needs numerous
and Szalai, 2011). clinical studies with a huge cost. So, the manufacturers list them as
inactive ingredients used in artificial tears to avoid these trials. Exam
6.1. Conservative treatment ples of these agents are (Kathuria et al., 2021):
6.1.1. Tear substitution - Osmoprotectants: Agents help in protecting the ocular cells from
injury by hyperosmolarity within DED e.g., trehalose, erythritol,
6.1.1.1. Artificial tears. Artificial tears are topical eye formulations used levocarnitine.
5
Table 5 growth factors, immunoglobulins, vitamin A, enzymes, and proteins like

Artificial tears components as approved by FDA. albumin and lactoferrin. Although the use of autologous serum has
Component Specific use Concentration Notes disadvantages such as the possibility of contamination, denaturation of
Carboxymethylcellulose Demulcents 0.2 to 2.5% the component by time, and the need to blood sample collection from
sodium the patient for each preparation time, it is showing a beneficial effect on
Hydroxyethylcellulose Demulcents 0.2 to 2.5%
advanced and severe cases of DED (Akpek et al., 2019; Kojima et al.,
Hydroxypropyl Demulcents 0.2 to 2.5%
methylcellulose 2020; Milner et al., 2017).
Methylcellulose Demulcents 0.2 to 2.5%
Dextran 70 Demulcents 0.1% used with another 6.1.2. Anti-inflammatory agents
polymeric In the moderate to severe cases of DED, using anti-inflammatory
demulcent agent.
drugs is required. With environmental stress and physiologic changes
Gelatin Demulcents 0.01%
Glycerin Demulcents 0.2 to 1% with aging, inflammation of the ocular surface usually occurred. Also,
Polyethylene glycol 300 Demulcents 0.2 to 1% this ocular manifestation may be caused by systemic inflammatory
Polyethylene glycol 400 Demulcents 0.2 to 1% conditions (Kojima et al., 2020; Módis and Szalai, 2011). The inflam
Polysorbate 80 Demulcents 0.2 to 1%
mation of the ocular surface and the secretory components of the
Propylene glycol Demulcents 0.2 to 1%
Anhydrous lanolin Emollients 1 to 10% Used in
lacrimal system (the lacrimal gland and/or lacrimal ducts) consider the
combination with core features of DED pathogenesis. This inflammation affects greatly the
one or more amount and the composition of produced tears causing tear deficiency
oleaginous and usually building up over time causing severe chronic cases (Milner
emollient agents.
et al., 2017). Therefore, controlling inflammation is a critical step to
Lanolin Emollients 1 to 10% Used in
combination with prevent and treat chronic DED (Aragona et al., 2021).
one or more
oleaginous 6.1.2.1. Cyclosporine. Cyclosporine A (CsA) is a fungus-derived peptide,
emollient agents.
which has anti-inflammatory and immunosuppressive properties by
Polyvinyl alcohol Demulcents 0.1 to 4%
Povidone Demulcents 0.1 to 2% preventing T-cell activation and inflammatory cytokines production.
Light mineral oil Oleaginous up to 50% Used in Cyclosporine A (0.05%) topically eye drop was approved by FDA for use
Emollients combination with twice daily as targeting to treat ocular surface inflammation in DED
one or more
(Hessen and Akpek, 2014; Milner et al., 2017; Sall et al., 2000). The
emollient agents.
Mineral oil Oleaginous up to 50% Used in
application of topical cyclosporine A (0.05%) improves the Schirmer test
Emollients combination with value, corneal fluorescein staining, and increases goblet cell density. So
one or more that, it alleviates the signs and symptoms of DED in about 50% of pa
emollient agents. tients, although, the application of this drug is usually associated with
Paraffin Oleaginous up to 5% Used in
eye irritation (Aragona et al., 2021; Módis and Szalai, 2011). The
Emollients combination with
one or more combined use of steroid eye drops may be beneficial to decrease the side
emollient agents. effect of CsA (Sheppard et al., 2014).
Petrolatum up to 100%
White ointment up to 100%
6.1.3. Corticosteroids
White petrolatum up to 100%
White wax up to 5% Used in
In moderate to severe dry eye disease, using corticosteroid topically
combination with as unpreserved eye drops over 2 to 4 weeks e.g., 0.1% fluorometholone 2
one or more to 4 times/day for two-four weeks or hydrocortisone showing great
emollient agents. improvement in the symptoms and clinical signs. By long-term therapy,
Yellow wax up to 5% Used in
the corticosteroids’ side effects will appear (cataract formation and
combination with
one or more elevated intraocular pressure) (Marsh and Pflugfelder, 1999), so this
emollient agents. type of treatment is recommended only for short-term therapy
(Messmer, 2015; Módis and Szalai, 2011). Hydrocortisone is recom
mended to be used safely for a patient with severe DED; however, the
- Humectants: Hygroscopic agents that encourage the retention of occurrence of complications is still possible. In the case of systemic in
water on the ocular surface e.g., sodium hyaluronate. flammatory disease or autoimmune disorders (e.g., Sjögren syndrome)
- Hydroxypropyl Guar gum: A viscous protein-polymer used as a soft using corticosteroids systemically in a short pulse (e.g., 40 mg on
gel to increase the viscosity of the tear, therefore, increasing the alternate days) is recommended but under control. Generally, using
retention time of the aqueous layer to the mucins. topical or systemic corticosteroids improve both subjective and objec
- Oils: oils used to mimic the lipid layer of the tear film (e.g., flaxseed tive signs and symptom but they should be used under the monitoring of
oil, castor oil, mineral oil). specialists.
