DHAHIR et al.

Nanoemulsions as Ophthalmic Drug Delivery

Turk J Pharm Sci 2021;18(5):652-664

DOI: 10.4274/tjps.galenos.2020.59319 REVIEW

Nanoemulsions as Ophthalmic Drug Delivery

Systems
Oftalmik İlaç Taşıyıcı Sistemler Olarak Nanoemülsiyonlar
Rasha Khalid DHAHIR, Amina Mudhafar AL-NIMA*, Fadia Yassir AL-BAZZAZ

Department of Pharmaceutics, College of Pharmacy, University of Mosul, Mosul, Iraq

ABSTRACT

Nanoemulsions are liquid-in-liquid dispersion with a droplet size of about 100 nm. They have a transparent appearance, high rate of bioavailability,
and increased shelf life. Nanoemulsions mainly consist of oil, water, surfactant, and cosurfactant and can be prepared by high- and low-energy
methods. Diluted nanoemulsions are utilized for the delivery of ophthalmic drugs due to their capability to penetrate the deep layers of the ocular
structure, provide a sustained release effect, and reduce the frequency of administration and side effects. These nanoemulsions are subjected to
certain tests, such as safety, stability, pH profile, rheological studies, and so on. Cationic nanoemulsions are prepared for topical ophthalmic delivery
of active ingredients from cationic agents to increase the drug residence time on the ocular surface, reducing their clearance from the ocular
surface and improving drug bioavailability. This review article summarizes the main characteristics of nanoemulsions, ophthalmic nanoemulsions,
and cationic nanoemulsions and their components, methods of preparation, and the evaluation parameters for ophthalmic nanoemulsions.
Key words: Nanoemulsion, cationic nanoemulsions, ophthalmic drug delivery

ÖZ

Nanoemülsiyonlar, yaklaşık 100 nm’lik bir damlacık boyutuna sahip sıvı içinde sıvı dispersiyonudur. Şeffaf bir görünüme, yüksek biyoyararlanıma ve
artırılmış raf ömrüne sahiptirler. Nanoemülsiyonlar esas olarak yağ, su, yüzey aktif madde ve yardımcı yüzey aktif maddeden oluşur ve yüksek ve
düşük enerjili yöntemlerle hazırlanabilir. Seyreltilmiş nanoemülsiyonlar, oküler yapının derin katmanlarına nüfuz etme, sürekli salım etkisi sağlama
ve uygulama sıklığını ve yan etkileri azaltma kabiliyetleri nedeniyle oftalmik ilaçların verilmesi için kullanılır. Bu nanoemülsiyonlar, güvenlik, stabilite,
pH profili, reolojik çalışmalar vb. gibi belirli testlere tabi tutulur. Katyonik nanoemülsiyonlar, ilacın oküler yüzey üzerinde kalış süresini artırmak,
oküler yüzeyden klirensini azaltmak ve ilaç biyoyararlanımını geliştirmek için katyonik ajanlardan aktif bileşenlerin topikal olarak oftalmik taşınımı
için hazırlanır. Bu derleme, nanoemülsiyonların, oftalmik nanoemülsiyonların ve katyonik nanoemülsiyonların temel özelliklerini ve bileşenlerini,
hazırlama yöntemlerini ve oftalmik nanoemülsiyonlar için değerlendirme parametrelerini özetlemektedir.
Anahtar kelimeler: Nanoemülsiyon, katyonik nanoemülsiyonlar, oftalmik ilaç verilmesi

INTRODUCTION The drug is removed from the precorneal area within several
Ophthalmic drug delivery system is one of the most important minutes after instillation due to lacrimal secretion and
routes of drug administration, but it is regarded as a challenging nasolacrimal drainage.3,4
attempt encountered by pharmaceutical scientists.1 Most
ophthalmic diseases are treated by topical eye drop instillation; Various problems, including the issue on stability, high cost, and
however, several problems, such as poor bioavailability, are tedious preparation methods, are associated with the scalingup
associated with these formulations.2 of nanoemulsions.5

*Correspondence: amnah.mudhafar@uomosul.edu.iq, Phone: 009647736976794, ORCID-ID: orcid.org//0000-0003-4090-0698

Received: 16.03.2020, Accepted: 22.06.2020
©Turk J Pharm Sci, Published by Galenos Publishing House.

652
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 653

For the above reasons, pharmaceutical scientists attempt to improve drug absorption and bioavailability.8,9
formulate ophthalmic preparations that can overcome such
Barriers for intraocular drug transport
problems. Although the incorporation of drugs in different
pharmaceutical vehicles, such as ointments, suspensions, and Each layer of the ocular tissue has distinct features and poses a
emulsions, can improve the bioavailability and provide sustained diverse barrier following drug administration via a certain route
drug release, they cannot be regarded as the formulation of (Figure 1).10
choice given their ocular adverse effects, including irritation, Tears
redness of the eye, interference with vision, and low product Tears can influence the administration of ophthalmic drugs
stability. In addition, chronic administration may increase through binding with the administered drug, resulting in
systemic availability and cause severe systemic complications. enhanced clearance and drug dilution. Tear turnover is one
Formulations containing preservatives also induce adverse of the dynamic barriers that significantly decrease drug
reactions upon systemic absorption.3,6,7 availability, leading to inhibition of therapeutic effect.1,11
Nanotechnology is one of the most important promising Cornea
approaches for ophthalmic drug delivery. This technology is The cornea, which is a non-vascular structure, consists of three
currently being applied for drug delivery to the anterior and
main layers: the outer epithelial layer which is a lipophilic layer,
posterior segments of the eye. Nanotechnology-based systems
with an appropriate particle size can be formulated to ensure the middle stromal layer which is hydrophilic in nature, and the
low irritation to the patient’s eye, adequate bioavailability, inner endothelial layer that separates the aqueous humour and
and compatibility with the ocular tissue. Such systems are an the stroma.5 The corneal epithelium forms the most important
excellent approach for the delivery of lipophilic drugs, which barrier to drug absorption by topical administration; the corneal
involves the application of cationic nanoemulsion, benefitting cells of glycosyl amino glycans lining the ocular surface are
from the negatively charged corneal and conjunctival cells that negatively charged at physiological pH.5,6 When applying a
can prolong the drug residence time on the ocular surface and positively charged formulation to the eye, an electrostatic

