gels
Review
Drug Delivery Challenges and Current Progress in
Nanocarrier-Based Ocular Therapeutic System
Md Habban Akhter 1, *, Irfan Ahmad 2 , Mohammad Y. Alshahrani 2 , Alhanouf I. Al-Harbi 3 ,
Habibullah Khalilullah 4 , Obaid Afzal 5 , Abdulmalik S. A. Altamimi 5 , Shehla Nasar Mir Najib Ullah 6 ,
Abhijeet Ojha 7 and Shahid Karim 8
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Citation: Akhter, M.H.; Ahmad, I.;
Alshahrani, M.Y.; Al-Harbi, A.I.;
Khalilullah, H.; Afzal, O.; Altamimi,
A.S.A.; Najib Ullah, S.N.M.; Ojha, A.;
Karim, S. Drug Delivery Challenges
and Current Progress in
Nanocarrier-Based Ocular
Therapeutic System. Gels 2022, 8, 82.
https://doi.org/10.3390/gels8020082
Academic Editor: Rajendran JC Bose
Received: 29 December 2021
Accepted: 18 January 2022
Published: 28 January 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affiliations.
*
School of Pharmaceutical and Population Health Informatics (SoPPHI), DIT University,
Dehradun 248009, India
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University,
Abha 62521, Saudi Arabia; irfancsmmu@gmail.com (I.A.); moyahya@kku.edu.sa (M.Y.A.)
Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University,
Yanbu 46477, Saudi Arabia; alhanouf.ibraahim@gmail.com
Department of Pharmaceutical Chemistry and Pharmacognosy, Unaizah College of Pharmacy,
Qassim University, Unaizah 51911, Saudi Arabia; h.abdulaziz@qu.edu.sa
Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University,
Al-Kharj 11942, Saudi Arabia; o.akram@psau.edu.sa (O.A.); as.altamimi@psau.edu.sa (A.S.A.A.)
Department of Pharmacognosy, Faculty of Pharmacy King Khalid University, Abha 62521, Saudi Arabia;
shehlanasar2005@gmail.com
Six Sigma Institute of Technology and Science, College of Pharmacy, Rudrapur 263153, India;
abhi_pharm1@rediffmail.com
Department of Pharmacology, College of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
shahid.karim@yahoo.co.in
Correspondence: habban.akhter@dituniversity.edu.in
Abstract: Drug instillation via a topical route is preferred since it is desirable and convenient due
to the noninvasive and easy drug access to different segments of the eye for the treatment of ocular
ailments. The low dose, rapid onset of action, low or no toxicity to the local tissues, and constrained
systemic outreach are more prevalent in this route. The majority of ophthalmic preparations in the
market are available as conventional eye drops, which rendered <5% of a drug instilled in the eye.
The poor drug availability in ocular tissue may be attributed to the physiological barriers associated
with the cornea, conjunctiva, lachrymal drainage, tear turnover, blood–retinal barrier, enzymatic drug
degradation, and reflex action, thus impeding deeper drug penetration in the ocular cavity, including
the posterior segment. The static barriers in the eye are composed of the sclera, cornea, retina, and
blood–retinal barrier, whereas the dynamic barriers, referred to as the conjunctival and choroidal
blood flow, tear dilution, and lymphatic clearance, critically impact the bioavailability of drugs.
To circumvent such barriers, the rational design of the ocular therapeutic system indeed required
enriching the drug holding time and the deeper permeation of the drug, which overall improve
the bioavailability of the drug in the ocular tissue. This review provides a brief insight into the
structural components of the eye as well as the therapeutic challenges and current developments in
the arena of the ocular therapeutic system, based on novel drug delivery systems such as nanomicelles,
nanoparticles (NPs), nanosuspensions, liposomes, in situ gel, dendrimers, contact lenses, implants,
and microneedles. These nanotechnology platforms generously evolved to overwhelm the troubles
associated with the physiological barriers in the ocular route. The controlled-drug-formulation-based
strategic approach has considerable potential to enrich drug concentration in a specific area of the eye.
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
Keywords: ocular therapeutic system; drug delivery; hydrogel; nanomicelles; nanoparticles; implant;
microneedle
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Gels 2022, 8, 82. https://doi.org/10.3390/gels8020082
https://www.mdpi.com/journal/gels
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1. Introduction
The eye is a unique, complex, and highly important part of the human body, which is
related to various physiological and anatomical barriers. Topical drug instillation in the
ocular surface is a popular route for the treatment modalities of eye disorders. However,
the poor drug retention and permeation resulting in the erratic bioavailability of drugs
is a major concern, which should be considered for addressing effective therapy. The
blinking, baseline, and reflex lachrymation, as well as drainage to remove foreign substances, including drugs, rapidly from the surface of the eye, results in suboptimal ocular
bioavailability [1]. It has been reported that 90% of eye drops available in the market only
supplemented 5% of drug bioavailability, and the rest of the drug washed away through
different elimination routes such as tear fluid, nasolacrimal secretion, protein binding,
enzymatic degradation, or metabolism by protease, and esterase enzyme. Despite these,
numerous physiological barriers play significant roles in poor drug retention, including the
blood–retinal barrier and the blood–aqueous barrier, along with the corneal barrier [2].
There are many eye ailments, including conjunctivitis, blepharitis, glaucoma, cataract,
diabetic retinopathy, and macular degeneration (age related), which affect the anterior and
posterior region of the eye; sometimes, the patient may also lose eyesight. The critical
challenge ahead of topical application is to improve the drug holding time, by the rationale
design of formulation approach, which, ultimately, results in consistent and uniform drug
absorption at the site of application in the eye being indigently addressed. Based on
conventional techniques, several types of ophthalmic drug delivery systems are available
in the market. Aside from eye drops, other topical preparations available in the market
are eye ointments, gels, and ocular inserts such as eye dosage formulations, which tend
to somehow increase the holding time of drugs in the eye, but the appearance of blurred
vision and the related inconvenience has limited their use. Moreover, the systemically given
drug for action in the eye has limited access due to poor blood flow in the corneal cells and
tissues. Injection into the eye cavity is sometimes recommended for drug delivery into the
posterior region, which is painful and causes patient incompliance. The speedy drainage of
the drug from topical application reduces the pharmacological action of the drug, which
needs to be compensated with increased dosing frequency as well as the part of the drug
that has reached systemic circulation through the various routes that could cause a systemic
toxic effect. Indeed, to surmount these problems, novel ophthalmic preparations, viz., NPs,
liposomes, prodrug, nanomicelles, nanosuspensions, dendrimers, contact lenses, implants,
microneedles, and in situ gel, have promising results, which have been explicated in the last
few decades to alleviate better drug solubility, dissolution, absorption, and bioavailability
in a controlled, sustained, and prolonged period [1,3].
2. Ocular Anatomy
The human eye consists of different layers with specific internal structures, and each
part perform performs specific functions.
2.1. The Sclera, Cornea, and Conjunctiva
The sclera is the white part of the eye that appears as an opaque, hard white sheath,
which comprises the outer layer of the eye ball. It resembles a stiff fibrous membrane that
preserves the eye shape. It continues within the cornea and is much thicker towards the
posterior part of the eye than the anterior part of the eye. It is composed of collagen fibers
and proteoglycans engrafted in the extracellular matrix. The hydrophilic solutes are more
permeated through the sclera than the conjunctiva and cornea, due to diffusive transport
across the leaky region of collagen fibers. The presence of charges (+/−) on the surface of
molecules also influences permeability across the sclera. The cornea is the principal route in
the topical drug instillation, while conjunctiva and sclera allow hydrophilic drugs to diffuse
through the ciliary body. It gives protective covering, maintains intraocular pressure, and
is an attachment site for the ciliary muscles [4,5].