The artificial tears exist as units preserved (multidose) or united non- 6.1.4. Rebamipide
preserved (single dose) preparations. Benzalkonium chloride, chlor However, rebamipide is an oral drug used for the treatment of gastric
obutanol, and cetrimide are usually used as preservatives in multidose ulcers; it has been shown to increase the amount of mucin-like sub
artificial tears. The non-preserved type is preferred for use when the stances and the number of conjunctival goblet cells on the ocular sur
patient needs four times daily administrations. This recommendation is face. In addition, it has anti-inflammatory action by suppressing T cell
attributed to the aggravation of symptoms by disruption of the ocular activation and cytokine production, so it has been indicated as oral
epithelial cell-cell junction and inducing toxic epitheliopathy in case of mucin secretagogues in DED management (Tandon et al., 2012).
long-lasting application of preserved products (Javadi and Feizi, 2011).
6.1.5. Lactoferrin
6.1.1.2. Autologous serum. Tears may also be substituted with naturally Lactoferrin secreted by the lacrimal gland into tears provides a
occurring biologic fluids, such as serum (autologous serum tears), which protective effect to ocular cells against cell death by oxidative ultraviolet
are prepared from the patients’ blood. It includes many components e.g.,
6
Table 6
New devices used in the treatment of DED.
Name of device Definition Advantages Disadvantages Availability References
Intranasal tear neuro- It applies small electrical currents to - Use the device four times /day - Nasal (pain, burning, Approved by (Gumus et al., 2017;
stimulator stimulate the mucosal nerves ending for 180 days (Schirmer scores congestion), facial pain, and FDA Yu et al., 2021)
that increases natural tear production were significantly higher, headache.
through a process named (the improvement of ocular - Not to be used in case of
nasolacrimal reflex pathway of the symptoms). patients having cardiac
lacrimal function unit). - Most useful in patients with pacemakers, implanted
aqueous tear deficiency. metallic or electronic devices
in the head or neck.
- A highly costive technique.
Extranasal tear neuro- It stimulates the external nasal nerve by Significant improvement in the • No reported adverse events. Approved by (Yu et al., 2021)
stimulator applying small electrical currents mean of Schirmer score after FDA
superficially on the skin of the nose at using the device for 30 seconds
the junction between the nasal cartilage at a time at least twice daily for
and nasal bone. 30 days.
Scleral Lenses - These are lenses applied to the sclera; - Significantly improve DED The lengthy and costly fitting Available (Nguyen et al., 2018;
they should not touch the corneal signs and symptoms. process. (Since 2013) Romero-Rangel
surface. They act as a fluid-filled et al., 2000)
reservoir.
- They are used for patients with the
irregular corneal surface.
Amniotic Membrane - It is a basement membrane substitute - Promoting epithelial wound - Costly process. Currently (Cheng et al., 2016;
or temporary graft coverage of the healing on the eye surface. - Pain and inflammation of lid available McDonald et al.,
epithelium to allow healing. - Recommended for severe or/and conjunctiva from 2018)
- It has anti-inflammatory and anti- indications that require longer symblepharon ring.
scarring effects. treatment.
- It contains growth factors that impart - Significant decrease in
anti-inflammatory properties. symptoms after treatment
duration of five days.
Aero Pump’s med spray It is a new ophthalmic drug delivery - Administered easily without Currently (Kraus, 2020)
device that can be applied micro-and the need to tilt the head back. available
nanotechnology-based ocular - Used for numerous
formulation from a close distance commercially ophthalmic
directly onto the open eye, without products for DED (Low and
causing a blink reflex. high viscosity products).
stress and inhibits the production of various cytokines, so it suppresses α) and lowering the activity of several matrix metalloproteinases,
the eye inflammation of DED. Lactoferrin is used orally as an enteric- collagenase, and phospholipase A2. They have been used successfully in
coated tablet (270 mg/day) for one month to treat DED. A significant the treatment of meibomian gland dysfunction and corneal ulceration in
improvement in symptoms was observed. small oral doses (40 - 400 mg/day for doxycycline and between 50 - 100
mg/day for minocycline), however, in large doses skin and gastroin
6.1.6. Fatty acid supplements testinal tract side effects appear (Javadi and Feizi, 2011; Messmer,
Omega-3 and omega-6 are polyunsaturated essential fatty acids 2015). Several studies using experimental DED models demonstrated
absorbed from food. Both of them are included in all body cell mem that the use of these drugs in small doses for 6 to 12 weeks improves
branes, however, omega-3 competes with omega-6 for inclusion ac corneal surface regularity, tear production, and tear film stability (De
cording to their dietary intake (Kathuria et al., 2021; Vickers and Gupta, Paiva et al., 2006a, 2006b).
2015). Arachidonic acid which is one of the omega-6 fatty acids com
ponents is transformed into pro-inflammatory mediators, once the cells 6.1.8. Macrolides
are activated by external stimuli. This mediator decreased when omega-3 In general, antibiotics play important role in the management of
displaces omega-6 as a result of increasing omega-3 intake. This is the DED, especially when bacterial meibomian glands infection is the
main anti-inflammatory mechanism of omega-3(Garrigue et al., 2017; causative agent of DED. Azithromycin is one of the macrolides that have
Surette, 2008). In a recent study, researchers found a relation between the anti-inflammatory and antibacterial effects. Several studies reported
ratio of omega-6 to omega-3 and tear film stability whereby increasing that the use of 1% azithromycin eye drops for the treatment of ble
this ratio the symptoms of DED are exaggerated. Further, they found that pharitis and meibomian gland dysfunction improved the lipid layer
the signs and symptoms of DED improved with increased omega-3 dietary secretion and tear film stability(Foulks et al., 2010; Haque et al., 2010).