Figure 1. Ocular barriers for drug transport10

Permission has been obtained from the author for the use of the figure
654 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

attraction will possibly occur, which will prolong the residence including drugs, depends on the hydration degree of sclera and
time of the formulation on the ocular surface.5,12 its intraocular pressure. Intraocular pressures in the normal
range of 15-20 mmHg have negligible effects on permeability,
Conjunctiva
whereas the trans-scleral permeability of solute molecules
The conjunctiva of the eye is a thin layer that lines the inside
is affected by their high intraocular pressure up to (>20-60
of eyelids and maintains the tear film. The stroma between
mmHg).11
the outer conjunctival epithelium and inner sclera has an
abundance of blood and lymphatic vessels throughout the Choroid/Bruche’s membrane
subconjunctiva, and it acts as a dynamic barrier to hydrophobic This part of the eye is regarded as the most vascularized part
drug absorption. Given the rich capillaries and lymphatic of the body. The choroidal thickness decreases with age. By
vessels in the stroma, the drug administered to the conjunctival contrast, the thickness of Bruch’s membrane increases with
sac can be rapidly cleared.8,12 The conjunctival epithelium is age, and the changes in the thickness of choroid and Bruch’s
more penetrable to larger molecules and has 20 times larger membrane may affect drug penetration into the retina.8 With
surface area than the cornea because of its wider intercellular aging, the choroid becomes thinner, and the Bruch’s membrane
spaces. The conjunctival pathway favors the absorption of becomes thicker, leading to alteration in the barrier property
large hydrophilic molecules (with molecular weight nearly which in turn alters drug permeation of drug molecules over
less than 20 kDa), such as proteins and peptides, different the years.11
from the corneal route which favors lipophilic small molecules
Retina
(the majority of drugs). Meanwhile, the retardation of the
passive pathway can occur by the tight junctions present in the The retina is located at the back of the eye, on which an image
conjunctival epithelium. Therefore, if drug absorption through is formed from the light that enters the eye from the cornea,
passing across the anterior part until it reaches the retina in
the conjunctiva is compared with that through the cornea, the
the posterior part of the eye, where it can then be interpreted
former is considered as non-productive, leading to the low
in the brain. The retina may be subjected to diseases that affect
bioavailability of ophthalmic drugs.11,12
the posterior segment of the eye, such as age-related macular
Sclera degeneration and diabetic retinopathy. All of the drugs in the
The sclera is the outer layer of the eyeball and is known as the vitreous can be eliminated by anterior and posterior route; the
white of the eye. This part can maintain the eye shape through drugs can be eliminated across the retina after passing through
its fibrous structure. The hydrophobic nature of drugs affects the internal limiting membrane that separates the retina and the
the permeability of sclera; when the lipophilicity of a drug vitreous.8,9
increases, the permeability across the sclera will decrease, and CD44 is over expressed on the retina surface and is important
vice versa.8 Moreover, the permeation of therapeutic molecules, in targeting a number of drugs and gene-based therapeutics.

Table 1. Anatomical barriers for intraocular drug transport13

Anatomical barriers Characteristics
Epithelium is a major barrier to passage of hydro-philic drugs; tight intercellular junctions restrict
Cornea paracellular diffusion.
Stroma is a barrier to passage of highly lipophilic drugs.
Drugs bind with mucin, dilution of topical drugs.
Tear
Induced lacrimation and tear film turnover increase drug clearance.
More permeable than cornea to hydrophilic drugs and macromolecules; has greater surface area.
Conjunctiva
Epithelium-tight intercellular junctions.
Hydrated stroma better absorption of hydrophilic drugs.
Sclera More permeability to macromolecules.
Molecular radius is an important parameter to determine permeation.
Receives less blood flow, resulting in less drug permeation from the systemic circulation.
Choroid
Choroid Bruch’s membrane limits permeation of lipophilic drugs.
Hyaluronan- is more permeable to anionic drugs (due to negatively charge).
Vitreous humour
Large, lipophilic/hydrophilic drugs retained more in vitreous humor.
Permeable to small, lipophilic, or hydrophilic molecules.
Retina
Inner limiting membrane limits entry of drugs from vitreous into retina.
Blood aqueous barrier- tight junctions limit entry of solutes into aqueous humour and entry of hydrophilic drugs from
plasma into aqueous humour.
Blood ocular barriers
Outer blood retinal barrier- major barrier to hydrophilic drugs.
Inner blood retinal barrier- major barrier which limits entry of systemic drugs into retina.
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 655

Retina demonstrates the presence of 15-20 nm-wide proteins. Current studies focus on the role of these barriers in
intercellular spaces without tight junctions. As a result, small ophthalmic drug delivery.15,16 Efflux transporters for anticancer
hydrophilic/lipophilic drugs can permeate the retina. However, drugs, antibiotics (ofloxacin and erythromycin), and steroids are
large cationic molecules exhibit resistance to permeation in the recognized and limit drug bioavailability.14 However, different
retina. Inner and outer plexiform layers are major barriers to studies suggest various concepts, such as the conjugation
the diffusion of large molecules in human retina. This condition of drugs to the dendrimer to enable the bypassing of efflux
is supported by observations showing the persistence of hard transporters, resulting in an increased drug solubility and
exudates in hypertensive or diabetic retinopathy for months therefore increased drug bioavailability. In a study, propranolol
in the retina because molecules greater than 76 kDa diffuse (a calcium channel blocker), a well-known substrate of the
through the retina very slowly, whereas macromolecules with a p-glycoprotein efflux transporter, was conjugated to lauroyl-G3
molecular weight greater than 150 kDa are arrested by the inner dendrimers. This conjugation showed enhanced drug solubility.17
limiting membrane.10-12 However, the oral application of dendrimers for drug delivery is
Table 1 presents all the above barriers and their characteristics.13 in its infancy but may emerge as a promising strategy in the
Main challenges and key considerations in ocular drug delivery future.18

