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Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 269
5.7 Microemulsions
5.8 Niosomes
Microemulsions are colloidal dispersions comprised of different
phases, i.e., oil phase, aqueous phase, surfactant, and cosurfactant
in specific proportions. Droplet size in microemulsion ranges from
10 to 100 nm. Microemulsions may be either o/w (more water
content) or w/o (more oil content) type emulsion. They are the
most potential submicron drug carriers, particularly for poorly
water-soluble drugs [
78]. Microemulsions have the advantages of
overcoming various ocular obstacles, reduced dosing frequency,
thermodynamic stability, cost-effectiveness, and ease of preparation. Thus, they are widely explored as a multiple drugs delivery
vehicle to different segments of eye. Triamcinolone acetonide
(TA)-loaded microemulsion with oleic acid, cremophor EL, and
propylene glycol is the most effective (complete drug release within
24 hours) in uveitis. It reduces inflammation, protein content, and
inflammatory cells compared to commercially available
suspensions [
79].
Niosomes are bilayered self-assembled vesicles composed of selfaggregated non-ionic surfactants, cholesterol, or other amphiphilic
molecules. Structurally, they are similar to liposomes but have
advantages of longer storage time, improved drug stability, prolonged drug release, biodegradability, biocompatibility, and
non-immunogenic [
69]. They could enhance permeability and
efficacy of both lipophilic and hydrophilic drugs. Niosomal system
composed of span 60, cholesterol, poloxamer 407, hydroxypropyl
methylcellulose, cyclodextrin, and chitosan has high drug entrapment, enhanced corneal permeation, and activity with reduced side
. I
80]
effects [
amide to treat glaucoma is seen with span 60, cholesterol, and
Carbopol
mproved duration of action and efficacy of acetazol-
®
934P [81]. Niosomal gatifloxacin composed of span
60, cholesterol, and chitosan has enhanced antimicrobial activity
and greater ocular permeation with no toxicity [
Niosomes system
composed of polysorbate 60, cholesterol, and
82].
1, 2-di-O-octadecyl-3-trimethyl- ammonium propane to deliver
epalrestat drug is a good choice in diabetic patients. It encapsulates
more drug (encapsulation efficiency 99.76%), protect premature
degradation, increase solubility, and promote drug delivery to
intraocular tissues (75% drug release within 20 days) with better
biocompatibility as compared with contact lenses containing epalrestat or free drug solution [
83].
Betaxolol-loaded niosomes mixed
into pH-responsive in situ gels has a high encapsulation efficiency
(69 ± 4.8%), a negative surface charge, and a nanoscale hydrodynamic diameter to prolong precorneal drug retention. It reduces
IOP with enhanced bioavailability and is promising in glaucoma
treatment [
84]. Similarly, latanoprost niosomes incorporated into
gels resulted in more than 88% drug encapsulation efficiency with
prolonged anti-glaucoma effect and no irritation as compared to
normal latanoprost eye drops [
However, low drug loading,
85].
270 Anuradha Nema
physical instability, encapsulated drug leakage, and high production
cost are certain limitations of niosomes in ocular drug
delivery [53].
5.9 Nanofibers
Nanofibers are produced through electro-spinning process of natural polymers (gelatin, collagen, chitosan, silk, fibronectin, and
ethyl cellulose) or synthetic polymers (PLA, PLGA, and PCL) or
both. Nanofibers are 1–100 nm in diameter and have unique
advantages of a high surface-to-volume ratio, high porosity, modifiable mechanical properties, high drug-loading capacity, more
encapsulation efficiency, overcoming ocular barriers, long-term
controlled drug release, and delivery of multiple drugs simultaneously [
86]. Polyvinyl alcohol (PVA) nanofibers loaded with mel-
atonin (MEL) release drug quickly (within 20 minutes) and
completely with greater bioavailability to exert neuroprotective
effects on retinal damage [
87]. Additionally, multiple drugs can
be loaded as nanofibers. Electrospun polymer fibers loaded with
gentamicin and dexamethasone are immediately dissolved in the
tear fluid, quantitatively releasing the two active substances to treat
bacterial conjunctivitis [
88]. PLGA and polyvinylpyrrolidone nano-
fibers loaded with moxifloxacin antibiotic and anti-scarring agent
pirfenidone are used for the treatment of corneal abrasion. After
24 hours, pirfenidone is released from outer layer of PLGA, and
about 70% of moxifloxacin from inner layer of polyvinylpyrrolidone
89]. Dual drug-loaded nanofibers have potential in inhibiting
[
infection as a single dose to treat cor neal abrasion. This extracellular
matrix-like structure is easier to prepare and less expensive than
other nanostructured drug delivery systems. Additionally, to
broaden application of nanofibers, it can be combined with other
technologies. Nanofibers when combined with biodegradable
hydrogels for intravitreal anti-VEGF drug delivery change the peptide concentration to adjust the dose to treat age-related
degeneration [
90].