supplement intake (Kangari et al., 2013; Liu and Ji, 2014). Omega-3 fatty
acids (eicosapentaenoic acid, docosahexaenoic acid, and a-linolenic acid) 6.2. Topical mucin secretagogues
are recommended as a 500 mg/day oral dose for patients with dry eye
disease associated with systemic autoimmune inflammatory disorders, Secretagogues are agents that stimulate mucin secretion as a mech
but increasing omega-3 fatty acid intake may increase the risk of prostate anism of action. Topical secretagogue formulations are a novel treat
cancer (Rashid et al., 2008). Recently, to overcome this problem, the ment that is applied to the ocular surface to induce aqueous and/or
omega-3 fatty acid is applied topically as an eye drop. It has the potential mucin secretion. They are available internationally and used for the
benefit to improve ocular inflammation in DED but is still currently under treatment of DED in Japan and South Korea but are not currently
investigation (Rashid et al., 2008). available in the United States. This drug is a P2Y2 purinergic receptor
agonist that stimulates the receptors in ocular tissues as stimulates
6.1.7. Tetracyclines and their derivatives conjunctival epithelial cells for water secretion (e.g., diquafosol tetra
Tetracycline and its derivatives Doxycycline and Minocycline have sodium 3% ophthalmic solution) and conjunctival goblet cells for mucin
anti-inflammatory, as well as bacteriostatic effects. They act by lowering secretion (diquafosol tetrasodium 3% ophthalmic solution and 2%
the production of interleukin-1 (IL-1α) and tumor necrosis factor (TNF- rebamipide ophthalmic suspension). They have a beneficial effect on
7
Table 7
New process used for the treatment of DED.
Name of Definition Advantages Disadvantages Availability References
process
Intense pulsed This technique is used for the hyper- - Reducing inflammation and - Localizing redness and FDA-approved for (Dell et al., 2017;
light (IPL) evaporative type of DED by applying bacterial growth on the swelling. dermatological treatment and Gupta et al., 2016)
infrared light that is converted to eyelid. - There are no used recently for DED as off-
destructive heat upon absorption. - Melting the viscous lipid in significant adverse label.
meibomian glands to improve effects.
the flow.
Vectored - The applied heat and therapeutic - Improving both signs and - Minimal side effects A clinical trial is needed to (Blackie et al., 2016;
Thermal pressure on both eyelids. symptoms of DED. were noted as eyelid become available. Hagen et al., 2018)
Pulsation - Preferred in the treatment of DED - The single treatment effects discomfort only.
with a defect in meibomian gland lasting six to nine months. - The device is
dysfunction. expensive.
Meibomian The applied stainless steel probe - The significantly faster - Need skill and Numerous placebo-controlled (Magno et al., 2021;
Gland directly into the meibomian gland improvement lasted for 11.5 experience. trials are needed. Maskin and Testa,
Probing orifices to open the closed orifice. months. 2018; Syed and
- It an application for the Sutula, 2017)
patient’s suffering from DED
with meibomian glands
dysfunction
stabilizing the tear film and repairing the corneal epithelial damage Despite a good understanding of the DED pathogenesis and the
(Jones et al., 2017; Kojima et al., 2020; Li et al., 2019; Milner et al., presence of different types of treatment strategies, DED is still incom
2017). Increased tear secretion by using secretagogues agents can be pletely treated. Several challenges in the management of DED are still
achieved by a local or systemic application. present. Using eye lubricants is still considered an important step in DED
The most used eye drops as artificial tears are 0.1% and 0.3% sodium management. However, they only relieve the symptoms and do not in
hyaluronate ophthalmic solution. It has been reported that the combi fluence the real causes of DED. Furthermore, the chronic use of preser
nation of sodium hyaluronate and diquafosol sodium as an aqueous vative lubricant formulations can lead to damaging effects on the ocular
secretagogue, increases the retention time of water secreted by diqua surface so preservative-free artificial tears are needed for long term
fosol. Therefore increase the wettability time of the ocular surface and therapy (Jones et al., 2017). Moreover, using topical corticosteroids for
the therapeutic effect of diquafosol drug (Kamiya et al., 2012). Finally, a long time will lead to several problems, containing opportunistic in
most secretagogues agents are still under investigation (Kojima et al., fections and cataracts (Jones et al., 2017).
2020; Milner et al., 2017; Módis and Szalai, 2011). New alternative therapies are needed to be developed. Table 8
summarizes the recently developed therapies for the treatment of DED
7. New treatments used for the management of DED that may particularly impact in the future, they are classified as:
Recently, the developed techniques used to investigate and diagnose - A mucin-like glycoprotein group e.g., Lacritin and Lubricin
the different types as well as stages of DED help in the decision of the
suitable treatment protocol. Up till now lubricant eye drops or ointments They present naturally as a lubricant on the ocular surface and
to overcome the symptoms of DED are the mainstay treatment, however, protects the ocular surface against shear forces of physiological eyelid
they cannot relieve the underline causes of DED. There are new pro blinks. Therefore, lowering the production of lubricin and/or lacritin
cedures, devices, and topical medications introduced into the field of elevates the shear stress at the ocular surface, which may cause
DED treatment, where some of them are under investigation or in early inflammation and build-up of inflammatory mediators (e.g., IL-1α, IL-6,
clinical trials (Akpek et al., 2019; Kojima et al., 2020; O’Neil et al., TNF-α) and proteases (e.g., MMP-9) in the tear film. So the adminis
2019). tration of Lacritin and/or Lubricin locally as eye drops will improve both
Nowadays, there are numerous devices for the treatment of DED. signs and symptoms of DED.