Challenges Definition of nanoemulsion

The eye is a unique organ anatomically and physiologically, Nanoemulsions can be defined as a clear and stable dispersion
and it contains highly varied structures with independent of oil and water. They are mainly composed of the internal,
physiological functions. This complexity of the eye provides dispersed, and external phases or the dispersion medium. The
special challenges to ocular drug delivery strategies.13 One of surfactant and cosurfactant molecules play an effective role in
the challenges is the absorption; as with traditional eye drops, the formation of nanoemulsions due to their capability to reduce
ocular bioavailability after topical administration is low at 3%- the interfacial tension and create a small particle size due to
4% due to the eye’s impermeable nature and small surface area. their function in the formation of stable preparations as a result
Other challenges include poor drug solubility. Lipophilic drugs of the repulsive electrostatic interaction and steric hindrance. In
cannot be incorporated in conventional aqueous eye drops. For general, surfactants are molecules that have a bipolar structure
this reason, they must be formulated as suspensions. Regarding composed of hydrophilic and hydrophobic parts.8,19
patient compliance, frequent instillations are usually needed Nanoemulsions are colloidal carriers of drug molecules with a
with eye drops to reach the desired therapeutic range of the droplet size in the range of 500-1000 nm (preferably from 100
drug. High tolerability or comfort demands limit the formulation nm to 500 nm). As a drug delivery system, they increase the
options. As for excipient choice, limited numbers of expedients therapeutic efficacy and minimize the adverse effects and toxic
are listed in ophthalmology. Finally, the delivery of conventional reactions of the administered drug.20,21
eye drops to the posterior segment of the eye is impossible.8,9 Nanoemulsions can be distinguished from microemulsions in
Considerations terms of their droplet size and physical stability characteristics.
Ocular drugs typically achieve <10% ocular bioavailability. If Microemulsions are isotropic and transparent systems that
a drug is applied to the outer surface of the eye, it may pass contain spherical droplets of the water or oil phase (diameter
ocular blood barriers where it will encounter metabolizing range: 10-100 nm) and dispersed in an external oil or water
enzymes and cellular transporters before it reaches the site of phase, respectively. Microemulsions are thermodynamically
action. Thus, the anatomy and physiology of the eye, including more stable than nanoemulsions given the necessity of
the mucus layer, eyelids, metabolism, and blink drainage, must introducing thermal and/or mechanical energy in the
be considered. Other considerations include tear composition, preparation of nanoemulsions (i.e., mixing and heating) and
such as enzymes, lipid outer layer, and stability of the tear film; phase separation after a certain period after the preparation
disease state and occurrence of keratitis or inflammation on of nanoemulsions. This condition is one of the most distinctive
absorption, drug clearance, and ocular comfort and tolerability differences between microemulsions and nanoemulsions in
of the formulation, including viscosity, drop size, pH, and terms of stability.20,22
osmolality. In addition to the above considerations, patient The preparation of nanoemulsion can be classified into two main
anticipation, squeeze capability, and type of packaging must be classes, namely, high-energy methods such as highpressure
accounted for.8,9,14 homogenization and ultrasonication, and low-energy methods
Efflux transporters and ophthalmic drug bioavailability such as phase inversion.23
The primary barriers result in poor absorption of the drug and The translucent appearance of nanoemulsions is due to a
poor bioavailability, especially for anterior segment ophthalmic droplet size of less than 100 nm. With such a small droplet
drug delivery. Several of these barriers have been identified in size, the nanoemulsion is thermodynamically unstable during
epithelial cells of various ocular tissues in humans and rabbits; dispersion. The required high-concentration of surfactants
these barriers include p-glycoprotein (also called multidrug results in the sticky texture of the formulation. A yellowish
resistance protein 1), multidrug resistance-associated proteins appearance and rancid odor occur after storage due to the
(MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, and presence of phospholipids, which are generally used to stabilize
MRP9), lung resistance proteins, and breast cancer resistance nanoemulsions. Thus, a formulation was developed and
656 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

presented to overcome these problems (US6335022b1); this interfacial activity were studied. Various data, in addition to the
formulation utilizes oxyethylenated and non-oxyethylenated physical stability of the formulated emulsions with different
sorbitan fatty esters as surfactants.16 The contrivers believed compound polysaccharides, were studied. The results showed
that the use of surfactants selected from oxyethylated or that emulsions formulated with compound polysaccharides
nonoxyethylated sorbitan fatty esters with a molecular weight manifested small average particle sizes, and the stability
of more than 400 g per mole, which are solid at a temperature analysis showed that the emulsion formulated by compounding
of less than 45°C, can result in a stable formulation. In addition, polysaccharides had preferable physical stability.30
a similar formulation-stabilizing effect can result from
Components of nanoemulsions
amphiphilic lipids from a group of alkaline salts of cholesterol;
these formulations can be used as effective delivery vehicles The prime components of nanoemulsions are oil, aqueous
for antiglaucoma, anti-inflammatory, antiviral, and antiallergic phase, and emulsifying agents. Different types of oils, such
effects.23,24 as medium-chain triglycerides, mineral oils, and vegetal oils
including castor oil, can be used in ophthalmic nanoemulsions.31
The bioavailability of ophthalmic preparations can be improved
Emulsifying agents are important in maintaining product
by enhancing the drug residence time on the cornea through
stability because without these agents, the oil and water
increasing the viscosity of formulations. This effect can phases will separate into two layers. These compounds may
be achieved by increasing the fraction of the dispersed oil be surfactants, such as polysorbates, cremophors, poloxamers,
phase and by incorporating water-soluble polymers, which tyloxapol, and vitamin E-TPGS. Emulsifying agents should have
can form a gel with the continuous aqueous phase. Certain certain properties, including compatibility with the product and
studies demonstrated that caution should be recommended in non-toxicity.5,21
considering the ideal concentration of water-soluble polymers
to obtain the required viscosity with a transparency of the Desirable properties of emulsifying agents21,32,33
preparation.25 1. They should have the capability to reduce the surface tension
Prostaglandins affect a wide range of physiological activities, to less than 10 dyne/cm.
such as blood pressure, pain awareness, and clotting 2. They should form a stable and coherent film around the
mechanisms. Several of these analogs are utilized in ophthalmic dispersed phase globules to prevent coalescence.
antiglaucoma preparations, such as travoprost, latanoprost, and 3. They should provide adequate viscosity and zeta potential for
bimatoprost. However, such analogs are chemically unstable in optimum stability.
aqueous preparations and have a poor water solubility. 4. They should be effective in low concentration.
Thus, various strategies have been suggested to avoid these Types of films around dispersed globules in nanoemulsions34,35
challenges. These strategies include pH adjustment and
Monomolecular film
complexation with cyclodextrin to improve solubility and
stability. Solubility can also be improved by the addition of The surfactants that stabilize nanoemulsions form a monolayer
benzalkonium chlorides. The problem associated with these of ions or adsorbed molecules at the interface, and this
monolayer reduces the interfacial tension; to date, a combination
preparations is the ocular intolerability associated with the
of emulsifying agents can be used; such a combination is
positively charged resultant preparation. Carli et al.26 discovered
composed of a hydrophilic emulsifying agent at the aqueous
that neutral zeta potential and non-toxic preparations can be
layer and lipophilic one at the lipoid layer to produce a complex
obtained from a nanoemulsion formulation that consists of
film at the interface.36
prostaglandin containing oil phase as an internal phase and is
dispersed in the aqueous external phase, utilizing two or more Multimolecular film
non-ionic surfactants.27 Cyclosporin A is used widely for the A multimolecular film around the droplets is formed by hydrated
treatment of dry eye disease. However, precipitation of the lyophilic colloids; these agents do not lower the surface tension
drug occurs as a result of its poor solubility in the aqueous significantly but can increase emulsion stability through their
medium. In patent disclosures US4649047 and US6582718, the tendency to enhance the viscosity of the external phase.34
improved formulation of this drug has been reported.28 Solid particulate film
Positively charged ophthalmic preparation strategy is applied This type of film is produced by emulsifying agents, which
by utilizing the negative charge of corneal barriers. United are small solid particles and form a film around the dispersed
States patent no. 6007826 describes an oil/water preparation droplets, hence inhibiting their coalescence.34,35
consisting of surfactants/lipid; this preparation has a positively Preparation of nanoemulsions
charged polar group, resulting in a cationic preparation that can
Two main methods are used for nanoemulsion preparation:
bind strongly to the corneal surface.29
High-energy and low-energy methods. Low-energy methods
Wang et al.30 and colleagues from Hainan University, China involve changing the composition or temperature, which results
developed coconut oil-in-water emulsions that were formulated in system reversal and the formation of small droplets. The
using three polysaccharides. The main effects of the ratio of most common low-energy methods are emulsion inversion
compounded polysaccharides on their apparent viscosity and point (EIP) and phase inversion temperature (PIT) methods.32,37
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 657