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The cornea is clear and transparent, and it lacks the blood supply situated at the most
anterior part of the eye. It consists of different parts such as corneal epithelium externally,
Bowman’s membrane, corneal stroma, and the endothelial layers internally. The corneal
permeability is important in how the drug penetrates and retains in the aqueous humor.
The trans-corneal diffusion of lipophilic drugs is mediated via corneal epithelial, which is a
rate-limiting barrier for such drugs. The corneal stroma is made up of hydrophilic collagen
and causes the hindrance for the diffusion of the lipophilic drugs and is interconnected by
several ciliary nerves [6]. The conjunctiva inside the eye is a fragile, slim, and transparent
epithelial barrier, which channelizes inward toward the eyelids and comprehends the
anterior and one-third of the eyeball part. The conjunctiva is constituted of an upper layer,
epithelium cells, and their inherent substantia propria. The conjunctiva contributes to the
production of the tear film with substantial electrolytes, fluid, and mucus secretion and
thus prevents the microorganism entry and lubricates the eye cavity. The surface area of
the conjunctiva is larger than the cornea and is more permeable to the drugs. However, the
significant drug loss occurs due to their blood capillaries and lymphatic that is drawn into
the systemic circulation. The conjunctival drug absorption is considered futile due to the
conjunctival blood cells, capillaries, and tight junctions, leading to excess loss of drug in
the systemic circulation, hence resulting in poor ocular drug bioavailability [6].
2.2. Aqueous Humor
This is a nonvascular, transparent, clear fluid that occupies the posterior and anterior
parts of the eye. It provides essential nutrients such as sodium, chloride ion, ascorbate
salt, extricates waste products from the nonvascular tissue to the cornea, and maintains
intraocular pressure by controlling Schlemm’s canal and the shape of the cornea. Aqueous
humor drains out from Schlemm’s canal, a circular groove that enters there from the anterior
chamber and releases into the blood circulation via the anterior ciliary veins. The turnover
rate of aqueous humor formation in humans varies 1–1.5% of the anterior chamber volume
per minute. The rate of an aqueous humor formation is ~2.5 µL/min [7].
2.3. Pupil, Iris, and Ciliary Muscle and Vitreous Humor
The central dark part of the eye is a chamber associated with the passes of light into
the eye. Light reflex is a vital phenomenon by which pupil shape and size are modulated
by the pupillary reflex. The iris is a circular, muscular contractile structure confronting
the lens back to the cornea. The diaphragm of the iris is of variable sizes that work to line
up the pupil size and regulate the incident light into the eye. It is a colored part of the
eye, ranging from blue to grey, which creates varying visual aspects. The ciliary muscle is
present in the middle eye layer, which controls and coordinates eyeshot to the objects with
the accommodating distances and controls the aqueous humor flow into the Schlemm’s
canal. The ciliary muscle is responsible for contraction or relaxation, which enables the
eye to focus near or far objects. The vitreous humor constitutes ~80% of the total volume
in each eye in the human body. Physically, it appears as a jelly-like transparent substance
present in the chamber back to the eye lens [8]. A detailed schematic expression of the
components of each eye part is illustrated below (Figure 1).
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Figure 1. The anatomy of ocular system representing anterior (A) and posterior segments (B). The
anterior segment includes conjunctiva, ciliary body, iris, pupil, anterior chamber, cornea, and lens.
The posterior segment consists of sclera, choroid, retina, macula, and optic nerve. Modified from
ref. [8]; permission under a creative common license (CC BY-NC-ND 4.0).
2.4. The Retina, Macula, Choroid, and Optic Nerve
The retina is situated at the posterior side of the eye. It consists of photosensitive rod
and cone cells, along with the glial, neural, vascular cells, and nerve fibers that convey the
light through nerve impulses and extended to the brain via the optic nerve. The macula is
located at the center of the retina and contains a vast number of photoreceptor cells that
transfer the light into the nerve signals.
The macula has a noval structure, a pigmented part situated near the central part of the
retina, having various ganglion cells and approximately 200 million neurons. The pigment
assimilates light and transmits the light signal to the brain through the optic nerve. The
optic nerve sends the signals from the eye to the brain, which contains image information
for processing by the central nervous system. A thin layer of tissue situated between the
sclera and retina is choroids that possess blood vessels that carry oxygen and nutrients to
the eye and restrict drug administration into the posterior chamber. The forepart of the
optic nerve is called an optic disk [8].
2.5. Accessory Parts in Eye
There are several parts of the eye that protect it against injury such as the eyebrows,
eyelids, eyelashes, and lacrimal apparatus. The eyebrow gives protection to the anterior
part of the eyeball from pollens, dust particles, and foreign bodies. The different layers of
tissues in eyelids with conjunctiva protect the fragile cornea and eye front. Upon instillation
of eye drops in the lower conjunctival sac, the lachrymal glands release the tear fluid, which
contains water, mineral salts, lysozyme, antibodies, and antimicrobial enzymes. The excess
of eye drops drains out into the gastrointestinal tract through the nasolacrimal system
immediately upon instillation, which may be because either the volume of the drug dose
exceeds the volume of lachrymal fluid or reflex tearing. The excess volume moves into the
gastrointestinal tract through the nasolacrimal drainage [9,10].
3. Constraints in Ocular Drug Delivery
The loss of a drug after instillation in the eye is a major constraint in the ocular
therapeutic system, and this may be from the ocular surface, lacrimal fluid secretion, and
the blood–ocular barrier.
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3.1. Precorneal Barrier
After administration of the eye drop, the onset of lacrimal fluid secretion swiftly
removes medicaments from the eye surface. Notably, the lacrimal fluid turnover rate
is ~1µL/min, and the redundant drug dose fluid is taken off in a short period of time
through the nasolacrimal ducts. The precorneal factors including the tear turnover and
reflex blinking clearance mechanism due to increased volume of liquid in cul-de-sac largely
limited the drug retention in the anterior eye segment. The volume of liquid more than
9 µL may turn into a tear and be drawn out through the nasolacrimal duct [10].
3.2. Corneal Epithelial Barrier
This is considered a primary barrier to the topical administration of a drug. The
diversified layer of columnar and squamous epithelial cells, as well as the intercellular
tight junctions, act as permeation barriers of therapeutics through paracellular routes. The
occurrence of calcium ion levels and various protein molecules congest the epithelial tight
junctions. However, the disruption of the tight junction membrane or the complexation of
calcium ions with EDTA somehow improves the drug permeability [11].
3.3. Lacrimal Sac Eye Barriers
Approximately 95% of a drug instilled into the eye is eliminated from blood circulation
through the nasolacrimal duct. It acts as a conduit for the tear flow into the nasal chamber
from the eye. The nasolacrimal drainage system consists of a lacrimal sac, canaliculi, and
nasolacrimal ducts. Due to the vascularized wall of the nasolacrimal and lacrimal sac, half
of the drug concentration is absorbed there. The constraint due to this also depends on the
volume of the topically applied drug solution, patients’ reflex blinking, and age. The drug
delivery design should enable it to be retained on the ocular surface to release a sufficient
concentration of the drug in the lacrimal fluid [12].
