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Biosensor-Based Drug Delivery Systems: Innovations, Applications, and… 249
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Chapter 12
Ocular Drug Delivery: Overcoming Barriers for Effective
Treatment
Anuradha Nema
Abstract
Eye is a complex organ responsible for vision with its unique anatomy and physiology. Conventional routes
for ocular drug delivery include topical, subconjunctival, intracameral, intravitreal, transscleral, retrobulbar,
and systemic. Among them, topical route is one of the preferred routes due to its non-invasiveness, safety,
and high patient compliance. However, presence of various anatomical and physiological ocular barriers
creates hindrance in active absorption and activity of therapeutic drugs to treat ocular diseases by any route.
To overcome various ocular barriers and improve drug bioavailability, development of nanotechnologybased ocular drug delivery system (ODDS) is advantageous. Ocular treatment is achieving the higher level
with several advantages due to advancement in nanocarriers. Nanostructured platforms have several positive
outcomes, including overcoming ocular barriers, increasing transcorneal permeability, lengthening drug
residence time, reducing drug degradation, decreasing dosing frequency, achieving sustained release,
improving patient compliance, drug targeting, and gene delivery. Many nanocarriers, such as nanoparticles,
nanosuspensions, nanomicelles, nanofibers, nanoemulsions, liposomes, etc., have proven excellent delivery
potential in both in-vitro and in-vivo studies, enhancing drug permeability across the ocular barriers and
increasing drug bioavailability in the eye. In future, more innovations are needed to achieve greater results
in management of ocular diseases.
Key words Drug targeting, Gene delivery, Nanocarriers, Nanotechnology, Ocular barriers, Ocular
drug delivery system, Residence time, Transcorneal permeability
1 Introduction
Vision, a complex and multipart process, gives a sense of sight and is
accomplished by a highly complex sense organ, the eye. Eye is the
only organ to directly observe nervous system (optic nerve) and
peripheral vasculature (retinal arterioles and venules) and thus is
helpful in diagnosing various systemic diseases [
anatomy and physiology offer eye with challenges for drug delivery
to targeted sites. Anatomically, it is divided into anterior and posterior segments [
2]. Both segments of eye are vulnerable to a variety
of diseases either due to local cause or systemic problems, causing
251
1]. Complicated
252 Anuradha Nema
visual impairment. Structurally and functionally, ophthalmic tissues
are protected by certain dynamic and static protective barriers
3]. These barriers are precorneal barriers, corneal barrier and
[
blood-ocular barriers. Tear film, reflex blinking, eyelid, conjunctiva,
cornea, and nasolacrimal drainage prevent the eye surface from
foreign substances [
4]. Blood-ocular barriers include the blood-
aqueous barrier (BAB) in the anterior segment and blood-retinal
barrier (BRB) in the posterior segment of eye that prevent the toand-fro movement of etiological agents between eye and blood
circulation [
it
still
is
. Although eye has multiple protective mechanisms,
5]
vulnerable to infection, trauma, and other diseases. Cataract, glaucoma, diabetic retinopathy, keratitis, uveitis, etc. can cause
vision impairment, and their adequate treatment is of utmost
importance to improve quality of life [
6]. Medicinal treatment is
the primary treatment for most of eye diseases. Delivering drugs to
target eye tissues at the desired therapeutic concentration without
affecting other unaffected tissues is of prime concern [
protective barriers,
which are considered as boon for eye protection
7]. Besides,
on one hand, serve as hindrance in ocular therapy on the
other hand.
To achieve therapeutic effects, medications are either applied
topically, delivered subconjunctivaly, intraocularly (intracameral or
intravitreal), periocularly (subtenon, retrobulbar, or juxtascleral),
or systemically [
8]. Ocular barriers create a substantial challenge in
treating ocular problems in relation to attainment at the desired site
and residing there for an appropriate duration. As a consequence,
bioavailability of medications is often less than 5% [
For a
ffective therapeutics, ocular drug delivery systems
n e
9].