High-energy methods consist of two main steps, which result occurs. This method requires no energy to form the emulsion
in the formation of the nanoemulsion. The first step involves owing to the low interfacial tension between the oil and water
the mixing of oil, water, and surfactant for a sufficient period in interface, which results in the formation of small droplets. In
a simple stirrer system, resulting in the formation of oil/water the PIT method, the initial water/oil macroemulsion is formed at
macroemulsion. The second step includes the conversion of the a temperature higher than the PIT, and conversion occurs after
macroemulsion into a nanoemulsion through a homogenizer, cooling to produce the required oil/water emulsion without the
which forces the macroemulsion through a narrow gap; this need for energy (Figure 2b).31,41,42 Figure 2 was used with the
homogenization is repeated several times until a constant personal permission from Gupta et al.31
droplet size is achieved (Figure 2a).22,31,38 Zhang et al.39
prepared tacrolimus-loaded cationic nanoemulsions by using Instability of nanoemulsions9,21
a highpressure homogenization method. Meanwhile, Dukovski 1. Flocculation can be defined as an aggregation of small
et al.40 used a microfluidizer and homogenizer to prepare an globules to form large floccules.
ibuprofenloaded cationic nanoemulsion.
2. Creaming refers to the settling down or rising up of floccules,
Different from high-energy methods, low-energy methods start
which form a concentrated layer. Upon agitation, the emulsion
with a water/oil emulsion, which is converted into an oil/water
can be reconstituted.
emulsion due to the changes in temperature and composition.
The EIP method involves the conversion of a water/oil 3. Cracking is the permanent instability of a nanoemulsion, in
macroemulsion, which is formed initially at room temperature, which the internal phase separates as a layer. In this case, upon
into an oil/water nanoemulsion through gradual dilution until agitation, the emulsion cannot be reconstituted, and additional
it passes over the inversion point, at which transformation amounts of surfactants may be beneficial.

Figure 2a. Overview of high-energy methods, such as high-pressure homogenization and ultrasonication, for the preparation of oil/water nanoemulsion31

Figure 2b. Overview of low-energy methods for the preparation of oil/water nanoemulsion
Other nanoemulsion preparation methods, such as as bubble bursting, evaporative ripening, and microfluidization, are also employed31
658 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

4. Miscellaneous instability denotes the instability of a be taken in by oil droplets, with a very small amount present
nanoemulsion due to extreme temperature and light. In this in the aqueous phase. These preparations show an important
scenario, the emulsion should be stored in a tight-colored role in prolonging the residence time of drugs on the ocular
container. tissue, which is greater than that observed in anionic oil/
5. Phase inversion occurs as a result of changes in the volume water nanoemulsions. In addition to their important biological
ratio of phases or addition of electrolytes, which lead to the effects, cationic surfactants can stabilize nanoemulsions and
changes in the emulsion type from water/oil to oil/water, and prolong their shelf life through preventing the coalescence of
vice versa. oil droplets (Figure 3) due to their repulsive force.44,45 Table 3
summarizes several important physicochemical features of a
Important factors during the preparation of nanoemulsions7-9,34
cationic oil/water nanoemulsion.
One of the most important factor during nanoemulsion
preparation is the careful choice of surfactants to achieve The reason behind the discovery of these cationic nanoemulsions
an extremely low interfacial tension. The concentration is that different attempts that had been made to extend drug
of surfactants must be sufficiently high to stabilize the residence time at the ocular surface; the use of excipients
microdroplets to yield the nanoemulsion. In addition to the above with bioadhesive and viscosity enhancement properties, such
factors, adequate flexibility and fluidity of surfactants should be as cellulose derivatives and propylene glycol, are associated
considered to support the formation of nanoemulsions. with problems, including ocular disturbance; excipients are
only applicable to hydrophilic drugs; in addition, many lipophilic
Advantages of nanoemulsions34,35 drugs formulated as topical ocular oily or micellar solutions,
Nanoemulsions enhance drug bioavailability, are non-irritant, ointments, and creams are not only uncomfortable to the patient
non-toxic, and physically stable, and improve drug absorption but also show restricted efficacy.46
due to their high surface area and small droplets size.
Nanoemulsions can also be formulated in different formulations, Protective properties of cationic oil-in-water nanoemulsion
dissolve lipophilic drugs, require less amount of energy, and vehicle
promote taste masking. Regarding lipophilic drugs, the application of cationic
nanoemulsions to increase ocular bioavailability through
Disadvantages of nanoemulsions34,36
prolonging the drug residence time and spreading properties
Nanoemulsions require the addition of large amounts of is accompanied by surprising valuable effects on the ocular
surfactants and cosurfactants to maintain their stability; surface.47
they have a limited capacity to solubilize high-melting-point
By mixing the oil phase in cationic oil/water nanoemulsions
substances. In addition, the toxicity of surfactants should be
with the lipid layer of the tear film, water evaporation from the
considered, and different environmental parameters can affect
nanoemulsion stability. Table 2 summarizes the advantages and
disadvantages of nanoemulsions and several of their physical
properties.
Cationic oil-in-water nanoemulsion
Cationic nanoemulsions are preparations that utilize cationic
surfactants, which concentrate around the surface of oil
droplets to make them positively charged. Owing to the
negative nature of the ocular surface, cationic nanoemulsions
can improve the residence period of the product in the
eye through the electrostatic interaction with the opposite
charges of the eye surface mucus layer. Therefore, cationic
nanoemulsions probably improve therapeutic efficacy due
to an increase in the retention time at the ocular surface.25,43 Figure 3. Schematic of one of the oil nanodroplets present in the cationic
Cationic surfactants should have an adequate lipophilicity to oil-in-water nanoemulsion50