3.4. Blood–Ocular Barriers
The blood–ocular barrier encompasses the blood–aqueous barrier (BAB) and the blood–
retinal barrier (BRB), which are significant barriers in topical drug delivery in the anterior
and posterior chambers of the eye. BRB, related to the anterior chamber of the eye, consists
of the ciliary endothelium (nonpigmented) and the ciliary blood vessels/endothelium of the
iris. This cell layer expresses the tight junctions of the endothelial cells of the retina and thus
restricts the entry of a drug molecule into intraocular surroundings. BRB, however, prevents
drug entry from the blood into the posterior chamber. It comprises retinal capillaries,
which include the inner retina barrier and the retinal pigment epithelium cells (RPEs),
considered as the outer blood–retinal barrier, respectively [13,14]. The drug permeability
across RPEs is easier to determine, but it is hard to quantitate the permeability values of
the vascular component of the BRB. The particle size is a concern for the permeation of a
drug molecule from retinal capillaries. A radio-labeled tracer study revealed that retinal
capillaries prevent the penetration of carbon NP of size 20 nm, but small molecules of
molecular weight in Dalton (fluorescin and mannitol) were easily permeated. It has also
been reported that epithelial tight junction has spaces of 2 nm, and similar size molecules
can easily permeate. Another study has also reported that a retinal capillary is a vital
barrier that allows only those molecules to permeate with a size of ≤2 nm [15]. The RPE is
a tight junction located between choroid and photoreceptors and maintains homeostasis in
the neural retina. Studies suggested that the permeability toward RPE is dependent on the
lipophilicity and size of the compound. The orally or intravenously (i.v.) administered drug
prominently enters the choroids rather than retinal capillaries, due to high vasculature.
The choroid capillaries also assist in attaining an equal concentration of drug molecules in
blood circulation and in extravascular spaces in choroids and also prevent the drug entry
into the retina. The BAB comprises endothelial cells, iris, ciliary muscle, and pigmented
and nonpigmented epithelium cells. The tight intercellular junctions are also present in the
epithelial components of BAB. The simultaneous elimination of the drug molecules together
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from BRB and BAR makes it difficult to estimate the drug permeability separately [9].
Therefore, the blood–retinal barrier is still a major gainsay for topical drug delivery into
the retina. To overcome the retinal barrier by permeating the inner limiting membrane
(ILM), Tavakoliet al. developed PEGylated liposomes for better permeation in the retinal
cells. The particle size and surface charge play pivotal roles in retinal permeation; sizes of
liposomes >100 nm are betrayed to pass through the ILM, as the study revealed. Smaller
sizes of anionic PEGylated liposomes (~50 nm) were found to have excellent distribution
and penetration into the retinal cells [16]. An illustrative diagram showing various barriers
in the ocular route is presented in Figure 2.
Figure 2. Drug delivery barriers in ocular route. The barriers may be from the anterior segment
including corneal barriers, e.g., corneal epithelium, tear film, conjunctiva, and blood–aqueous barrier.
The posterior segment barrier may be due to the blood–retinal barriers comprising retinal vessels,
ganglion cells, pigment cells, retinal endothelium, and the vitreous barrier. These barriers overall
reduced drug availability in the ocular tissues of the posterior segment. Permission received under
Creative Commons Attribution 4.0 International License [17].
3.5. Efflux Protein Barrier
The efflux protein barrier is present in the apical cell membrane of the conjunctiva
epithelial cells, nonpigmented ciliary epithelial cells, and retinal endothelial cells. It has
control over enhancing or retarding the drug absorption based on cellular localization.
The major efflux protein responsible for the drug absorption is P-glycoprotein, which
acts as an efflux pump and prevents entry of hydrophilic and lipophilic molecules, in
both abnormal and normal cells. P-glycoprotein is also said to be multidrug resistance
mutation 1 (MDR1), an ATP-dependent efflux transporter that greatly reduced the drug
concentration in multidrug-resistant tumor cells. The multidrug resistance protein (MRP)
is also a membrane-bound efflux transporter and is detected in different ocular tissues.
Among the different types of efflux transporter investigated by Chen et al., MRP1–4 and
MRP6 are located in the corneal epithelium. The expression level of MRP2–4, MRP6, MDR1,
and breast cancer resistance protein (BCRP) is detected in the basal cell layer of the human
conjunctiva, while MRP1 and MRP7 are expressed in the entire conjunctival epithelium [18].
Zhang et al., investigated drug transporter and cytochrome P450 mRNA expression level
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in the ocular drug disposition and revealed low levels of BCRP and MRP2 in the human
cornea [19].
4. Conventional Ocular Therapeutic Systems
In the market, surplus ocular/ophthalmic products such as eye drops are available;
this covers ~70% or more of prescription drugs available, due to ease of application,
noninvasiveness, patient compliance, and cost effectiveness.
4.1. Eye Drops
The eye drop is a simple and convenient, noninvasive, patient compliant, and safer
way of delivering medicament into the eyes. The drug release from eye drops follows a
pulsatile pattern immediately post instillation, and the concentration of the drug rapidly
declines thereafter. The drug release from the eye drops follows first-order kinetics. The
critical challenge in topical drug delivery is to improve the contact time of therapeutics in
the eye, which may enhance the bioavailability of the drugs. To this end, novel additives
may be incorporated to increase the viscosity of the formulation, which, in turn, improve
the precorneal residence and ocular permeation of drugs. Certain viscosity enhancers such
as carboxymethyl cellulose, sodium carboxymethyl cellulose, and hydroxymethylcellulose
are used to improve precorneal residence time and bioavailability. For enhancing the
permeation rate in cornea cyclodextrin, ion-pairing forming agents and iontophoresis
technique are used [20,21].
The permeation enhancers including polyoxyethylene glycol ethers, ethylene diamine
tetra-acetic acid sodium, Tween 80, span 80, and Brij-35 ameliorate corneal uptake through
altering the corneal integrity and physiological environment in the ocular surface [21].
4.2. Liquid Dosage Form
4.2.1. Emulsions
An emulsion is a biphasic therapeutic system that consists of two immiscible phases;
it is conventionally used and still a good option to enhance solubility, dissolution, and drug
absorption. For dispensing medicaments in an emulsion vehicle, it is prepared as oil in
water (o/w) and water in oil (w/o), which is commercially available for ophthalmic drug
delivery. The o/w type emulsion is largely explored in the ocular formulation, compared
with the w/o type, due to ocular tolerance, with less or no irritation, in which hydrophobic
drugs are blended in the oily phase and aqueous phase thereafter. An example of the
ophthalmic eye drop is a cyclosporine-A (Restasis), which comprises 0.05% emulsion of
cyclosporine-A and is used in chronic dry eye treatment. Cyclosporine improves tear production by reducing the inflammation in the eye. The azithromycin ophthalmic emulsion
(AzaSite® ) is composed of 1% azithromycin ophthalmic emulsion intended for the purpose
of bacterial conjunctivitis and other ocular complications. AzaSite® ophthalmic emulsions
are available in the United States. Refresh Endura is a nonmedicated emulsion used for dry
eye disease [22]. Many studies quoted in the literature have successfully manifested the
relevancy of using emulsions for better precorneal residence, enhanced corneal permeation
of the drug, the provision of prolonged or sustained release of medicine, and overall,
improved ocular bioavailability.
For delivering medicine into the anterior ocular tissue, Tajika et al., demonstrated
the enhanced anti-inflammatory action of 0.05% difluprednate, a prednisolone derivative,
using an emulsion as a vehicle. An animal study on rabbit’s revealed that emulsion was
successfully delivered into the anterior chamber of the animal eye, with little concentration
of the drug transferred to the posterior part of the eye following instillation of the eye drop
one or more times in a day [23].