Some of these devices are useful for patients with aqueous tear defi
ciency as intra or extra nasal neurostimulators whereas scleral lenses can - Mucin secretagogues e.g., Rebamipide, Diquafosol, Sulglycotide,
be used as a fluid-filled reservoir for a patient with an irregular corneal Tavilermide, Gefarnate, Ecabet sodium, Mycophenolate mofetil, and
surface. Also, the amniotic membrane is prescribed for various ocular 15(s)-HETE (Icomucret).
surface disorders and can be used for the DED as it has anti-
inflammatory and restorative properties. Recently, Aero Pumpʼs med Mucins are heavy glycoproteins, classified as gel-forming mucins
spray is considered an alternative device to eye droppers that can be (MUC2, MUC5AC, MUC5B, MUC6, and MUC19) and soluble mucins
applied an ophthalmic medication from a close distance onto an open (MUC7 and MUC9). The most important gel-forming mucin is MUC5AC
eye as an ultra-soft, slow-moving fine mist without causing a blink reflex which is secreted by the conjunctival goblet cells into the tear fluid
by using a micro-nanotechnology-based spray nozzle. The new open-eye however MUC7 is the greatest significant soluble mucin obtained from
spray offers a propellant and preservative-free multi-dose spray device. the acinar cells of the lacrimal glands. Mucins play significant roles on
On the other hand, there has been increasing attention to the study of the ocular surface (e.g., lubrication of the ocular surface, maintenance of
several processes for the treatment of DED. For example, using thermal lacrimal fluid, and barrier against pathogens) (Hori, 2018). In DED, the
or mechanical energy via Intense Pulsed Light and Vectored Thermal conjunctival goblet cells and mucin secretion are decreased.
Pulsation to express glands and re-establish the normal flow of meibum. Recently, the treatment strategies of DED are based on the stimula
Moreover, using the Meibomian Gland Probing technique by applying a tion of tears production rather than tear substitution. The stimulation of
solid stainless steel probe directly into meibomian gland orifices pro lacrimal glands chemically to produce aqueous tears using neuro-
vides a faster improvement in all DED measurements. The following stimulator drugs is still under investigation. On the other hand,
Tables 6 and 7 summarize the recently developed devices, and treatment several drugs act as mucin secretagogues, increase the secretion of
processes of DED respectively. mucin from conjunctival goblet cells and/or increase the goblet cell
8
Table 8
New topical eye therapies used in the treatment of DED.
Therapies Class Functions Stage of clinical References
trials
A mucin-like glycoprotein
Lacritin - A tear glycoprotein is secreted mainly by the - Increasing mucin amount. Phase II (McNamara et al., 2016;
lacrimal gland. - Reducing signs of epithelial Vijmasi et al., 2014)
damage.
Lubricin - It is a lubricant agent present naturally on the - Decreasing friction between Phase II (Lambiase et al., 2017;
ocular surface. cornea, conjunctiva, and eyelid. Schmidt et al., 2013)
- Decreased by increasing the production of - Preventing epithelial dysfunction
cytokines during inflammation. and degradation.
- Significantly outperformed sodium
hyaluronate in both signs and
symptoms of DED.
Mucin secretagogues
Rebamipide 2% suspension Quinolinone derivative. - Increasing mucin-like glycoprotein. - phase ІІІ trial in (Kinoshita et al., 2013)
- Stabilizing the mucin component of the US
the tear film after applying it four - Approved in
times daily for four weeks. Japan and South
Korea
Diquafosol sodium 3% A purinergic agonist of the ocular surface - Promoting fluid transfer and mucin (Koh, 2015)
(P2Y2 receptor agonist). secretion by activation of
phospholipase proteins.
- Increasing mucin production.
- Has anti-inflammatory action.
Tavilermide (MIM-D3 - Mimetogen (MIM-D3) is a synthetic (tyrosine - Stimulating TrkA receptors in the Phase II (Meerovitch et al., 2013)
(1% or 5%) kinase) neurotrophin mimetic that belongs to conjunctiva leads to mucin secretion.
the nerve growth factor (NGF) family. - Improving corneal damage healing.
- It is TrkA receptor agonist. - Improving DED symptoms after
administration twice daily for 28
days.
Ecabet sodium A new class of diterpenoids molecules - Increasing the quantity and quality Phase III (Mito et al., 2007)
of mucin.
- Improving both signs and
symptoms of DED after instillation
four times daily.
Mycophenolate mofetil Corticosteroid-sparing agent - Controlling the eye inflammation Phase II (He et al., 2010)
and enhancing the function of goblet
cells.
15(s)-HETE or Icomucret 15(S)-hydroperoxyeicosatetraenoic acid is a - Mucin stimulants. Phase III/II (Gamache et al., 2002)
metabolite of arachidonic acid - Relieving corneal injury and
reestablishing corneal integrity.
Anti-inflammatory and/or
immunosuppressive
Loteprednol etabonate 0.25% A retro-metabolically designed corticosteroid - Lowering the inflammation FDA-approved (Beckman et al., 2020)
suspension with low corticosteroid-related adverse associated with DED after being
effects. dosed four times daily for 28 days.
OCS-02 anti-TNFα antibody - Relieving severe ocular discomfort Phase II (Galor, 2021)
accompanied with DED effectively.
A higher concentration of - A T-cell immunomodulator in patients with - Increasing the density of goblet
cyclosporine (0.09 or 0.1) DED cells in the conjunctiva significantly Phase III (Tauber et al., 2018)
- It acts as an anti-inflammatory and after twice-daily administration. Phase II (Wirta et al., 2019)
immunosuppressive agent - 0.09% formulation (rapid onset of
action with the same safety of 0.05%
formulations).
- 0.1% water-free drug formulation
delivery solution (earlier onset of
action, more safe and tolerable).
Tacrolimus (0.03%) eye drops Macrolide antibiotics have anti- - Inhibiting the activation of Phase Ⅳ (Varela Rey et al., 2021)
inflammatory/immunosuppressive effects lymphocytes and the release of
inflammatory mediators
(interleukin-4, interleukin-8, and
tumor necrosis factor-a).
- Improving the symptoms and
clinical signs of DED.