Table 2. Advantages, disadvantages, and several properties of nanoemulsions

Advantages Disadvantages Other properties
Carrier of hydrophobic drugs Requires large amount of surfactant and cosurfactant Translucent/translucent system
Improves bioavailability of drugs Low capability to solubilize high-melting-point drugs High surface area/small droplet size
Good shelf stability Low stability especially in acidic condition Liquid morphology
Toxicologically safe Toxicity of surfactants and cosufractants is possible Has benefit to mask taste
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 659

Table 3. Summary of the physicochemical characteristics of a cationic oil-in-water nanoemulsion50

Parameter Description
Aspect White opaque to slightly translucent
pH 5.0-7.0
Osmolality (mOsmol/kg) 270
Droplet size (nm) <200
Zeta potential (Mv) Positive (+40)
Sterility Sterile

aqueous phase is reduced, which can promote the restoration of

the lacrimal film integrity and maintenance of product stability.
Such benefits are important for patients suffering from short
tear-film breakup time due to lipid deficiency in their tears
(meibomian disease). Nanoemulsions are also important in the
treatment of keratitis and in the reduction of dry eye disease
symptoms by their capability to mechanically stabilize the tear
film and increase the hypo-osmolarity of the aqueous film given
that hyperosmolarity is a proinflammatory factor. In addition,
these preparations have unexpected beneficial effects in the
wound healing process by reducing the size of the scraped
area.48,49
Choice of cationic agent
A high zeta potential of nanoemulsions is one of the most
important factors to be considered before selecting a cationic
agent. The entire cationic agent must be trapped in oil
nanodroplets, with the positive charge positioned at the oilwater
interface, to obtain a high zeta potential; a very small amount
of these agents may exist in the aqueous phase, therefore
requiring a high-lipophilicity cationic agent.49
The selection of cationic agent must be limited to those
that have been previously registered, used in ophthalmic
products, or submitted to the United States or European
pharmacopoeia. Given the large numbers of cationic agents,
such as stearylamine, oleylamine, polyethylenimine, polylysine,
and benzalkonium chloride derivatives, not all of them can be
selected due to their related toxicity.49,50 Figure 4 (presented
with personal permission from Jean-Sébastien Garrigue) Figure 4. Illustration of the phase distribution for the different alkyl
shows a drawing of the phase spreading of diverse alkyl derivatives of benzalkonium chloride in (a) emulsion and (b) aqueous
derivatives of benzalkonium chloride in (a) emulsion and (b) solution50
aqueous solution.50
Stearylamine is one of the most commonly used cationic
also used for cationic drug delivery systems; they are used in
agents. However, this primary amine is very reactive to
various nanoparticles as cationic agents, but several authors
various excipients. Thus, this compound is not described in
regard them as extremely toxic.52
pharmacopoeias. Oleylamine is a cationic lipid that has been
used for manufacturing ophthalmic nanoemulsions; however, it Quaternary ammonium compounds, such as benzalkonium
has as stability problem owing to the existence of unsaturated chloride, benzododecinium bromide, and cetrimide, are
sites in the aliphatic chain and the function of its primary preservatives that have surfactant properties and provide
amine.49,51 nanoemulsions with a positive charge. Their preservative action
Additional cationic molecules that are used for DNA is due to their capability to bind negatively charged bacteria
transfection, such as polyethylimine and poly-L-lysine, are and mycoplasma, which destroys their membrane. As a result,
660 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

their action is not only limited to microorganisms but also preparation allows limited blinking pain and good tolerance,
the epithelial cell lining of the ocular surface via an identical whereas a more viscous one can improve the residence time
mechanism; in addition, the preservative action of these agents of the drug and ocular bioavailability; the viscosity of eye drops
is neutralized by the emulsion because less amount of these should not be more than 20 mPa s.60,61
agents is present freely in the aqueous medium, which limits
Osmolality
their antimicrobial action and results in a toxic effect.53
The lacrimal fluid osmolality is between 280-293 mOsm/kg.
EVALUATION OF OPHTHALMIC NANOEMULSION However, when the eye is opened, the osmolality is between
231-446 mOsm/kg due to evaporation. When the osmolality
Parameters for evaluation of a solution is less than 100 or greater than 640 mOsm/kg,
Zeta potential the preparation will irritate the eye. However, the osmolality
Zeta potential is the measurement of charge repulsion among is reestablished 1-2 min after the instillation of a non-isotonic
oil nanodroplets. This variable is one of the most important solution.62
parameters affecting the dispersed system stability. A high zeta Ocular irritation study
potential results in a stable nanoemulsion. Its value depends These studies should ensure that corneal integrity and structure
on the differences between the electrical potential of the are not affected.62,63
dispersion medium and the stationary layer of fluid close to the
dispersed oil nanodroplets.50,54 Thermodynamic stability studies
These studies involve subjecting the nanoemulsion formulation
The optimum zeta potential range is between +20 mV and +40
to six cycles between 4°C and 45°C. Then, the stable
mV.5
formulations are exposed to centrifugation test at about 3500
Refractive index rpm; formulations that do not display phase separation will
The refractive index can be determined by using an Abbes be obtained for the freeze-thaw stress test; during this test,
refractometer. This index is used to determine any probable the formulation is exposed to three freeze-thaw cycles under
impairment of vision or distress after the administration of an standard laboratory conditions.56,64
eye drop.50,55 The refractive index for the tear fluid is 1.340 to
Analysis of droplet size
1.360. Eye drops must have refractive index values not higher
The droplet size is measured using a diffusion method, a
than 1.476.56
particle size analyzer, light scattering, and LS 230. In addition,
Percentage transmittance droplet sizes can be measured via correlation spectroscopy and
The percentage transmittance can be measured by a transmission electron microscopy.65
spectrophotometer50,54 at a specific wavelength with distilled
Viscosity measurement
water as a blank. The formulated nanoemulsion is considered
Viscosity can be determined by using a rotary viscometer at
transparent if the percentage transmittance is more than 99%.57
different temperatures.54
pH
Dilution test
The pH can be measured by using a pH meter, and the pH of
This test ensures that the stability of an ophthalmic
nanoemulsions should be about 7.2±0.2 for maximum comfort.
nanoemulsion remains unchanged its after dilution; it involves
When the pH of the instilled solution is different from the tear
the addition of the aqueous phase to the nanoemulsion without
pH, it results in discomfort and irritant effect, which depends on
showing any problem.54
the contact period with the eye surface, solution composition,
volume instilled, and buffering capacity. However, in most Drug content
cases in which the preparation is not buffered or only slightly A predetermined weight of nanoemulsion is extracted
buffered, a nanoemulsion with a different pH can be tolerated by dissolving it in an appropriate solvent, which is then
because the tear pH can be adjusted to physiological levels; the investigated using a spectrophotometer or high-performance
accepted pH of preparations is between 3.5-8.5.58,59 liquid chromatograph.54
Surface tension Polydispersity
The tear film becomes damaged when the surface tension of This test is performed to determine the droplet size uniformity
eye drops is greatly lower than that of the lachrymal fluid (40- using a spectrophotometer; the greater the polydispersity, the
50 mN/m).60 lesser the uniformity of droplet size.54
Rheological measurement Cytotoxicity test
The influence of an ophthalmic preparation on the normal tear This test examines the effects of a preparation on a certain
behavior should be as minimal as possible; a less viscous culture of mammalian cells.66,67
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 661