Formulation additives such as lipid soy lecithin and stearyl amine were used as carriers
for azithromycin, which showed improved ocular drug absorption and bioavailability. The
lipid emulsion of azithromycin was compared with plain drug solution at varying doses of
the drugto study the tear elimination feature. An animal study on rabbits revealed that after
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topical administration of azithromycin, emulsion showed a sustained release, improved
stability, and precorneal residence time [24].
Similarly, with the intent to improve the ocular drug availability using emulsion as
a vehicle, Shen et al. developed a flurbiprofen emulsion. The preparation comprised
flurbiprofen axetil, castor oil, and tween 80 as oil and surfactant, as well as an aqueous
phase. They prepared different emulsions with changing ratios of castor oil (0.1–2.5%) and
tween 80 (0.08–4%), which were labeled as formulation F1–F4, respectively. The topical
administration of F2 emulsion drop in albino rabbits showed improved pharmacokinetic
with castor oil/tween 80 (0.5:0.4) by weight%, compared with other preparations and drug
solutions. The F2 emulsion was better translocated and achieved higher concentration of
drug in the aqueous humor, compared with a 0.03% flurbiprofen sodium eye drop [25].
The conventional therapeutic approach in ocular delivery is shown in Figure 3.
Figure 3. Conventional mode of ocular therapeutic system.
4.2.2. Suspensions
Suspension is a biphasic liquid preparation method in which API is finely dispersed in
a dispersion medium or aqueous solvent essentially composed of a suspending agent and
a suitable dispersing agent. In other words, suspensions are API-saturated carrier systems.
The application of the eye drop suspension is inevitable for hydrophobic drugs due to
limited aqueous solubility. The drug in suspension state retains longer in cul-de-sac cavity
and ocular tissue, thereby increasing the ocular residence time and bioavailability and
efficacy of the drug, compared with eye drop solutions [26]. The particle size has a crucial
role in drug effectiveness in suspensions—larger particles will take more time to dissolve
and may show prolonged retention time; on the other hand, smaller particle sizes are easily
absorbed into ocular tissues from precorneal spaces. As regards patient compliance, the
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particle should be kept below 10 microns in eye drop suspensions. Notably, in addition
to particle size, at the same time, the surface morphology of suspended particles is also
taken into consideration with respect to shape and physical state (amorphous/crystal), as
it may cause irritation in the ocular tissue [27,28]. Thus, keeping optimum particle size in
suspensions improves their therapeutic efficacy. Eye drop suspensions in the market, such
as TobraDex® suspension, are widely used for bacterial eye infections. The preparation
consists of 0.3% tobramycin and 0.1% dexamethasone (Dex). The limitation of this commercial preparation is its high viscosity. Apart from these, adequate excipients (inactive) in eye
drop suspensions used as performance enhancers such as suspending agents prevent easy
settling or caking, stabilizing/wetting/complexing agents for solubilizing hydrophobic
drugs, and the preservatives used as antimicrobial agents are major concerns to be taken
into consideration. The redispersing of the suspension drug particle in the container has
to be uniform, and an effective dose should be delivered uniformly under therapeutic
conditions. The suspension manufacturing techniques are indeed considered, and the
fabrication of such dosage form requires suspension aseptic ball milling; thereafter, the
preparation is aseptically transferred into a hermetically sealed sterile container [28].
Recently, Scoperet al., sought to minimize the high consistency of TobraDex® and
ameliorate absorption of the drug with enhanced bactericidal properties. They modified
the preparation as TobraDex ST® , with a reduced concentration of Dex to 0.05%. The
sedimentation rate of the modified formulation showed very low particle settling over 24 h
(3%), compared with marketed TobraDex® (66%). An animal study exhibited high ocular
penetration, distribution, and concentration of Dex and tobramycin when treated with
TobraDex ST® , compared with TobraDex® . Thus, the modified suspension preparation
was promisingly efficacious, compared with TobraDex® , against S. aureus and P. aeruginosa.
The clinical trial of the modified formulation in human subjects also reported a high
concentration of tobramycin and Dex in the eye fluid, compared with TobraDex® [29].
4.2.3. Solutions
Aqueous solutions for ophthalmic applications must be sterile and are primarily used
for rinsing and cleaning the eyeballs. Ophthalmic solutions are safe, easy to use, and
noninvasive, and they show rapid action to the local ocular tissues. Aqueous solutions may
have some excipients for regulating osmotic pressure and viscosity, as well as simulating
the lachrymal fluid and pH. The multidose container may require preservatives [30]. The
ophthalmic solution is generally available as eye drop preparation. The solution as eye drop
provides immediate drug permeation after instillation, and thereafter, drug concentration
declines swiftly. To improve the drug retention time, absorption, and bioavailability in the
ocular tissue, compared with eye drop solutions, different additives may be incorporated
to enhance viscosity and permeation. For example, cellulose derivatives, such as sodium
carboxymethyl cellulose, are generally used as viscosity enhancers. Cyclodextrin is used as
a carrier for formulating lipophilic drugs in aqueous solutions and helps in drug release to
the biological surfaces [31].
4.2.4. Ointments
The ointment is meant for ocular applications, having a mixture of mineral oil, petrolatum, and paraffin, a solid hydrocarbon that melts at the physiological temperature of
the eye (34 ◦ C). Apart from bearing the consistency and biocompatibility of the selected
hydrocarbon base, it also offers the advantages of improved contact time and sustained
drug release. The ointment preparation may be monophasic or biphasic system due to the
presence of water and oil phases. The challenges with the use of ointments as the base are
patient related; they may cause soreness and blur vision ascribed to different refractive
indices of the lachrymal fluid and ointment base and are prone to inaccurate dosing, and
therefore, the wide application of medicated ophthalmic ointment is limited [32].
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5. Novel Ocular Therapeutic Systems
A few decades ago, many strategies were designed in terms of the therapeutic modality
of ocular diseases. The advent of nanotechnology-based therapeutic systems has acquainted
the novel facet toward the optimized nanosize particle, which enables minimizing irritation,
addressing the poor bioavailability, and improving ocular biocompatibility of therapeutics.
The various nanodrug delivery carrier systems employed in the ocular therapeutic system
are presented in Figure 4. The nanocarriers enlisted below have shown promised results for
enriching the ocular availability of therapeutics. The summarized nanotechnology-based
novel drug carrier system is favorable in the treatment of ocular disorders, which is shown
in Table 1.
Figure 4. Nanocarriers employed in ocular therapeutic systems.
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Table 1. Nanotechnology-based novel drug carrier system in the treatment of ocular disorders.
Carrier System
Payload
Composition
In Vitro Characteristics
In Vivo Observations
References
TA
The ME comprised a ratio of oil (Capmul MCM
C8): surfactant (AccononMC8-2): cosurfactant
(Transcutol): water of 5:35.5:4.5:55. Thereafter,
ME was PEGylated using 1,
2-distearoylphosphatylethanolaminepolyethyleneglycol 2000
(DSPE-PEG 2000).
The ME was small in size, uniform, and
transparent. The average size obtained
was 157.720 ± 17.85 nm.
The prepared PEGylated ME observed stable,
homogenous, and nonirritant to the eye after
animal study and had the potential to target the
posterior segment of the eye after
topical administration.
[2]
Polymer
micelles
Netilmicin and Dex
Nanomicelles using copolymers of
polyhydroxyethylaspartamide (PHEA) and
pegylated PHEA for topical anterior segment
drug delivery.
In vitro permeation study on
conjunctival and corneal epithelial cells
performed using drug-loaded polymer
micelle (PHEA-C16 and
PHEA-PEG-C16 ).
The drug-loaded polymeric micelles increased
40% ocular bioavailability, compared with
Dex suspension.