(ODDS) are designed so as to: (a) deliver drugs to target ocular
tissues by overcoming ocular barriers, (b) enhance drug stability
and treatment efficiency, (c) lengthen drug retention time and
decrease dosing frequency, (d) facilitate multiple drug combinations, and (e) increase patient compliance and diminish drugrelated side effects [
Ocular medications
10].
used are either in liquid (drops, suspension, and emulsion), solid (powder, insert, contact lens), semi-solid
(gels and ointments), or mixed (in-situ gel) form. Among all, eye
drops are the commonest form of medications used. But they are
limited mostly to deliver the medications into the anterior part of
11].
eye and have short residence time [
For a drug to be effective, it
must reach and preserve an acceptable drug concentration with
minimum quantity of active therapeutic component. It is achieved
by appropriate corneal penetration along with effective precorneal
residence time. To overcome all ocular therapeutic challenges,
innovative nanotechnology is evidencing dynamic progress in the
field of ocular drug delivery. These technologies are providing new
ophthalmic therapeutic interferences by overcoming ocular obstacles, reducing drug degradation, increasing dr ug residence time,
2 Eye’s Anatomy
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 253
enhancing trans-corneal permeation across barriers, and reducing
dosing frequency. Nanosystems with numerous advantages are to
the next level as compared to traditional drug administration by
improving patient compliance, achieving sustained and controlled
release, drug targeting, and gene delivery [
12]. Nanocarriers, such
as nanoemulsions (NEs), nanomicelles, microemulsions, nanoparticles (NPs), nanofibers, dendrimers, liposomes, nanowafers,
microneedles (MNs), etc., are effective in therapy of anterior and
posterior ocular diseases. Gene therapy, exosome, and self-nanoemulsifying drug delivery systems (SNEDDS) are emerging as
potential tools in ocular drug delivery [
ophthalmic treatment, a novel
non-invasive ODDS is important to
13]. Hence, for effective
overcome ocular barriers, sustained drug release, and its maintained
effective drug concentrations at the targeted site.
Anatomically eye is divided into anterior and posterior segments.
Anterior segment includes tear film, cornea, pupil, conjunctiva, iris,
ciliary body, aqueous humor, and lens, while the posterior segment
is composed of sclera, choroid, vitreous body, retina, and optic
nerve. Anatomy of eye is demonstrated in Fig.
1. Quantity and
Fig. 1 Anatomy of the eye. (1) Anterior segment; (2) posterior segment; (3) tear
film; (4) sclera; (5) eyelid; (6) cornea; (7) anterior chamber; (8) iris; (9) pupil;
(10) lens; (11) vitreous body; (12) retina; (13) optic nerve; (14) blood vessels;
(15) choroid
254 Anuradha Nema
quality of tear film are controlled by orbital glands. Cornea is
composed of five layers, epithelium, bowman’s membrane, stroma,
descemet’s membrane, and endothelium. It is known as a lipidaqueous-lipid sandwich, where stroma (hydrophilic) is sandwiched
between epithelium and endothelium. Transparency of cornea is
preserved by endothelium [
mucous membrane, is divided into palpebral
5
]. Conjunctiva, a delicate transparent
and bulbar conjunctiva. It is composed of epithelium, substantia propria enclosing
nerves, lymphatic and blood vessels, and submucosa layer. Iris,
the pigmented portion of eye, regulates the quantity of light
penetrating the eye through control of pupil size. Ciliary body is
composed of pigmented and non-pigmented epithelium, stroma,
and muscles. Capillaries of ciliary body is res
cation between anterior and posterior segments.
ponsible for communi-
Transparent lens
focuses the light onto retina. Vitreous humor, a gel-like, clear,
avascular tissue, maintains the shape of eye. It is made of 99.9%
water, hyaluronic acid, and collagen. Sclera is made of collagen and
mucopolysaccharides. Choroid, situated between sclera and retina,
is a vascular layer. The retina is composed of neural and glial cells
that produces electrical impulses and deliver
brain [
11].
them via optic nerve to
3 Ocular Barriers Hindering Absorption of Drugs
Static and dynamic absorption barriers in eye prevent extraneous
substances, including therapeutic agents, from reaching to targeted
sites. Dynamic barriers principally include tear film, tear turnover,
nasolacrimal duct drainage, conjunctival and choroidal blood flow,
and lymphatic clearance. Cornea, conjunctiva, sclera, vitreous body,
BAB, and BRB form static barriers of eye. Barriers can also be stated
as precorneal, corneal, and blood-ocular barriers. Various ocular
barriers are depicted in Fig.
various ocular therapeutic drugs, thereby reducing their
bioavailability [14].