Examples of ophthalmic nanoemulsion studies and new products be used in the preparation of nanoemulsions, whereas phase
Nanoemulsions are promising for ophthalmic disease treatment. separation may occur after preparation. Thus, nanoemulsions
Thus, diverse studies cover the use of nanoemulsions as are thermodynamically less stable than microemulsions.
ophthalmic drug delivery vehicles, as summarized in Table 4.
The translucent appearance of nanoemulsions is due to
When formulated as nanoemulsions, drugs, such as timolol,
a droplet size of less than 100 nm. As a result of this small
dexamethasone, indomethacin, levobunolol, pilocarpine, and
droplet size, nanoemulsions exist as thermodynamically
chloramphenicol, exhibit preferred advantages over other
unstable dispersion. A high concentration of surfactants is
traditional formulations (Table 4). Moreover, a number of
required, resulting in the sticky texture of the formulation.
nanoemulsion products are available either on the market,
A yellowish appearance and rancid odor occur after storage
such as Restasis® (Allergan company) which is used as a
nanoemulsion formulation for dry eye disease, or in clinical due to the presence of phospholipids, which are generally
trials (brimonidine tartrate eye drops for dry eye disease under used to stabilize nanoemulsions. Nanoemulsions are easily
phase III). All these new examples are shown in Table 5.68,69 manufactured system prepared by methods which may or may
not rely on energy.
CONCLUSION Unlike traditional ocular solutions and suspensions, which
Owing to the innovation of nanoformulations, which is preferred have considerable bioavailability and require frequent dosing,
over the systemic route, a significant improvement has been nanoemulsions have huge potential in enhancing bioavailability
achieved in ocular disease therapy. Heating and/or mixing must and reducing the frequency of drug administration. Surfactants

Table 4. Studies of several ophthalmic nanoemulsion formulations with types of surfactants and cosurfactants and oil used68
S. no. Drug Surfactants and co-surfactants Oil Comment
Nanoemulsion bioavailability in aqueous
1 Timolol Lecithin Isopropyl myristate humour was 3.5 times more than Timolol
alone.
Enhanced ocular bioavailability (about three
2 times compared with the conventional dosage
Dexamethasone Cremophor EL, ropyleneglycol, Isopropyl myristate
form) and sustained effect of drug without
ocular irritation.
Significant increase in corneal permeability
compared with the marketed formulation
3 Indomethacin Phospholipids miranol-MHT MCT (Indocollyre®) and showed almost 4 times
corneal permeability coefficient without
toxicity in ex vivo studies.

4 Improved in vitro permeability with a reservoir

Levobunolol Lecithin, glycerol Soybean oil
effect.
Macrogol 1500- Enhanced ocular bioavailability of up to 1.68
5 Pilocarpine glyceroltriricinoleate, Isopropyl myristate times with sustained effect and no ocular
6PEG 200, propylene glycol, toxicity in comparison with aqueous solutions.
Improved stability in nanoemulsion formulation
Isopropyl palmitate and
6 Span20, Span80, in comparison to conventional system
Chloramphenicol isopropyl
Tween20, Tween80 as chloramphenicol is relatively prone to
myristate
degradation in conventional dosage form.

Table 5. Ophthalmic nanoemulsions products69

Nanoemulsions in the market for ophthalmic disease treatment
Trade name Drugs Formulation Disease Company
Restasis ®
0.05% cyclosporin A Nanoemulsion Dry eye disease Allergan
Cyclokat® 0.1% cyclosporin A Cationic nanoemulsion Dry eye disease Santen pharmaceuticals
Nanoemulsion under clinical trials for ophthalmic disease treatment
Products Administration method Disease Trial Phase
Brimonidine tartrate Eye drops Dry eye disease NCT03785340 III
662 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