[33]
NPs
Melatonin
PLGA-PEG NPs
Decreased surface charge of in
PLGA-PEG than the PLGA alone
accorded good and enhanced
interaction of NPs with eye surface.
The effective lowering of intraocular pressure
(IOP), compared with melatonin PLGA NPs and
drug solution with the same concentrations, was
observed in the rabbit’s eye.
[34]
DEX-loaded poly(lactic acid–co-glycolic acid)
NPs (DEX-NPs)
DEX-NPs showed narrow size
distribution with a particle size
diameter of 232 ± 5.4 nm and a
polydispersity index of 0.19. The drug
encapsulation efficiency
was 56.0%. The constant drug release of
97% was observed for upto 35 days.
Ophthalmic investigations based on fundus
examination, IOP measurement, and
ultrasonography have shown no abnormalities till
50 days after DEX-NPs instillation in the rabbit’s
eye. The intravitreal injection provided sustained
release of drugs in the posterior segment of the
eye disease. The DEX-NPs showed sustained
drug release for 50 days in the vitreous humor,
and a mean concentration of 3.85 mg/L−1 was
constantly found for >30 days.
[35]
LDH nanosheets showed a mean size of
47.5 ± 12.1 nm and polydispersity
index (0.210 ± 0.021), and zeta
potential ~ (35.4 ± 0.9) mV. The burst
release of PRN solution was ~100% in
2 h, while 74.6% of PRN release was
reached in a sustained manner from
CG-VV-PRN-LDH nanosheets over a
12 h time period.
The epithelial cell (HCEpiC) and retinal pigment
cell (ARPE-19) uptake demonstrated complete cell
internalization via clathrin and endocytosis
pathways. The active transport of PepT-1 is
implied in the CG-VV-LDH NPs and CG-VV-LDH
cell internalization process. The
CG-VV-PRN-LDH NPs eye drops werepermeated
~5.2fold higher than the marketed product. The
CG-VV-LDH NPproveda promising nanocarrier
in ocular disease therapy, while CG-VV-LDH
nanosheets extended the precorneal retention and
were found suitable for ocular surface diseases.
[36]
Microemulsion
(ME)
NPs
Hybrid NPs
and nanosheets
Dex
Pirenoxine sodium(PRNs)
A multifunctional organic–inorganic hybrid
NPs and nanosheets, new
chitosan–glutathione–valine–valine-layered
double hydroxide (CG-VV-LDH) nanosheets.
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Table 1. Cont.
Carrier System
Nanosuspensions
Nanosuspensions
Liposomes
Liposomes
Liposome complex
Cationic and
anionic liposomes
Payload
In Vitro Characteristics
In Vivo Observations
References
Nanosuspensions, suspension,
and solutions state
-
The crystalline drug suspensions of these drugs
(Dex, prednisolone, and hydrocortisone)
enhanced the rate and extent of absorption, as
well as the intensity of drug action in
ophthalmic delivery. Despite these, all
preparations were enable to lower the high IOP,
compared with drug solutions.
[37]
Flurbiprofen
Eudragit RL 100
The developed nanosuspension had spherical
particle shape, particle diameter around 100 to
200 nm, surface charge ranges from +6.6 ± 2.2
to +19.0 ± 3.1 mV, and drug encapsulation
recorded in between 54.67 ± 3.4 to 90.32 ± 3.2%.
The nanosuspension underwentsustained
release of drug (60%) over 12 h, compared with
marketed preparation (Flur eye drops). The
in vivo study in animals reported it to be
nonirritant and safe based on
histopathological studies.
[38]
Besifloxacin
Liposomes developed with
phosphatidylcholine (LP PC)
or phosphatidylcholine
and spermine (LP PC: SPM)
The mean vesicle diameter of liposome (LP PC)
was found to be177.2 ± 2.7 nm, with a surface
charge of −5.7 ± 0.3 mV, and for liposome
(LP PC: SPM), the mean diameter and zeta
potential were observed as 175.4 ± 1.9 nm
and +19.5 ± 1.0 mV.
The MIC and MBC of the liposomal formulation
werelower than the marketed preparation,
Besivance against P. aeruginosa.
[39]
Latanoprost
DPPC
(di-palmitoyl-phosphatidyl-choline),
organic solvent chloroform:methanol
mixture (2:1)
The average size and least PDI of the vesicle
were reported around 100 nm and 0.11. The
vesicle size may vary depending upon the
drug/lipid ratio.
No increase in inflammation or vascularity was
noted after subconjunctival injection. The single
subconjunctival injection of liposomes
demonstrated lowering IOP due to sustained
ocular drug delivery and was a suitable
alternate option to the conventional eye drops.
[40]
-
The outcomes of in vivo study demonstrated
that modified liposome expressed effective
Rpe65 gene delivery in a specific and further
alleviated long-term expression of the Rpe65
gene in the RPE disease model resulting in
rectification in blindness.
[41]
-
The observed concentration of the drug in the
cornea for drug solution, positive (+) and (−)
charged liposomes were 253.3 ± 72.0,
1093.3 ± 279.7, and 571.7 ± 105.3 ng/g. The
absorbed drug concentration from positively
charged liposomes was 2-times higher than (−)
charged liposomes and 5-times
higher than the drug solution.
[42]
Dex, prednisolone,
and hydrocortisone
DNA
Acyclovir
Composition
Liposome–protamine–DNA complex
(LPD), a biomimetic virus modified with
cell-penetrating peptides
Liposomes prepared using stearylamine
(cationic) and dicetylphosphate as anionic
charge-inducing agents
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Table 1. Cont.
Carrier System
Dendrimer
Dendrimers
Nanoliposomes
dispersed within
thermo-sensitive hydrogels
TAC-SLNs ISG
In situ gel
with TL-NPs
Payload
Pilocarpine nitrate
and tropicamide
Composition
PAMAM solutions, fluorescein dye
and carbopol (0.2% w/v)
In Vitro Characteristics
In Vivo Observations
References
-
The PAMAM dendrimer with carboxylic and
hydroxyl surface groups showed longer ocular
residence time than dendrimer solutions. The
residence time of PAMAM dendrimer in the
cornea was size- and
molecular-weight dependent.
[43]
[44]
brimonidine tartrate
Polyamidoamine dendrimers
The drug release kinetics and safety
concerns of nanofiber mats were securely
investigated in vitro.
The dendrimer did not show toxicity or irritation
at the therapeutic dose in the animal. The
single-dose administration of DNF indicated
significant improvement in efficacy, compared
witha drug solution, for 3weeksprovedthat
dendrimer nanofibers can effectively be given in
glaucoma therapy.
Senicapoc
DPPC (Carboxyfluorescein) liposomes,
Pluronic F-127 polymers, organic solvents
(chloroform and methanol)
In vitrostudy has shown that Senicapoc was
sustainably released from DPPC liposomes
for a prolonged time of 28 days
and achieved a cumulative
release of 81.2 ± 1.7%.
In vivo results showed that Pluronic F-127
hydrogel at (24 wt %) concentration enhanced
nanoliposomes residence time on the surface of
the eye and thus increased bioavailability. Further,
senicapoc sub-conjunctival injection maintained
the drug concentration upto 24 h.
[45]
Compritol® 888 ATO (0.25% w/v) and GMS
(2% w/v), TAC SLNs and Poloxamer 188
(12% w/v)/Poloxamer 407 (26% w/v).
The probe sonicated particle of TAC-SLNs
ISG had particle sizes of 122.3 ± 4.3 nm.
TAC-SLNs-ISG showed
a pseudoplastic flow.