3.1 Precorneal Barriers
3.1.1 Tear Film, Tear Turnover, and Nasolacrimal Duct Drainage
Tear film, eyelids and their reflex blinking, conjunctiva, and nasolacrimal drainage prevent foreign substances away from the eye
surface. It prevents drugs from reaching the cornea and other
ocular tissues. Variations in capacity of cul-de-sac also affects therapeutic drug concentration in eye.
A thin, transparent tear film is composed of an outer lipid layer,
middle aqueous layer, and inner mucin layer. Negatively charged
mucin layer protect the eye surface from harmful molecules and
infections through electrostatic forces. The aqueous and lipid layers
act as barriers for lipophilic and lipophobic drugs, respectively
15]. The non-specific binding of drugs to tear enzymes and
[
2. All barriers limit absorption of
Fig. 2 Ocular barriers
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 255
proteins also obstruct drug absorption and entry through cornea
and anterior chamber. Additionally, after topical application of
drugs tear turnover increases, resulting in rapid removal of drug
through nasolacrimal drainage (1–2 minutes). This drainage is a
major barrier in the precorneal region [
16]. In view of maintaining
effective drug concentration, residence time of the drug must be
attained by different mechanisms.
3.1.2 Capacity of Cul-desac
3.1.3 Conjunctival and Scleral Barriers
Cul-de-sac, a shallow pocket in the lower eyelid where palpebral
and bulbar conjunctiva meet, has a maximum capacity of approximately 30 μL [
17]. In inflammatory and allergic conditions of eye,
capacity of cul-de-sac is further minimized. The low capacity of culde-sac reduces the residence time and concentration of the drug in
eye, thereby reducing its therapeutic effects.
After topical administration, the non-corneal alternative route of
drug entry is through conjunctiva and sclera. Conjunctival mucous
membrane is formed by epithelium and stromal layer. It produces
and maintains tear film and protects the eye from external pathogens. Conjunctival surface area is approximately 17 times greater
than that of cornea. Hence, it is more permeable than the cornea
for absorption of macromolecules and hydrophilic compounds
18]. Additionally, being highly vascularized medicines remain
[
localized for shorter duration and systemically absorbed to be
distributed throughout the body. This non-productive huge drug
loss into the systemic circulation reduces ocular region bioavailability. To overcome this loss and to enhance drug efficacy, high
256 Anuradha Nema
concentrations with repeated instillations of drug are required
[
19]. However, in this way, patient compliance is negatively influ-
enced and possibility of side effects is increased.
After permeation from conjunctiva, drug travels through transscleral route from sclera to anterior segment. Sclera, the white part
of eye is an opaque, hard sheath and is relatively more permeable
with larger surface area than cornea. The scleral penetration of drug
is mainly determined by the size of drug and scleral thickness. Drug
spread across the sclera through perivascular space and between
scleral fibrils, to reach the choroid and retina [
20].
3.2 Corneal Barrier
3.3 Blood-Ocular Barriers
Cornea, the outermost clear, avascular layer, protects eye from
diverse chemical and mechanical injuries. It is composed of epithelium, stroma, and endothelium and poses a significant challenge for
ocular rug delivery. Only small and lipophilic drugs can pass
through epithelium, whereas stroma permits hydrophilic drugs.
Besides, the presence of cytochrome P450 (drug-degrading
enzymes) and drug efflux pumps in epithelium are responsible for
low drug bioavailability. Endothelium, due to its hydrophobic
nature, restricts the penetration of hydrophilic drug and macromolecules into aqueous humor. Thus, trans-corneal permeation is
rate-limiting step for drug transfer from lacrimal fluid into aqueous
humor that depends on drug molecular weight, hydrophobicity
charge, and degree of ionization [
21].
These barriers prevent the non-specific entry of foreign compounds
into the blood stream and are classified as blood-aqueous bar rier
(BAB) in anterior segment and blood-retinal barrier (BRB) in
posterior segment of eye. Additionally, they limit the entry of
compounds into the eye from systemic circulation. The bloodaqueous barrier consists of non-pigmented ciliary body of iris vasculature and epithelial tissue of the endothelial cells. The permeability of drugs across BAB is determined by the osmotic pressure
and physicochemical properties of therapeutic agents. Lipophilic
and small-molecule drugs can permeate more rapidly through barrier than hydrophilic and large-molecule drugs. This specialized
tissue barrier creates a challenge for ocular drug delivery and hin-
.
ders therapeutic efficacy [
The blood-retinal
22]
barrier is the most important barrier in posterior part of eye and comprises of internal and external components. The inner BRB is formed by tight junctions between retinal
capillary endothelial cells, while close junctions between retinal
pigment epithelial cells forms outer BRB. It prevents entry of
plasma components, drugs, and toxic substances into retina.