and cosurfactants are important constituents of nanoemulsions 12. Suri R, Beg S, Kohli K. Target strategies for drug delivery bypassing
and should be carefully selected. Their concentrations should ocular barriers. J Drug Deliv Sci Technol. 2020;55:101389.
be high enough to obtain ultra-low interfacial tension. 13. Singh V, Ahmad R, Heming T. The challenges of ophthalmic drug delivery:
a review. Int J Drug Discov. 2011;3:56-62.
However, their toxicity presents a concern. In addition, cationic
surfactants can be utilized to increase the product residence 14. Agban Y, Thakur SS, Mugisho OO, Rupenthal ID. Depot formulations
time on the eye. Accordingly, the use of nanoemulsion systems to sustain periocular drug delivery to the posterior eye segment. Drug
for topical ocular therapeutics can overcome the problem of Discov Today. 2019;24:1458-1469.
multiple daily doses of traditional ocular therapy and improve 15. DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug
patient compliance. To date, increasing interest surrounds efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2012;52:249-273.
nanoformulation studies, and the growing literature in this field 16. Ruponen M, Urtti A. Undefined role of mucus as a barrier in ocular drug
is causing a great shift in the management of eye diseases, delivery. Eur J Pharm Biopharm. 2015;96:442-446.
with the creation of successful products on the market and in
17. D’Emanuele A, Jevprasesphant R, Penny J, Attwood D. The use of a
clinical trials. dendrimer-propranolol prodrug to bypass efflux transporters and
enhance oral bioavailability. J Control Release. 2004; 95:447-453.
ACKNOWLEDGEMENTS 18. Parveen S, Misra R, Sahoo SK. Nanoparticles: a boon to drug delivery,
The authors are grateful to the College of Pharmacy, University therapeutics, diagnostics and imaging. Nanomedicine. 2012;8:147-166.
of Mosul, Mosul, Iraq, for their support in this research. 19. Zdziennicka A, Krawczyk J, Szymczyk K, Jańczuk B. Macroscopic and
microscopic properties of some surfactants and biosurfactants. Int J
Conflicts of interest: No conflict of interest was declared by the Molecular Sci. 2018;19:1934.
authors. The authors alone are responsible for the content and
20. Čalija B. Microsized and nanosized carriers for nonsteroidal anti-
writing of this article inflammatory drugs: formulation challenges and potential benefits.
Belgrade: Academic Press; 2017.
REFERENCES 21. Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of
1. Bucolo C, Drago F, Salomone S. Ocular drug delivery: a clue from drug delivery system. 3 Biotech. 2015;5:123.
nanotechnology. Front Pharmacol. 2012;3:1-3.
22. Delmas T, Piraux H, Couffin AC, Texier I, Vinet F, Poulin P, Cates ME,
2. Al-bazzaz FY, Al-kotaji M. Ophthalmic in-situ sustained gel of Bibette J. How to prepare and stabilize very small nanoemulsions.
ciprofloxacin, preparation and evaluation study. Int J Appl Pharm. Langmuir. 2011;27:1683-1692.
2018;10:153-161.
23. Park H, Han DW, Kim JW. Highly stable phase change material emulsions
3. Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Nanoemulsion as a fabricated by interfacial assembly of amphiphilic block copolymers
potential ophthalmic delivery system for dorzolamide hydrochloride. during phase inversion. Langmuir. 2015;31:2649-2654.
AAPS PharmSciTech. 2009;10:808-819.
24. Ako-Adounvo AM, Nagarwal RC, Oliveira L, Boddu SHS, Wang XS, Dey S,
4. Kumari A, Sharma PK, Garg VK, Garg G. Ocular inserts: advancement in Karla P. Recent Patents on ophthalmic nanoformulations and therapeutic
therapy of eye diseases. J Adv Pharm Technol Res. 2010;1:291-296. implications. Recent Pat Drug Deliv Formul. 2014;8:193-201.
5. Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. Successfully 25. Subrizi A, del Amo EM, Korzhakov-Vlakh V, Tennikova T, Ruponen M,
Improving Ocular Drug Delivery Using the Cationic Nanoemulsion, Urtti A. Design principles of ocular drug delivery systems: importance of
Novasorb. J Drug Deliv. 2012;2012:604204. drug payload, release rate, and material properties. Drug Discov Today.
6. Shah J, Nair A, Jacob S, Patel R, Shah H, Shehata T, Morsy M. 2019;24:1446-1457.
Nanoemulsion based vehicle for effective ocular delivery of moxifloxacin 26. Carli F, Baronian M, Schmid R, Chiellini E, inventors; AZAD Pharma AG,
using experimental design and pharmacokinetic study in rabbits. assignee. Ophthalmic oil-in-water emulsions containing prostaglandins.
Pharmaceutics. 2019;11:230. United States patent application. 2013; US 13/804,794.
7. SCCS. “Guidance on the safety assessment of nanomaterials in 27. Toris CB. Pharmacotherapies for glaucoma. Curr Mol Med. 2010;10:824-
cosmetics”(2012). Avaialable from: https://ec.europa.eu/newsroom/ 840.
sante/items/661871
28. Khan W, Aldouby YH, Avramoff A, Domb AJ. Cyclosporin nanosphere
8. Yen CC, Chen YC, Wu MT, Wang CC, Wu YT. Nanoemulsion as a strategy formulation for ophthalmic administration. Int J Pharm. 2012;437:275-
for improving the oral bioavailability and antiinflammatory activity of 276.
andrographolide. Int J Nanomedicine. 2018;13:669-680.
29. Benita S, Elbaz E, inventors; Yissum Research Development Co of
9. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: Hebrew University, assignee. Oil-in-water emulsions of positively
An overview. World J Pharmacol. 2013;2:47-64. charged particles. United States patent US 6,007,826. 1999 Dec 28.
10. Huang D, Chen YS, Rupenthal ID. Overcoming ocular drug delivery Available from: https://patents.justia.com/assignee/yisum-research-
barriers through the use of physical forces. Adv Drug Deliv Rev. development-company-of-the-hebrew-university-of-jerusalem
2018;126:96-112.
30. Wang B, Tian H, Xiang D. Stabilizing the oil-in-water emulsions using the
11. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. mixtures of dendrobium officinale polysaccharides and gum arabic or
AAPS J. 2010;12:348-360. propylene glycol alginate. Molecules. 2020;25:759.
 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery 663