Rapamycin (sirolimus) Anti-inflammatory and immunomodulatory Improving the signs and symptoms Phase І (Linares-Alba et al., 2016)
of DED
EBI-005 Interleukin-1 receptor antagonists (IL-1R - Improving the signs and symptoms Phase ІІІ (Kovalchin et al., 2017)
antagonists) with an anti-inflammatory. of moderate to severe DED.
Resolvin E1 analogues Lipid-derived autacoids play a role in the - Increasing the tear production. Phase ІІ (Cholkar et al., 2016)
resolution phase of inflammation. - Inhibiting the inflammatory
enzyme COX2.
- Inhibiting the ocular inflammation.
- Protecting the corneal integrity.
Biological components
(continued on next page)
9
Table 8 (continued )
Albumin 5% A major component of human serum - Improving corneal healing without Phase ІІ (Higuchi et al., 2007;
adverse events was observed in Shimmura et al., 2003)
patients after treatment every four
hours for four weeks.
Estradiol A synthetic form of naturally occurring - Estradiol eye drops improve both - phase II (Schmidl et al., 2021)
estradiol, a steroid sex hormone. signs and symptoms of moderate to
severe DED in postmenopausal
women.
N-acetylcysteine A naturally-occurring amino acid (a derivative - Anti-inflammatory, anti- phase II (Li et al., 2018; Schmidl
of L-cysteine). collagenolytic and antioxidant et al., 2017)
properties.
- Improving the ocular symptoms of
DED after being used topically four
times per day for two weeks.
Thymosin b4 - A naturally occurring G-actin-binding - Lowering pro-inflammatory phase II (Kim et al., 2018; Sosne
protein cytokines and improving symptoms et al., 2015; Sosne and
- Found in high concentrations in ocular and signs in DED after application Kleinman, 2015)
surface fluid) for 28 days.
- Improving the symptoms of DED in
a murine model.
Amniotic membrane extract eye - As cryopreserved amniotic membrane - Helping in the corneal wound Phase I / ІІ (Murri et al., 2018; Perez
drops - Including growth factors, cytokines, and healing. et al., 2021)
collagens - Lowering the fibroblast activity.
- Decreasing the ocular surface
inflammation.
- Limiting use due to difficulty in
processing and preserving.
Mesenchymal stem cells - Multipotent stem cells can distinguish into - Lowering the ocular surface Phase I / ІІ (Lu et al., 2020; Zhang
numerous cell types. inflammation. et al., 2015)
- Have immunomodulatory and anti- - Restoring of tear production.
inflammatory effects. - Restoring of conjunctival goblet
cells.
- Improving the symptoms of
patients with aqueous deficient DED.
Other’s products
Visomitin (SkQ1) - A synthetic antioxidant - Decreasing the tear film instability. phase II / III (Brzheskiy et al., 2015;
- Lowering the production of TNFα and IL-6 - Improving the functional state of Zernii et al., 2017)
the cornea.
- Improving symptoms of patients
with mild to moderate DED.
Tivanisiran (SYL1001) - a 19-base small interfering RNA (siRNA) - Reducing ocular pain and phase III (Benitez-Del-Castillo et al.,
- Reducing the levels of the human transient discomfort in patients with moderate 2016)
receptor potential vanilloid 1 (TRVP1) protein to severe DED.
within the cells
Osmoprotectants - Naturally occurring small molecules that - Preventing ocular cell death and Erythritol and L- (Deng et al., 2014;
(e. g., erythritol, L-carnitine, and lower the concentration of intracellular reducing inflammation in DED carnitine in lipid- Giannaccare, 2016;
trehalose) organic salts without disturbing cellular significantly by lowering the based eyedrops Kaercher et al., 2009)
components. hyperosmolarity of tear fluid (currently used) (Orobia et al., 2017)
A trehalose
solution of 3%
(currently used)
Types of osmoprotectants: (Chen
et al., 2013; Giannaccare, 2016;
Orobia et al., 2017; Simmons et al.,
2015)
polyelectrolytes as carbohydrates
(trehalose and hypromellose)
▪ polyols (glycerol, erythritol,
inositol, and sorbitol)
▪ zwitterions as amino acids (e.g.,
glycine, betaine, proline, and
taurine)
▪ methylamines/methyl sulfonium
solutes (e.g., L-carnitine and
Erythritol).
numbers become available in the market and give good improvement prostaglandin and mucus glycoprotein synthesis and also inhibits in
results. Several agents act as mucin secretagogues some of them are on flammatory cytokines and reactive oxygen species (Hori, 2018).
the market and others are in preclinical and clinical development. In
Japan regarding secretory mucins, two eye drops secretagogue (diqua - Anti-inflammatory and/or immunosuppressive e.g., loteprednol
fosol and rebamipide) were approved in December 2010 and January etabonate, OCS-02, a higher concentration of cyclosporine, dapsone,
2012, respectively for treating DED (Hori, 2018). tacrolimus, rapamycin (sirolimus), EBI-005, and resolvin E1
Diquafosol as a P2Y2 purinergic receptor agonist stimulates the analogues.
secretion of mucin from conjunctival goblet cells into the tear film after
local instillation. On the other hand, rebamipide might cure the ocular As previously discussed ocular inflammation is the core feature of
surface and increase the goblet cell numbers as it stimulates the DED pathogenesis. Consequently using anti-inflammatory drugs
10
consider one of the effective treatment approaches during DED man pathologies, it rapidly progresses to become a chronic refractory disor
agement, so the development of this class attracts the attention of sci der. Hence, several pharmacological treatments are often concurrently
entists. Some of these agents are already used like cyclosporine and recommended to treat DED efficiently. Moreover, the treatment courses
loteprednol etabonate but there are higher concentrations and new of DED take a long time with repeated drugs instillation daily.