Hence, BRB is essential to maintain normal visual function [
23].
Ocular Drug Delivery: Overcoming Barriers for Effective Treatment 257
4 Various Routes for Ocular Drug Delivery
Conventional routes of ocular drug administration primarily
include topical, conjunctival and scleral, intracameral, intravitreal,
retrobulbar, and systemic routes. Figure
routes for ocular drug delivery. Table
of ocular drug administration with their advantages, challenges
encountered, and applications. Drug administration done by any
route has to bypass one or more ocular barriers to reach the
targeted site. Table
with their preferred route of administration and uses.
2 demonstrates some common ocular drugs
3 demonstrates various
1 summarizes various routes
4.1 Topical Administration
Topical administration is the commonest and easiest non-invasive
route of ocular drug administration. It represents more than 95% of
commercially available ocular products but with low bioavailability
(<5%). As compared to other routes of administration, it has the
advantages of (a) being non-invasive, (b) relative ease of drug
administration, and (c) minimum systemic side effects of drug.
Hence, ophthalmic solutions are the foremost choice for many
anterior segment eye diseases management, such as dry eye, inflammation, infection, allergy, and glaucoma [
24]. But, due to insuffi-
cient corneal permeation and short residence time, bioavailability is
low. Furthermore, bioavailability is reduced by tear drainage, reflex
blinking, and non-productive absorption to systemic circulation
through conjunctiva and nasolacrimal region. To overcome this
Fig. 3 Routes for ocular drug delivery. (1) Topical; (2) intracameral; (3) subconjunctival; (4) transscleral; (5) intravitreal; (6) retrobulbar; (7) systemic (oral or
parenteral)
258 Anuradha Nema
Table 1
Various routes of ocular drug administration, their advantages, disadvantages/challenges, and their
applications
Route of drug
S. No.
administration
1 Topical Non-invasive, self-
2 Intracameral Provides high anterior
3 Subconjunctival Site for depot
4 Transscleral Bypasses anterior segment
Advantages
administrable with high
patient compliance,
minimum systemic side
effects
chamber drug
concentration,
eliminates usage of
topical drops, avoids
corneal, conjunctival
and BAB barriers,
reduces corneal and
systemic side effects
seen with topical
steroid therapy
formulations to deliver
drugs to anterior and
posterior segment,
avoids corneal and BAB
barriers, large sized
molecules can pass
sclera which are
impermeable
to cor
nea
Disadvantages/
challenges encountered
Corneal barrier, higher
tear dilution, and
turnover rate, efflux
pumps, low
bioavailability (<5%),
high dosing
Toxic endothelial cell
destruction syndrome
(TECDS) and toxic
anterior segment
syndrome (TASS) may
occur with
inappropriate doses and
preparations
Subconjunctival
hemorrhage, increased
toxicity with choroidal
and conjunctival
circulation
Invasive, low
bioavailability as
compared to
intravitreal
Applications
Keratitis, dry eye,
conjunctivitis,
episcleritis, scleritis,
blepharitis, uveitis
Anesthesia,
inflammation,
prevention of
endophthalmitis
after surgery,
glaucoma, pupil
dilation
Corneal opacity,
glaucoma, retinitis
Glaucoma, retinitis, to
deliver antiangiogenic drugs to
target sites
5 Intravitreal Direct delivery to vitreous
and retina, high
bioavailability, evades
BRB
6 Retrobulbar Site for drug depot,
selective delivery to
both anterior and
posterior segments,
avoidance of corneal
and conjunctival
barriers, long duration
of action
Due to vitreous fluid
turnover- frequent
IVTs may cause
increased IOP,
hemorrhage, retinal
detachment, cataract,
endophthalmitis,
patient incompliance
Poor patient compliance
due to invasiveness,
pain, risk of
hemorrhage, eyeball
perforation or optic
nerve damage
Retinal vein occlusion,
cytomegalovirus
retinitis, diabetic
macular oedema
Anesthesia
(continued)