5.10 Dendrimers
Dendrimers are symmetric, tree-shaped, or star-shaped highly
branched 3D nanostructure (2–100 nm). They are composed of
repetitive molecules enclosing a central core and several terminal
groups that make them appropriate for delivery of both hydrophilic
and lipophilic drugs to both segments of eye [
69]. Dendrimers
have high capabilities of drug encapsulation and conjugation of
surface groups. They have advantages of increased residence time,
extended activity, enhanced bioavailability, and targeted delivery
91].
[
Dendrimers entrapping acetazolamide have increased residence time, extended release, and increased activity to treat glaucoma [
92]. Timolol maleate-loaded dendrimers utilizing
polyethylene glycol have improved permeation and increased cellular uptake [
93]. Dendrimer-triamcinolone acetonide conjugates
(D-TA) significantly inhibit choroidal neovascularization (> 80%),
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 271
i.e., 50 times better than free drug [94]. Dendrimers can be combined with other technologies for ocular drug delivery. Dendrimer
gel particles (nDHPs), the combination of dendrimers, hydrogels,
and NPs, are used to enhance efficiency and efficacy of two antiglaucoma drugs, brimonidine tartrate and timolol maleate. Compared with conventional drug solutions, nDHPs increase drug
corneal permeability by 17 times, deliver drug precisely, and significantly lower IOP on once daily administration for 7 day
95]. Thus, dendrimers are an effective carrier for ophthalmic
[
drug applications. However, they have
disadvantages of low drug
loading capacity.
s
5.11 Nanowafers
5.12 Cubosomes
Nanowafers are small transparent disks that slowly release drugs,
prolong the retention time of drugs on the ocular surface, and
facilitate their absorption. Disk is applied on eye’s surface with a
fingertip that remains unaffected by continuous blinks.
Dexamethasone-loaded nanowafer (Dex-NW) has better efficacy
with only two doses of Dex-NW over a 5-day treatment period to
treat dry eye disease (DED) as compared to twice daily topical
dexamethasone eye drops [
96]. Nanowafers also act as a protective
shield, protecting corneal surface damage in DED.
Furthermore, polyvinyl alcohol (PVA) nanowafers loaded with
PnPP-19 (synthetic peptide with hypotensive effect on eye) prolongs residence time, maintains its fluorescence intensity for more
than 180 min., and thus has potential to treat glaucoma more
efficiently as compared to common eye drops [
97]. Thus, due to
potential efficacy and easier application on ocular surface, nanowafers are promising in ophthalmic treatment.
Cubosomes are prepared by emulsification of lipids in water using a
stabilizer to form cubic liquid crystalline nanocarriers. They have
advantages of entrapment of high number of drugs due to large
surface area, easy to prepare, stability, biodegradability, and safety.
Brimonidine tartrate-loaded cubosomes with glyceryl monooleate
and poloxamer 407 have improved permeation, sustained release,
and enhanced bioavailability and efficacy [
98]. Beclomethasone and
glyceryl monooleate cubosomal system has improved corneal permeation and anti-inflammatory activity [99].
5.13 Bilosomes
These are bile salts containing bilayered nanocarriers with minute
particle size, high drug entrapment, safety, enhanced corneal permeation, and activity. Terconazole-loaded bilosomes with cholesterol, span 60, has great entrapment, improved permeation, and
enhanced activity [
100].
272 Anuradha Nema
5.14 Olaminosomes
5.15 Contact Lenses
Olaminosomes are nanocarriers primarily composed of oleic acid
and oleylamine. Oleic acid is a safe, biodegradable, and biocompatible natural unsaturated free fatty acid used as ocular nanocarriers
101]. Oleylamine, an unsaturated fatty amine, is extensively used
[
as a surfactant [
102]. Olaminosomes have a small particle size, high
drug entrapment ability, safety, improved corneal permeation, and
activity.