In vivo study showed that eye drops and
TAC-SLNs had Cmax 4657.7 ng/mL and
1892.6 ng/mL within 30 min, while
TAC-SLNs-ISG had achieved 2132.3 ng/mL
within 2 h. The AUC0–t of TAC-SLNs-ISG and
TAC eye drops were 590,355.9
and 222,382.5 ng.min/mL, i.e., 2.65-folds higher
for TAC-SLNs-ISG than for TAC eye drops.
[46]
Ophthalmic TL-NPs preparation with
different percentages of methylcellulose.
The ophthalmic TL-NPs preparation
yielded an average particle size of ~93 nm
using MC (0.5–3%) or without
using MC (0.5–3%).
The gel preparation TL-NPs with 0.5 and 1.5%
MC improved the preconjunctival contact time of
the drug, resulting in higher drug contents found
in the cornea and conjunctiva after topical
instillation, compared with TL-NPs with or
without 3% MC.
[47]
Tacrolimus
Tranilast
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Table 1. Cont.
Carrier System
Nanocapsule
Microspheres
and nanospheres
Nanosphere colloidal
suspensions
Solid lipid NPs
Solid lipid NPs
Payload
Tacrolimus
Tyrosine kinase inhibitor
Acyclovir
Natamycin
Atorvastatin
Composition
In Vitro Characteristics
In Vivo Observations
References
Polymer PLGA of MW 100 and 50 kDa;
Tween® 80; Cremophor® EL Lipoid® ;
E80 Solutol® HS15 and PVA
Agood lyophilization was observed for PLGA:
HPβCD ratio of (1:10). No significant
differences were observed in sizes (143.9
and 172.8 nm) incurred before and after this
process with a PDI value of 0.2.
The ex vivo corneal permeability established the
PLGA NCs retention and permeation in the
cornea by >40-fold higher than drug solution,
probably owing to smaller particles entrapment in
the tight junction of corneal epithelial cells. The
PLGA NCs showed a superior anti-inflammatory
effect on the anterior chamber LPS-induced
keratitis model in comparison with the drug
in oil solution.
[48]
PLGA microspheres and nanospheres
In vitro characterization of microspheres and
nanospheres revealed particle sizes of ~2.6 µm
and ~360 nm.
The intravitreal injection led to the generation of
optic nerve within two weeks. Further,
nanospheres were found superior tomicrosphere
in regrowth of the optic nerve.
[49]
PLA nanospheres were modified with
the PEGylation technique.
-
The high molecular weight polymer led to
reduced nanosphere size, and the PEGylated
formulation showed sustained drug release and
improved pharmacokinetics, well tolerated in the
eye. The efficacy of PEGylated PLA nanospheres
was significantly higher than the PLA nanosphere.
[50]
The formulation comprised a solid lipid
(4–10% w/w), a surface-active agent,
Precirol ATO 5® as Pluronic f68
(3–7% w/w), and a sonication
frequency (40 to 80 kHz).
The optimized formula of SLN has been
revealed to be 42 r.nm (radius in nanometers),
with a surface charge of 26 mV, and EE%
reached ~85%. SLN formulation achieved >90%
of drug release during 10 h. A corneal
permeation study indicated the permeability
coefficient (Papp) and steady-state flux (Jss)
reached 11.59 × 10−2 cm h−1 and 3.94 mol h−1 ,
compared with 7.28 × 10−2 cm h−1
and 2.48 mol h−1 of the drug solution.
Antifungal activity indicated the increased zone
of inhibition was 8 and 6 mm against Aspergillus
fumigatus (ATCC 1022) and a clinical isolate of
Candida albicans, respectively. The MIC value
was reduced to 2.5-times against each
strain of fungus.
[51]
The ATS-SLNs havespherical shapes, and the
average particle size and PDI
are 256.3 ± 10.5 nm and 0.26 ± 0.02.
The finding suggested that ATS-SLNs showed
12-times higher bioavailability than plain drugs in
the ocular tissues. The stability of the formulation
was found to be 13.62-times higher including
photostability, compared withthe drug solution.
F-SLNs haveshown effective uptake and
prolonged the ocular residence time upto 7 h.
[52]
The formulation is composed of
Comprise® 888 ATO (lipid), ATS,
and PEG 400, P188 and P 90H.
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Table 1. Cont.
Carrier System
Silica NPs
AuNP
Payload
Tacrolimus
-
Composition
In Vitro Characteristics
In Vivo Observations
References
Silica NPs functionalized with
aminopropyltriethoxysilane
(MSNAPTES)
The cytotoxicity of developed formulation
MSNAPTES and MSNAPTES-TAC in ARPE-19
cells was reported to be dose dependent. The
chorioallantoic membrane (CAM) assay model
investigated biocompatibility and safety in vivo
after intravitreal injection, with a clinical
assessment of intraocular pressure and fundus
ophthalmoscopy, electroretinography (ERG),
and histologic studies in rats’ eyes.
No alteration in retinal cells function was
observed after 15 days of intravitreal injection
indicated by ERGs and by histopathological
studies of rats’ eyes. The 15 µm silica particles
with 10 nm pore sizeswerefound to be safe in the
animals’ eyes and retained there for >2 months.
[53]
-
After injecting AuNP into C57BL/6 mice retinal
cells lacking 100 nm particles, on the other hand,
20 nm particles were well detected and
distributed through the BRB in the retinal layers.
The percentage distributions of these 20 nm
particlesin the retina were 75 ± 5% in retinal
neurons, 17 ± 6% in endothelial cells, and 8 ± 3%
in peri-endothelial glial cells, where the NPs
bounded onto the membrane.
[54]
The average size recorded is 28 nm using an
AuNP:siRNA weight ratio of 3.
No cytotoxicity to the corneal cells was reported
using AuNP-PEI NPs, indicating nanomaterial
was safe and suitable for siRNA delivery inocular
complications. Moreover, PEI-crowned AuNPs
with EpCAM siRNA were internalized
prominently in Y79 cells, as shown in
fluorescenceand flow cytometry studies, and
resulted in significant apoptosis of Y79 cells.
[55]
Gold NPs obtained a size of 20 nm.
AuNP
siRNA
AuNPs are covered with
polyethyleneimine (PEI) and ligated with
antibodies, siRNA, and epithelial cell
adhesion molecule (EpCAM).
Contact lens
Moxifloxacin (MF) and Dex
The contact lens comprises polymer
chitosan, polyethylene glycol,
and glycerol.
Drug-loaded contact lenses exhibited higher
corneal drug distribution post 24 h of the
incubation period, compared with pure
drug solutions.
Both invitro and in vivo investigations showed
the drug-loaded contact lens was superior to pure
drug solution.
[56]
Contact lens
Dex, Dex 21-disodium
phosphate (DXP), and Dex
21-acetate (DXA)
Poly(hydroxyethyl methacrylate)
(PHEMA) contact lenses
The transport of DX and DXA is diffusion limited,
with diffusivities of 1.08 × 10−11
and 1.16 × 10−11 m2 /s, predicted using
the transport model.
The contact lenses of these drugs have shown
much higher bioavailability than eye drops.
Further, among these drugs, the DXA has shown
the highest bioavailability.
[57]
Contact lens
Lidocaine
Dimyristoyl phosphatidylcholine (DMPC)
liposomes in poly-2-hydroxyethyl
methacrylate (p-HEMA) hydrogels
-
Liposome-incorporated p-HEMA gels are
transparent and enable drug release
for upto ~8 days.
[58]
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Table 1. Cont.