ophthalmic delivery systems of them under development of clinical Commonly, the excipients used in commercial eye drops can exhibit
trials. Other drugs were performed to assess their safety and efficacy of ocular toxicity and aggravate the signs and symptoms of DED (Epstein
them in patients with DED, but up to now, they are still under et al., 2009; Walsh and Jones, 2019). So, the challenge in the treatment
investigation. of DED is using ocular formulations suitable and applicable; increasing
ocular retention time, and improving ocular bioavailability with effi
- Biological components e.g., albumin, topical steroid hormones, N- cient safety upon use for a long time.
acetylcysteine, thymosin b4, amniotic membrane extract, mesen Nanomedicines, as delivery systems, have great development in
chymal stem cells. ophthalmology. They increase ocular drug bioavailability via over
coming ocular physiological barriers through mucoadhesive ability
Human serum albumin; blood derivatives can be used for the treat aiming to deliver drugs to the target site with appropriate concentration.
ment of DED. It is similar to natural tears; includes growth factors, lipids, Moreover, they deliver drugs in a preprogrammed sustained release
proteins, and antimicrobial elements. Application of It improves signs and fashion. For DED specifically, the pharmaceutical formulators do their
symptoms of DED. Moreover, mesenchymal stem cells can be differenti best to produce safer formulations without preservatives (Gote et al.,
ated into several cell types and have an anti-inflammatory and immuno 2019; Weng et al., 2017).
modulatory effect. Mesenchymal stem cells are effective in DED treatment The topical ophthalmic formulation for hydrophobic drugs has been
by enhancing reparative activities of the lacrimal gland after modulation a great challenge for ocular drug delivery. Cyclodextrins (CDs) are three
of macrophage polarization and so suppress the inflammation in the types of cyclic oligosaccharides (α, β, and γ) that have a hydrophobic
lacrimal gland. In addition, they enhanced the restoration of conjunctival cavity and hydrophilic outer surface. Usually, CDs are used to improve
goblet cells and the production of tears (Giannaccare et al., 2020). the solubility of hydrophobic drugs by forming water-soluble complexes
Amniotic membrane extract like amniotic membrane is offered (Agarwal and Rupenthal, 2016). This complex between drug and CD
beneficial substances counting cytokines, growth factors, and collagens enhances drug solubility in the aqueous part of tear film and penetration
to induce corneal healing and decrease ocular surface inflammation. to the mucin layer that provides sustained drug release and so, increases
Like other biological components thymosin b4; presents naturally in the ocular drug bioavailability. Further, the solubility of the hydrophobic
ocular surface promotes healing of the ocular surface and inhibit pro- drugs is increased by using micelles. Micelles are a spherical system with
inflammatory cytokines. Moreover, the beneficial treatment of the a hydrophobic core and hydrophilic shell formed by the self-assembling
ocular signs and symptoms of DED was indicated after using topical of surfactant molecules. The corneal drug uptake increased by using
hormone therapy. This potential effect on DED was elucidated by the micelles in nano-size. So, this approach was evaluated for a different
presence of receptors for sex hormones on the meibomian and the drug to treat DED. The preservative-free 0.09% CsA micelle formulation
lacrimal glands that regulate the function of these glands (Barabino is the first approved FDA micelle formulation for the treatment of DED
et al., 2012). N-Acetylcysteine is a naturally occurring derivative of (Mandal et al., 2019). Liposomes are phospholipid bilayer structures,
L-cysteine amino acid with mucolytic, anticollagenolytic, used to increase the solubility of both hydrophilic and hydrophobic
anti-inflammatory, and antioxidant properties (Ziment, 1988). The drugs. Specifically for DED treatment, phospholipids in liposomes play a
clinical result observed after topical application of N-acetylcysteine role in the renewing of the lipid layer of the tear film (Acar et al., 2018).
showed significant improvements in signs and symptoms of DED. Liposomal spray, non-drug-loaded, was recently introduced for the
treatment of DED. The clinical studies of liposomal eye drop as well as
- Other’s products e.g., visomitin, tivanisiran, and osmoprotectants. liposomal spray provide their effectiveness in the treatment of DED.
The development of liposomal formulations is limited due to several
Visomitin is an antioxidant drug that accumulates inside the cells and factors; poor stability, low encapsulation efficacy, and difficulty in the
lowers the damage of overproduction to reactive oxygen species by sterilization manufacturing process. Therefore, the proliposomes, dry
mitochondrial. Also, it decreases the production of TNFα and IL-6 and so powder that freely assembles to form liposomes, have been developed to
enhances the protection of the cornea (Skulachev, 2013). Tivanisiran is a overcome some of these limitations.
selective inhibitor to transient receptor potential vanilloid 1 (TRPV1); Nano-emulsions are another form of lipid-based therapy as lipo
stimulated by inflammatory mediators and hyperosmolarity in DED and somes. They are composed of both aqueous and oil phases that make
leads to transmitting a pain signal to the brain (Bourinet et al., 2014). them useful in the delivery of both hydrophilic and hydrophobic drugs
Using Tivanisiran in clinical trials for the management of DED has been to ocular tissue. For lipophilic drugs, oil in water emulsions as a topical
investigated and shows promising results in lowering ocular pain and ophthalmic delivery system is more useful due to the increasing ocular
discomfort. Osmoprotectants are naturally occurring molecules; they permeability and cellular uptake of a drug (Gan et al., 2013). According
decrease the intracellular organic salts concentration without disturbing to the chemical nature of components added during the formulation, the
cellular components. They investigated to lower the tear fluid hyper emulsions are classified into two types anionic and cationic. Both types
osmolarity associated with DED (Yancey, 2005). of emulsion increase a drug ocular bioavailability as their small size can
enhance drug uptake by the cornea. A 0.05% preservative-free CsA
8. Ocular drug delivery systems anionic oil-in-water nanoemulsion was approved by FDA in 2003. On
the other hand, a double concentration of CsA has displayed better
Commercially available ophthalmic drug formulations are effective ocular tolerability and higher bioavailability in a cationic nanoemulsion
but less efficient to manage DED. Ocular instillation is the most widely formula and was approved by the EU in 2015. Moreover, a 0.05% CsA
preferred route of drug administration, particularly for the management nanoemulsion formula was established by the self-nano emulsifying
of anterior segment diseases, such as DED. Local therapies to the anterior drug delivery system (SNEDDS) to provide better physicochemical drug
segment, the targeted ocular tissues, have low bioavailability; restricted stability and solubility. SNEDDS are water-free homogenous mixtures of
by major challenges of physiological eye defences such as tear turnover, a drug, oil, a surfactant, and a co-surfactant. Upon the addition of water,
nasolacrimal duct drainage, and eye complex structure. Thus drug transparent emulsions are formed in nanometers droplet size.