Contact lenses that are used to correct refractive errors can be
composed of either hydrophilic or hydrophobic polymers. Two
main types of contact lenses for drug delivery are soft contact
lenses, which are made of hydrogels or silicone polymers, and
hard gas-permeable contact lenses [
103]. As these drug-loaded
contact lenses are in close contact with cornea, they prolong drug
retention time, decrease required dose and its frequency, and
improve ocular bioavailability by at least 50% with less systemic
drug absorption [
104]. Combination of contact lenses and nano-
technology is proving beneficial in ocular drug delivery. Immersion
of contact lenses in drug-containing NPs (preferably <100 nm) is
the simplest and cost-effective method of preparation. Contact
lenses immersed in zinc oxide NPs (20–40 nm) has antibacterial
activity against ocular microorganisms [
105]. Additionally, contact
lens can be coated with NPs containing drugs. A novel contact lens
composed of polyacrylamide semi-interpenetrating network hydrogel of quaternary ammonium chitosan and tannic acid possesses
antibacterial and antioxidant properties. Besides, tannic acid works
against oxidative stress and protects cells from ROS-induced cytotoxicity and is helpful in treating ocular infectious and inflammatory diseases [
106]. Contact lens device with embedded drug
microtubes has improved bioavailability, decreased risk of side
effects and prolonged drug release time to treat glaucoma. Moreover, as IOP fluctuates, it changes the curvature of contact lens,
resulting in more drug release. Thus, this is an adaptive drugrelease device providing dynamic and adaptive anti-glaucoma
treatment [
107].
5.16 Hydrogels
Hydrogels used as in-situ gels have high water retention capacity
and are composed of hydrophilic polymer chains. Administered as a
liquid, they transformed into a gel upon eye contact. Three main
stimulation-responsive materials mostly used are heat-responsive,
pH-responsive, and ion-responsive materials [
108]. Hydrogels
have advantages of prolonged drug retention time, sustained drug
release, and co-delivery of multiple ocular drugs [109]. Combination of nanotechnology and hydrogels has significantly improved
the therapeutic effect of ophthalmic drugs. A polypseudorotaxane
hydrogel prepared by mixing Soluplus micelles (99.4 nm) with
cyclodextrin solutions is beneficial in treating anterior uveitis.
This combination has improved drug retention ability (21.2
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 273
folds), corneal permeability (1.84 folds), intraocular bioavailability
(17.8 folds), sustained release, and anti-inflammatory effect compared with drug solutions [110]. Thus, compounding hydrogels
and nanotechnology increases ocular therapeutic efficacy.
5.17 Microneedles (MNs)
Microneedles are minimum invasive approach in treating ocular
diseases. MNs used in ophthalmic applications can either be solid
MNs, hollow MNs, or dissolved MNs. They have the advantages of
controlled drug release, excellent efficacy, enhanced patient tolerance, and cost-effective preparation [
array patch based on polylactic acid (PLA) and hyaluronic acid
penetrates the cornea rapidly and is efficient to treat fungal keratitis
(FK) [
112]. Additionally, controlled drug release is superior as
compared to eye drops. Hence, MNs may be a safe and effective
delivery method for drugs impermeable to the ocular surface.
However, loading capacity, safety, bending property, and tissue
damage are certain limitations to its clinical application.
6 Alternative Ocular Drug Delivery Approaches
Apart from nanotechnology-based ocular drug delivery systems,
other promising alternative ocular drug delivery approaches, such
as gene therapy, exosomes, and SNEDDS, are depicted in Fig. 5.
111]. A dissolved microneedle
Fig. 5 Alternative ocular drug delivery systems
274 Anuradha Nema
6.1 Gene Therapy
Gene therapy is a novel approach to treat genetic (retinitis pigmentosa, retinal vascular disease, etc.) as well as non-genetic ophthalmic
diseases. Gene therapy restores the function of non-functional or
missing proteins either by gene editing or gene addition or knocks
down proteins to block their function by gene silencing [
113].
Gene therapies chiefly involve viral vectors, non-viral vectors, gene
editing techniques (mainly CRISPR-Cas9), and epigenetic treatments with antisense oligonucleotide (ASO) and RNAi
therapeutics.