31. Gupta A, Eral HB, Hatton TA, Doyle PS. Nanoemulsions: formation, 49. Dell SJ, Gaster RN, Barbarino SC, Cunningham DN. Prospective
properties and applications. Soft Matter. 2016;12:2826-2841. evaluation of intense pulsed light and meibomian gland expression
efficacy on relieving signs and symptoms of dry eye disease due to
32. Tadros TF. Emulsion formation, stability, and rheology. Emulsion
meibomian gland dysfunction. Clin Ophthalmol. 2017;11:817-827.
formation and stability. 2013;1:1-75.
50. Daull P, Lallemand F, Garrigue JS. Benefits of cetalkonium chloride
33. Qiu H, Chen X, Wei X, Liang J, Zhou D, Wang L. The emulsifying
cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery.
properties of hydrogenated rosin xylitol ester as a biomass surfactant
J Pharm Pharmacol. 2014;66:531-541.
for food: effect of ph and salts. Molecules. 2020;25:302.
51. Campbell PI. Toxicity of some charged lipids used in liposome
34. Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of
preparations. Cytobios. 1983;37:21-26.
drug delivery system. 3 Biotech. 2015;5:123.
52. Manosroi A, Podjanasoonthon K, Manosroi J. Development of novel
35. Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S. Nanoemulsions as
topical tranexamic acid liposome formulations. Int J Pharm. 2002;235:61-
vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech.
70.
2007;8:E104.
53. Draz MS, Fang BA, Zhang P, Hu Z, Gu S, Weng KC, Gray JW, Chen FF.
36. Nikam TH, Patil MP, Patil SS, Vadnere GP, Lodhi S. Nanoemulsion: a brief
Nanoparticle-Mediated Systemic Delivery of siRNA for Treatment of
review on development and application in parenteral drug delivery. Adv
Cancers and Viral Infections. Theranostics. 2014;4:872-892.
Pharm J. 2018;3:43-54.
54. Wu TH, Craven A, Tran T, Tran K, So K, Levi DM, Li RW. Enhancing
37. Sharma N, Mishra S, Sharma S, Deshpande RD, Sharma RK. Preparation coarse-to-fine stereo vision by perceptual learning: An asymmetric
and optimization of nanoemulsions for targeting drug delivery. Int J Drug transfer across spatial frequency spectrum. Invest Ophthalmol Vis Sci.
Dev Res. 2013;5:37-48. 2014;55:751.
38. Chávez-Zamudio R, Ochoa-Flores AA, Soto-Rodríguez I, Garcia-Varela 55. Liu DX, Zhao XT, Liang W, Li JW. The stability and breakage of oil-in-water
R, García HS. Preparation, characterization and bioavailability by from polymer flooding produced water. Pet Sci Technol. 2013;31:2082-
oral administration of O/W curcumin nanoemulsions stabilized with 2088.
lysophosphatidylcholine. Food Funct. 2017;8:3346-3354.
56. Patel N, Nakrani H, Raval M, Sheth N. Development of loteprednol
39. Zhang J, Liu Z, Tao C, Lin X, Zhang M, Zeng L, Chen X, Song H. Cationic etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for
nanoemulsions with prolonged retention time as promising carriers for sustained delivery and enhanced ocular bioavailability. Drug Deliv.
ophthalmic delivery of tacrolimus. Eur J Pharm Sci. 2020;144:105229. 2016;23:3712-3723.
40. Dukovski BJ, Juretić M, Bračko D, Randjelović D, Savić S, Moral MC, 57. Gurpreet K, Singh SK. Review of nanoemulsion formulation and
Diebold Y, Filipović-Grčić J, Pepić I, Lovrić J. Functional ibuprofen- characterization techniques. Indian J Pharm Sci. 2018;80:781-789.
loaded cationic nanoemulsion: Development and optimization for dry eye
58. Mahran A, Ismail S, Allam AA. Development of Triamcinolone Acetonide-
disease treatment. Int J Pharm. 2020;576:118979.
Loaded Microemulsion as a Prospective Ophthalmic Delivery System for
41. Kumar M, Bishnoi RS, Shukla AK, Jain CP. Techniques for Formulation Treatment of Uveitis: In Vitro and In Vivo Evaluation. Pharmaceutics.
of Nanoemulsion Drug Delivery System: A Review. Prev Nutr Food Sci. 2021;13:444.
2019;24:225-234.
59. Salimi A. Preparation and evaluation of celecoxib nanoemulsion for
42. Kotta S, Khan AW, Ansari SH, Sharma RK, Ali J. Formulation of ocular drug delivery. Asian J Pharm. 2017;11:543-550.
nanoemulsion: a comparison between phase inversion composition
60. Mahboobian MM, Foroutan SM, Aboofazeli R. Brinzolamide-loaded
method and high-pressure homogenization method. Drug Deliv.
nanoemulsions: in vitro release evaluation. Iran J Pharm Sci. 2016;12:75-
2015;22:455-466.
93.
43. Henostroza MA, Melo KJ, Yukuyama MN, Löbenberg R, Bou-Chacra 61. Lallemand F, Schmitt M, Bourges JL, Gurny R, Benita S, Garrigue JS.
NA. Cationic rifampicin nanoemulsion for the treatment of ocular Cyclosporine a delivery to the eye: a comprehensive review of academic
tuberculosis. Colloids Surf A Physicochem Eng. 2020;597:124755. and industrial efforts. Eur J Pharm Biopharm. 2017;117:14-28.
44. Chime SA, Kenechukwu FC, Attama AA. Nanoemulsions-advances 62. Sharif HR, Sharif MK, Zhong F. Preparation, characterization and
in formulation, characterization and applications in drug delivery. rheological properties of vitamin E enriched nanoemulsion. Pak J Food
Intechopen: London; 2014. Sci. 2017;27:7-14.
45. Frank SG. Emulsions: Theory and Practice. In: Becher P, Wilmington, 63. Sarı ES, Koç R, Yazıcı A, Şahin G, Çakmak H, Kocatürk T, SS Ermiş. Tear
DE, eds. Partnership with American Chemical Society. (3rd ed). Oxford: osmolarity, break-up time and schirmer’s scores in parkinson’s disease.
Oxford University Press; 2001. Turk J Ophthalmol. 2015;45:142.
46. Hussain A, Altamimi MA, Alshehri S, Imam SS, Shakeel F, Singh SK. Novel 64. Gallarate M, Chirio D, Bussano R, Peira E, Battaglia L, Baratta F, Trotta
approach for transdermal delivery of rifampicin to induce synergistic M. Development of O/W nanoemulsions for ophthalmic administration of
antimycobacterial effects against cutaneous and systemic tuberculosis timolol. Int J Pharm. 2013;440:126-134.
using a cationic nanoemulsion gel. Int J Nanomedicine. 2020;15:1073.
65. Khan NU, Ali A, Khan H, Khan ZU, Ahmed Z. Stability Studies and
47. Kulkarni SK. Nanotechnology: principles and practices. Switzerland: Characterization of Glutathione-Loaded Nanoemulsion. Journal of
Springer; 2014. cosmetic science. 2018;69:257-267.
48. Daull P, Feraille L, Elena PP, Garrigue JS. Comparison of the anti- 66. Gupta A, Narsimhan V, Hatton TA, Doyle PS. Kinetics of the change in
inflammatory effects of artificial tears in a rat model of corneal scraping. droplet size during nanoemulsion formation. Langmuir. 2016;32:11551-
J Ocul Pharmacol Ther. 2016;32:109-118. 11559.
664 DHAHIR et al. Nanoemulsions as Ophthalmic Drug Delivery

67. Al-Omari NA, Butrus NH. Preparation, characterization and 69. Meng T, Kulkarni V, Simmers R, Brar V, Xu Q. Therapeutic implications of
cytotoxic evaluation of novel au(iii) complexes of thioglycolate and nanomedicine for ocular drug delivery. Drug Discov Today. 2019;24:1524-
2-mercaptoglycolate ligands. Iraqi J Pharm Sci. 2013;13:28-40. 1538.
68. Rao R, Upadhyay SC, Singh MK. Nanoemulsion in ophthalmics: a newer
paradigm for sustained drug delivery and bioavailability enhancement in
ophthalmic manifestations. Int J Pharm Sci Rev Res. 2018;50:18-24.