Carrier System
Composition
In Vitro Characteristics
In Vivo Observations
References
Dex
PLGA polymer matrix
PLGA polymer matrix degrades into
lactic acid and glycolic acid and
accommodates Dex release for upto
6 months.
The clinical investigation revealed their
efficacy in reversing vision loss patients and
improving sharp vision in eyes associated
macular edema, i.e., vein occlusion
in the retina.
[59]
Nonbiodegradable
Vitrasert®
Ganciclovir
Ganciclovir encircled by PVA/EVA.
Vitrasert® released the drug for an
extended period of 7 months.
-
[59,60]
Nonbiodegradable
Retisert®
Fluocinolone acetonide
FDA approved in 2005, a silicone laminated PVA
or ethylene-vinyl acetate (EVA).
Fluocinolone acetonide was released from
Retisert® in a sustained manner
for up to 3 years.
-
[59,60]
Triamcinolone acetonide (TA)
Implant developed with variable TA
concentrations of 0.5%, 1%, and 2.5% w/w were
dissolved in N-methyl-2-pyrrolidone (NMP)
solvent and thereafter added into 30% w/w PLGA
(50/50 and 75/25) polymer to develop
homogenous injectable prepare.
The implant showed good syringeability
and rheological features, as well asshear
thinning properties. The preparation was
easy to administer due to free flowing.
The implants established sustained
release of drug for more than a month.
The PLGA/solvent-based phase inversion in
situ forming implants can ameliorate the
therapeutic treatment outcome in the ocular
disease by improving drug release for
extended periods and reducing the frequency
of injections.
[61]
Chitosan/polyvinyl alcohol (CS/PVA) nanofiber
had layered in Eudragit RL100 fabricated by
crosslinking technique intended for conjunctivitis.
The average diameters of single
electrospun nanofiber and crosslinked
were 123 ± 23 nm and 159 ± 30 nm.
The antimicrobial efficacy of both single-spun
and multi-spun nanofiber showed an
enhanced zone of inhibition against S. aureus
and E. coli. The ofloxacin release from
nanofiber inserts on the rabbit eye was
detected for upto 96 h. The in vivo study
showed 9–20-folds higher bioavailability,
compared withthe drug solution.
[62]
Fiber consisted of PVP 5%-HA 0.8% w/v
and PVP 10%-HA 0.5% w/v obtained
with diameters of ~100 nm. The
crosslinked nanofiber with ε-PL, blank
and FA-loaded inserts demonstrated
average thickness of 270 ± 21 µm
and 273 ± 41 µm, respectively.
The insert showed complete release of ε-PL
both from blank and FA-loaded inserts within
30 min. The FA-loaded inserts were shown
improved antimicrobial efficacy against
P. aeruginosa and S. aureus.
[63]
The in vitro performances established
that the ocular insert could render
controlled drug release upto 10 days.
AZT-loaded NPs-in-NFs has shown increased
ocular residence, reduced systemic side
effects, and improved bioavailability.
[64]
Biodegradable
Ozurdex®
Ocular implant
Nanofiber insert
Payload
Ofloxacin
Electrospinning
nanofiber
Ferulic acid (FA)
Hyaluronan (HA), ferulic acid (FA), an
antioxidant and an antimicrobial peptide
(ε-polylysine, ε-PL),
and polyvinylpyrrolidone (PVP).
Polymeric
nanofiber
Azithromycin
The ocular-insert was prepared with an
electrospinning technique using
polyvinylpyrrolidone.
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Table 1. Cont.
Carrier System
Composition
In Vitro Characteristics
In Vivo Observations
References
Azithromycin
Drug-loaded Eudragit® L100 NPs with
plasticizer, polyvinyl alcohol solutions. The
drug-loaded ocular film was prepared with
the solvent casting of cellulose derivates
hydroxypropyl methylcellulose (HPMC) or
hydroxyethyl cellulose (HEC) solutions.
The preparation of NPs had particle size
78.06 ± 2.3 nm; drug entrapment
62.167 ± 0.07%, surface charge
−2.45 ± 0.69 mV, and polydispersity
index 0.179 ± 0.007. The drug release
from the insert was burst, followed by
sustained release, which was significantly
higher than the drug solution in the
rabbit eye. The trans-corneal drug
permeation was reportedly
higher than the drug solution.
The developed inserts haveshown
antimicrobial effects on
S. aureus and E. coli cultures.
[65]
MNs
fluorescein sodium
and fluorescein
isothiocyanate–dextrans
The developed MNs have different
molecular weights (MWs)
polyvinylpyrrolidone (PVP), fluorescein
sodium, and fluorescein
isothiocyanate–dextrans (MW in between
70 k and 150 k Da).
Dimensionally MNs with a height of
800 µm and base diameter 300 µm, with
model drugs, were prepared and
characterized in vitro related to braking
forces, insertion forces (in the sclera and
cornea region), penetration depth using
OCT, and confocal imaging.
The high-MW PVP-fabricated MNs could
withstand greater forces. The polymer MNs
expressed rapid dissolution within 180 s
and varied with PVP’s MW. In vitro
demonstrated the high permeation of
macromolecule across scleral and corneal
tissues relative to aqueous solutions.
[66]
Microneedle (MNs)
sulforhodamine
-
-
High dissolution and release behavior from
MNs into the intrascleral region.
[67]
MNs loaded micro/NPs,
and fluorescent-tagged NPs
sulforhodamine
-
The microneedle retraction with
200–300 µm rendered 10–35 µL infusion
fluid in the tissue.
Better drug delivery in the sclera with
minimal invasiveness.
[68]
Hyaluronic acid (HA) and crosslinked
methacrylated HA.
The contact eye patch is developed with
an array of self-implantable
micro-drug-reservoir. The patch hasan
arrangement of pyramid-shaped MNs
with a tip diameter of ~10 µm, height
~500 µm, base width ~250 µm, and
inter-needle spacing of ~400 µm.
The developed MNs could enable a deeper
penetration to the ocular surface tissue and
had control over the drug release from these
micro-implanted reservoirs. The corneal
neovascularization model in eye disease
indicated MNs can reduce ~90%
neovascular region.
[69]
Ocular insert
MNs eye patch
Payload
monoclonal antibody
(DC101), diclofenac
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5.1. Microemulsion
MEs comprise of oil, surfactant, and cosurfactant with medicaments. In general, the
thermodynamic stability of oil in water emulsion (o/w) is a consequence of interfacial film
around water droplets [70]. ME as a drug delivery vehicle for eye preparation has been
widely explored to overcome the various barriers in ocular drug delivery. To improve the
significant concentration of drug in the posterior chamber of the eye, an overwhelming
study led by Nayak and Misra investigated the PEGylated ME delivery into the posterior
segment of the eye (Figure 5). They developed TA-loaded ME, post evaluation in vitro for
solubility, emulsion capability, and they construed a pseudoternary phase diagram. The optimum formulation comprised a ratio of oil (Capmul MCM C8 ): surfactant (AccononMC8-2 ):
cosurfactant (Transcutol): water of 5:35.5:4.5:55. The emulsion was PEGylated using 1,
2-distearoylphosphatylethanolamine-polyethyleneglycol 2000 (DSPE-PEG 2000). Moreover,
the PEGylated drug-loaded ME was characterized and investigated for topical application.
The prepared PEGylated ME was observed to be stable, homogenous, and nonirritant to
the eye, after animal study, and had the potential to achieve the target to the posterior
segment of the eye after topical administration [2].