6.1.1 Viral Vectors Viral vectors such as adeno-associated virus (AAV), adenovirus,
lentivirus, and retrovirus are widely used in ocular gene therapy
due to their high transduction competence. Viral vectors can transduce both dividing and nondividing cells. They do not integrate
into the host cell genome but live in cells as free DNA [
114]. Use of
vectors could avoid repeated intravenous injections to induce a
systemic blockade of VEGF-A, expressed in retina. Anti-angiogenic
microRNAs are useful in the treatment of corneal neovascularization. However, drawbacks of viral vectors are potential mutagenesis, poor immunoreactivity, limited loading capacity (< 5 kb for
AAV), and high production cost, resulting in impractical approach
for ocular disease treatment [
6.1.2 Non-viral Vectors Non-viral vectors, such as naked DNA and peptide-based vectors,
115].
are less immunogenic, pathogenic, less expensive, and easy to manufacture, and have unrestricted size of genes as compared to viral
vectors [
116]. Redox-responsive quasi-mesoporous magnetic
nanospheres (rMMNs) with an iron oxide core and disulfide
bond-bridged polyethyleneimine shell loaded with miR-30a-5p
upregulate the level of miR-30a-5p by targeting the transcription
factor E2F7 and inhibiting the malignant phenotype of ocular
melanoma. Additionally, rMMNs play a role in the control of cancer
by promoting cancer cell apoptosis by regulating M1-like macrophage polarization and activating the Fenton reaction [
117].
6.1.3 Antisense Oligonucleotides (ASOs), RNAi, CRISPR-Cas9
ASOs are brief (12–24 nt) single-stranded nucleic acids (DNA or
RNA) that regulate gene expression by binding to specific complementary mRNA targets through Watson–Crick base pairing. RNAi
controls mRNA stability and cell translation via double-stranded
small interfering RNA (siRNA) or short hairpin RNA (shRNA)
corresponding to their target RNA [
118]. Polyethene glycol-
grafted branched polyethyleneimine as a non-viral gene vector has
an anti-fibroblast effect through gene silencing technology and is a
good approach to prevent fibroblast eye disease [
119].
The
CRISPR-Cas9 system, an engineered endonuclease directed by a
short RNA, can recognize target DNA sites through complementary base pairing and precisely create nicks or cuts in the genome. It
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 275
is simple in structure and is the most popular genome editing tool
in gene therapy ocular applications [
120].
6.2 Exosomes
6.3 Self-nano Emulsifying Drug Delivery Structures (SNEDDS)
Exosomes consist of lipid bilayers, proteins, and genetic material
with 30–150 nm diameter. Exosomes are naturally secreted from
cells that play a dynamic role in inflammatory, intercellular communication, and immune regulation. As natural carriers, exosomes are
non-toxic, biodegradable, safe, able to cross barriers, and can
deliver various drugs as compared to synthetic nano-drug carriers
121]. Exosome is an ideal carrier for intraocular delivery of anti-
[
angiogenic peptide KV11 into retinal vasculature by retroorbital
injection, which inhibits neovascularization [122]. Moreover,
umbilical cord mesenchymal stem–derived exosomes are useful in
dry eye disease [13]. Exosomes when combined with drug-loaded
liposomes maintains tear balance, tear film stability, pH, and osmolality changes [
123]. Exosomes due to their low immunogenicity
are extremely attractive ocular drug carriers.
SNEDDS are mixtures of oil phases, surfactants, and cosurfactants
with droplet sizes below 200 nm. Oil-in-water NEs are spontaneously formed after slight agitation of aqueous phase dispersion
124]. Surfactant and lipid components synergistically enhance
[
bioavailability by promoting gastrointestinal tract absorption of
drugs. Moreover, SNEDDS are promising system for hydrophilic
and hydrophobic ocular drug delivery. A self-emulsified osmo-protective ophthalmic microemulsion (O/A) with an internal oily
phase (1.2%), an external aqueous phase (96.3%), and surfactants
(1.5%) proved good cell tolerance (≈100%) with stability at 8 °C for
9 months [
125]. Thus, self-emulsified microemulsions could be a
novel ocular drug delivery system. However, SNEDDS have certain
limitations, viz. high content of vehicles used in SNEDDS, risk of
drug precipitation, and less capacity of drug loading and
targeting [
126].
7 Clinical Status of Nanotechnology-Based Ocular Drug Delivery Systems
With the increasing number of products in the market, the development of nanotechnology is proving as a novel ocular drug delivery system in the treatment of ocular diseases. Hence, commercial
products are increasing over time to treat ophthalmic conditions.