therapeutic levels are not sustained for a longer period in target tissues. Other lipid-based therapies; solid lipid nanoparticles (SLNs), Lipid
Due to DED being a multifactorial disease involving several underlying nanocapsules, nanostructured lipid carriers (NLCs), and lipid-based
11
Table 9
Ocular drug delivery system used for management of DED
Ocular delivery Advantages Applications References
- Enhancing drug solubility in the aqueous tear fluid. - Aqueous cyclosporine A (CsA) (Agarwal and Rupenthal, 2016;
- Penetrating the mucus layer. eyedrops Mahmoudi et al., 2020; Soliman
- Providing sustained drug release. - Tacrolimus et al., 2017)
- Improving ocular drug permeation and bioavailability. - Loteprednol etabonate
- OCS-02 (anti-TNFα antibody)
Increasing uptake in all layers of the cornea. - Micellar CsA formulations (Lallemand et al., 2017; Mandal
- Diclofenac sodium eye drops et al., 2019; Quintana-Hau et al.,
2005)
Their phospholipids stabilize the lipid layer of the tear - CsA (Li et al., 2012; Soriano-Romaní
film. - Medroxyprogesterone acetate et al., 2017)
- Sirolimus
Proliposomes - Have a longer shelf-life. - CsA (Karn et al., 2014)

- High safety and efficacy.
liposome lid sprays - They are applied onto the outside of the lids, where the - Lipid-soluble vitamins with ocular (Agarwal et al., 2021; Garrigue
or liposomal spray polar phospholipids diffuse from the lid surface to the protective effects (e.g., vitamins A and et al., 2017)
tear film to provide a supplement. E)
- Providing lubrication, preventing tear film evaporation, - Tetracycline, diclofenac, Fluconazole,
and so treating DED symptoms. and CsA
- Replacing both aqueous and lipid components of the - Osmoprotectants activity through the
tear film. addition of L-carnitine or trehalose
Punctal plug - Acting as a drug reservoir. - Sustained-release dexamethasone (Vickers and Gupta, 2015)
“intracanalicular” - Biodegrading after completing the release of the drug
without the need for removal by the physician.
- Releasing the drug loaded for up to 30 days.
KPI-121 - Proprietary technology is known as mucus penetrating - It is specific for loteprednol etabonate, (Gupta and Venkateswaran,
particles (MPP). approved by the FDA in 2020. 2021; Popov, 2020; Schopf
et al., 2014, 2015)
- SFAs (semifluorinated alkanes) - SFA based Omega-3 eyedrops (ex vivo (Agarwal et al., 2019; Agarwal
■ Synthetic pharmacologically inert hydrophobic liquids studies) et al., 2018; Garnock-Jones,
of minimized. - SFA based CsA eyedrops (ex vivo 2012; Wirta et al., 2019)
■ Blurring of vision. studies)
■ Having extremely low surface tension, so spreading - SFA based azithromycin suspensions
rapidly on the ocular surface. eyedrops (ex vivo studies)
- No need for preservation when they are used. - Medium-chain triglycerides are used as
the oil phase in ocular emulsions
- Azithromycin 1.5%
Nano-emulsion - Improving ocular drug delivery. - A preservative-free CsA anionic oil-in- (Singh et al., 2020)
Anionic emulsions Cationic - Enhancing drug uptake into the cornea. water nanoemulsion (Daull et al., 2021; Lallemand
emulsions Anionic emulsion - CsA anionic oil-in-water nanoemulsion et al., 2017; Tong et al., 2020)
Decreasing eye irritation and vision disturbances contains sodium hyaluronate (Daull et al., 2013; Lallemand
Cationic emulsions - Cataionic nanoemulsion of CsA et al., 2012)
The positively charged nanodroplets interact with the
negatively charged mucin on the ocular surface.
Therefore this formulation prolongs drug residence time
and improves drug bioavailability.
Selfnanoemulsifying drug delivery Improving physicochemical properties of drugs and - CsA eyedrops with SNEDDS (Bang et al., 2019)
systems (SNEDDS) treatment efficacy in DED.
Polymeric Nanoparticles - Cationic nanoparticles - CsA nanoparticles are surface-modified (Liu et al., 2014)
-Improving mucoadhesion by ionic interaction with with phenylboronic once-weekly
negatively charged mucin. administration.
Solid lipid nanoparticles - Improving formulation shelf-life. - CsA formulated in compritol (Gökçe et al., 2009)
- Nanostructured Lipid Carriers - Improving drug ocular bioavailability. - A dexamethasone-encapsulated (Kumari et al., 2021)
- Lipid nanocapsules cholesterol-Labrafac™ lipophile system.