Restasis
water emulsion approved by the FDA for the treatment of DED in
2002 [127]. It has a particle size of 100–200 nm with no toxicity
but shows side effects such as epiphora and eye irritation. Cequa
a nano-micellar formulation containing 0.09% CsA with a particle
size of 12–20 nm to treat DED. It has enhanced drug delivery and
ocular penetration, and a strong encapsulation ability to increase
®
is the first preservative-free cyclosporine A (CsA) oil-in-
®
is
276 Anuradha Nema
Table 4
Examples of FDA-approved nanotechnology based commercial ophthalmic products
Nanostructured
Product Drug
®
Restasis
Durezol
®
AzaSite
Triesence
Tobradex ST
®
Ikervis
®
Cequa
®
Xelpros
®
Inveltys
Cyclokat
Cyclosporine A Nanoemulsion Dry eye disease
®
Difuprednate Nanoemulsion Postoperative ocular inflammation
Azithromycin Nanomicelles Ocular inflammation and infection,
®
Triamcinolone acetonide Nanoparticles Ocular inflammation, uveitis, dry eye
®
Tobramycin and
Dexamethasone
Cyclosporine A Nanoemulsion Keratitis, DED
Cyclosporine A Nanomicelles Dry eye disease
Latanoprost Nanoemulsion Open-angle glaucoma
Loteprednol etabonate Nanosuspension Postoperative ocular inflammation and
®
Cyclosporine A Nanoemulsion Dry eye disease
platform
Nanosuspension Ocular inflammation and bacterial
Ophthalmic conditions
DED, keratitis,
disease
infection
pain
Artelac
Rebalance
Vitamin B12 Liposomal eye
®
drops
CsA concentration ten times [128]. Xelpros® is a nanoemulsion
containing latanoprost approved by the FDA in 2018 to treat high
intraocular pressure. It has improved drug residence time (more
than 7 days) with 23 times efficacy as compared to latanoprost eye
drops [
129]. Table 4 demonstrates some FDA-approved nanotech-
nology-based commercial ophthalmic products.
Some nano-based ocular drug delivery systems are presently in
the clinical trial stage, which will promote the development of
advanced ophthalmic drug formulations. Catioprost, a nanoemulsion, is in phase II clinical trial to treat glaucoma. During the trial,
differences in intraocular pressure were measured after 3 months of
treatment to compare the efficacy and safety of catioprost NEs and
catioprost eye drops [
phase III clinical trial in the treatment of retinoblastoma. Table
depicts
some ophthalmic nanocarrier preparations in different
phases of clinical trials.
Dry eye disease
130]. Marqibo, a liposome-based drug, is in
5
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 277
Table 5
Examples of ophthalmic nanocarrier preparations in different phases of clinical trials
Ocular drug/product Nanocarrier Ophthalmic conditions Phase
Urea (Pluronic® F-127) Nanoparticles Cataract II
Dexamethasone (OCS-01) Nanoparticles Ocular inflammation, corneal pain II
Liposomal latanoprost Nanoparticles Ocular hypertension I
Paclitaxel Nanoparticles Intraocular melanoma II
ISV-305 Nanomicelles Post cataract surgery inflammation III
Cyclosporine OTX-101 Nanomicelles Dry eye disease III
Brimonidine tartrate Nanoemulsion Cataract III
OCU-310 Nanoemulsion Meibomian gland dysfunction III
Catioprost Nanoemulsion Glaucoma II
Difuprednate (PRO-145) Nanoemulsion Cataract III
D-4517.2 Dendrimers AMD II
Latanoprost (POLAT-001) Liposomes Open-angle
glaucoma
Vincristine Liposomes Metastatic malignant uveal
melanoma
ENV 515 travoprost extended
release
(XR)
AR-13503 Intravitreal implant Neovascular AMD, diabetic
Intracameral implant
(PRINT
technology)
Glaucoma II
macular
edema
8 Future Outlooks
Presently, conventional drug delivery methods are being used to
treat ophthalmic diseases with good results, but efficacy is not up to
the mark due to poor permeability, instability, and low bioavailability. Innovative drug delivery methods, such as NPs, nanomicelles,
nanosuspensions, dendrimers, liposomes, contact lenses, hydrogels, gene delivery, and other novel drug delivery methods, have
significantly enhanced the efficacy of drugs. Nevertheless, numero
challenges of complexity and cost of production, safety, meta-
us
bolic fate in ocular tissues, stability, and high technical necessities
limit the clinical conversion of nanotechnology-based ocular drug
delivery systems. In future, more work is needed to overcome these
limitations and increase the efficacy of novel drug-delivery systems
for ocular applications in clinical practice.
II
II
I
278 Anuradha Nema
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