- Lipid-based (lipomimetic) eyedrops - Promising corneal mucoadhesion, biodistribution, and - An aqueous ophthalmic, patient- (Eldesouky et al., 2021)
preclinical efficacy in rabbits. friendly, CsA formulation.
(Agarwal and Craig, 2021)
(continued on next page)
12
Table 9 (continued )
Ocular delivery Advantages Applications References
- Reducing the interfacial tension between the aqueous - Oil in water emulsion (soybean oil and
and lipid components of the tear film and improving tear egg yolk phospholipids in aqueous
film stability and continuity. sodium hyaluronate.
- Providing a more consistent barrier to excessive tear
evaporation.
Contact lens - Promoting residence time of drug on the cornea. - Polyvinylpyrrolidone (Maulvi et al., 2020)
- Increasing drug ocular bioavailability. - Hyaluronic acid (Chang et al., 2021; Maulvi
- Phospholipids et al., 2015)
- Hydroxypropyl methylcellulose (Pitt et al., 2011)
- Cyclosporine A (White et al., 2011)
- Dexamethasone (Choi et al., 2019)
- Diclofenac (Bengani et al., 2020)
- Betaine (Demirel and Sarac, 2012)
(Hsu et al., 2015)
Nanowafers - They are applied by patients easily. - Dexamethasone (Coursey et al., 2015)
- The system is slowly dissolved and so resulting in a long
duration of the drug.
Ocular inserts (Lacrisert) - A preservative-free. - Hydroxypropyl cellulose (Nguyen and Latkany, 2011)
- Applied once-daily.
- Used in moderate to severe cases.
- After application, they are softened and dissolved
slowly, which leads to stabilizing the tear film and
relieving symptoms of DED.
(lipomimetics) are attractive alternatives to aqueous artificial tears due now there is not sufficient data for complete restoring of tear film effi
to their lipid compositions are close to the tear film composition that ciency. Early and objective diagnosing of DED will manage the treat
leads to relieve DED symptoms and improve the stability of the tear film ment process.
directly after instillation. In addition to that, these lipid-based nano Nowadays several new diagnostic techniques are already estab
technologies provide a high degree of drug solubility, drug ocular resi lished. The use of these techniques shows a great impact on the deter
dence time, and tissue penetration. mination of the different types and causes of DED. Although the
Using cationic nanoparticles mainly prolongs the ocular residence underlying causes still need further elucidation. Usually, the ophthal
time. So, the CsA nanoparticle’s surface is modified with a cationic mologist prescribes various medicines that act as tear substitution or
phenylboronic acid proposing that the drug concentration remains punctual plugs to help alleviate the symptoms of DED, but actually,
within the therapeutic range even after once-weekly application. these don’t address the problem.
Moreover, mucus penetrating nanoparticles (MPN) have been developed Currently, to overcome the problem, researchers have focused on the
as another approach to reduce the entrapment of particles and increase development of devices, processes, and medicines that help in the
ocular bioavailability (Lai et al., 2009). Recently, in 2020 FDA approved stimulation of tear secretion. Some of them are approved and marketed;
loteprednol etabonate nanoparticles coated with Poloxamer 407 however, others are still under investigation. DED is a chronic and
(KPI-121) that were formulated by the MPN technology for short-term progressive disorder, using medical devices or processes in management
DED treatment. is not cheap as usual, so using medicines is more suitable and applicable
Semifluorinated alkanes (SFAs) are non-aqueous vehicles used to for patients. Pharmaceutical scientists facing a great challenge in
formulate eye drops free from preservatives. These carriers were intro developing ocular delivery systems those help in the treatment of DED
duced recently to DED formulations as they enhance the diffusion of a preserving patient compliance. Theoretically, topical application of
drug through the cornea, stabilize the tear film and relieve the DED drugs is the most appropriate for the management of DED, however, the
symptoms effectively. inefficient integrity of tear film increases the susceptibility to ocular
Contact lenses are thin-curved-disk of polymeric materials used as toxicity after long-lasting topical application. So, the ideal topical drug
drug carrier systems. They can be classified into types (soft, rigid, and delivery system should base on the compromisation between safety and
semi-rigid) accordingly to the polymers used. Generally, the drug efficacy. Practically, they are striving hard to improve ocular drug de
bounded and loaded to lenses by presoaked in the drug solution. Drug livery systems for topical applications that target multiple underlying
contact lenses offer higher ocular bioavailability than eye drops due to causes with high drug bioavailability in formulations lacking
their close contact with the cornea. On the other hand, ocular inserts are preservatives
solid or semisolid and soluble or insoluble polymeric devices that are
applied to the conjunctival sac. They increase ocular residence time,
prolong the drug release to the eye, and improve patient compliance by Declaration of Competing Interest
lowering administration frequency. Further, nanowafers are thin poly
meric membranes designed as rectangular. They act as a drug reservoir The authors declare that they have no known competing financial
to improve therapeutic drug efficacy. Moreover, punctual plugs are a interests or personal relationships that could have appeared to influence
biodegradable polymer that dispenses a drug onto the ocular surface up the work reported in this paper.
to 30 days after insertion.
Generally, nanomedicine entered to DED management field through Supplementary materials
numerous types of nanocarriers, listed in Table 9, some of them already
marketed, while others are still under investigation. Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.ejps.2022.106206.
9. Concluding remarks
Appendix
The present retrospective article is focusing light on the current
dealing with DED from a pharmaceutical point of view. In fact and up till
Table A1.
13
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European Journal of Pharmaceutical Sciences 175 (2022) 106206

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European Journal of Pharmaceutical Sciences

Current trends in pharmaceutical treatment of dry eye disease: A review

Table 5 growth factors, immunoglobulins, vitamin A, enzymes, and proteins like

Proliposomes - Have a longer shelf-life. - CsA (Karn et al., 2014)

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