Figure 5. Diagram showing the route of PEGylated ME entry into the posterior segment of eye (A)
and different parts of retina of eye (B). To overcome the cellular barriers, topical PEGylated ME may
cross the membrane barriers viz. cornea, conjunctiva, and sclera, thereby preventing opsonization
and improving circulation in lachrymal fluid and vitreous humor. Modified from ref. [2]; permission
granted from ACS publishers (https://pubs.acs.org/doi/10.1021/acsomega.9b04244, (accessed on
20 December 2021)).
The findings shown in Figure 6 illustrate that aseptically developed ME was free of
microbial contamination and did not corroborate the microbial growth. In the isotonicity
test shown in Figure 6II, the architecture of RBC is maintained in both normal ME and
PEGylated ME preparation, which confirmed that both formulations were isotonic to
ocular fluid, while they were ruptured in hypertonic (B) and swollen in hypotonic solution
(C). The blood and tear fluids possess the same osmolarity, and thus, RBC was utilized
for the isotonicity test. Figure 6III shows the nuclei of cornea incubated with normal
ME and PEGylated ME were safe, with no risk of side effects using them. Figure 6IV
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shows the corneal hydration and staining test, which confirmed the nonirritant nature of
formulations [2].
Figure 6. (I) Culture plate’s sterility test on incubation with (A) saline solution, (B) positive control,
(C) PEGylated ME, and (D) normal ME; (II) tonicity evaluation, RBCs treated with (A) saline solution,
(B) hypotonic solution, (C) hypertonic solution, (D) normal ME, and (E) microscopy of PEGylated ME;
(III) hematoxylin-and-eosin-stained corneal sections treated with (A) saline solution, (B) normal ME,
and (C) PEGylated ME observed under a microscope; (IV) corneal hydration test. Images captured
after 3 h of hen’s egg membrane treated with (A) saline solution, (B) NaOH solution, (C) normal ME,
and (D) PEGylated ME. Modified from ref. [2] (https://pubs.acs.org/doi/10.1021/acsomega.9b04244,
(accessed on 20 December 2021)).
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Kalam et al., (2016) prepared and evaluated gatifloxacin efficacy in the anterior segment of the eye with respect to good corneal adherence and permeation of the drug and
compared it with a conventional eye drop. The prepared ME used an oily phase as isopropyl myristate and a nonionic surfactant such as Tween 80, and Transcutol-P was used as
cosurfactant while applying an aqueous titration technique. The formulation appeared to
have uniform droplets, and size ranges varied from 51 nm to 74 nm, with a surface charge
on ME recorded as 15 mV to 24 mV and optimum physicochemical features desirable
for topical instillation. The optimized formulation improved stability and contact time,
and resulted in a twofold improvement in bioavailability of the drug, compared with
the conventional eye drop. Thus, the ME showed improved intraocular permeation and
trans-corneal penetration, as well as preventing precorneal loss and improving absorption
of gatifloxacin in the anterior segment of the eye [71].
Perminaite et al., developed a novel royal jelly containing 10-hydroxy-2-decenoic acidbased ME for ophthalmic delivery. Royal jelly obtained from natural worker honeybees
has potential biological activities such as anti-inflammatory and antioxidant activities.
The royal jelly ME prepared by oil titration method comprised royal jelly, Tween 80 as
surfactant and Tween 20 as cosurfactant, an oily phase as isopropyl myristate, and water,
characterized in vitro. Further, the ME was assessed for irritation in the rabbit’s corneal
cell culture. The results demonstrated that ME droplet size was 67.88–124.2 nm, with a
polydispersity index of <0.180. The10-hydroxy-2-decenoic acid release depended on the
surfactant and cosurfactant ratio employed in the formulation. The cell culture test results
indicated that ME was nonirritating [72].
5.2. Polymer Micelles
Nanomicelles are the amphiphilic self-assembling architecture of colloidal particles,
with sizes varying from 10 nm to 100 nm, and consist of a hydrophilic head and hydrophobic shell. The nanomicellar delivery system is commonly used to dispense therapeutics
into a transparent aqueous solution. It is a widely employed pharmaceutical vehicle for
solubilizing hydrophobic drugs. The poor solubility of the drug is a limiting factor for
formulating the ocular preparation because of subtherapeutic effects in ocular tissues,
which comprises an amphiphilic surfactant or a polymer in the aqueous phase. The carrier
system’s important key attributes include easy preparation techniques, high entrapment of
the drug, loading, nanosize, and capability to encapsulate hydrophobic drugs and remain
in their hydrophobic shell. The carrier system enabled protection against drug degradation
and increased drug stability in the aqueous phase. Micelles can be used for the delivery
of prodrug, drug–polymer conjugate, and polymer film for sustained release in the ocular
system [73]. An illustrative novel therapeutic strategy in ocular drug delivery is shown
in Figure 7.
Civiale et al., prepared Dex nanomicelles using copolymers of polyhydroxyethylaspartamide PHEAC (16) and pegylated PHEAC (16) for topical anterior segment drug delivery.
The animal studies of Dex nanomicelles were performed in rabbit’s aqueous humor, and
results depicted that drug-loaded micelles increased ocular availability of drug by 40%,
compared with a Dex suspension. In an attempt to enrich the drug concentration in the
posterior ocular tissue, a combination drug (Dex, voclosporin, and rapamycin) with mixed
nanomicellar preparation (0.1% and 0.2%) was designed. The tissue distribution analysis
after single drop administration indicated that nanomicellar preparation containing multidrug enabled therapeutic concentrations to be achieved in the posterior chamber of the
eye. These findings suggest that nanosize micelle could evade the physiological barriers in
the ocular region and efficiently deliver drug carriers to the posterior ocular tissues [33].
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Figure 7. Novel therapeutic strategy in ocular drug delivery.
Junnuthula et al., developed self-assembled block-copolymers of polymeric micelles
and polymersomes and investigated for physicochemical features, including interactions
and retention with vitreous liquid. Furthermore, they performed in vivo study in rabbits
for ocular kinetics via intravitreal injections. Their findings revealed that polymersomes
retention prolonged in the ocular tissue and deposited more to the retina, as well as the
optic nerve, in the head region [73].
Alami-Milani et al., designed Dex-encapsulated polycaprolactone–polyethylene glycol–
polycaprolactone micelles, and an ex vivo permeation test indicated thatmicelles could
potentially deliver the hydrophobic Dex in the ocular tissue [74]. Vaishya et al., (2014)
developed and characterized Dex-loaded polymeric nanomicelles for the posterior segment
uveitis treatment. Pertaining to this, a low-molecular-weight di-block copolymer was
synthesized and evaluated in vitro for the formulation of critical micelle concentration
and tested in ocular cells for toxicity. The nanomicelles size incurred 25–30 nm, with
uniform distribution and a polydispersity index of 0.125. The permeation of drug-loaded
nanomicelles was raised by 2-times across the conjunctival cell line and by 2.5-times across
the excised rabbit sclera, compared with a drug suspension. Thus, nanomicellar preparation
herein developed could achieve therapeutic levels in the posterior region of the eye after
topical instillation [75].
The topical treatment of posterior uveitis is noteworthy but goes against conventional
therapy to achieve therapeutic concentration. In a similar attempt, to maximize the drug
concentration in the posterior eye segment, Nikita et al., designed an everolimus-loaded
nanomicellar preparation using Soluplus® , a grafted copolymer of polyvinyl caprolactam–
polyvinyl alcohol–polyethylene glycol (PVCL–PVA–PEG) for enhanced permeation and
bioavailability in the ocular epithelia to treat the ocular uveitis. The nanomicelles had
a size of 65.55 nm and low CMC (7.2 µg/mL). The surface analysis was found to be
uniform, spherical, and smooth. The drug entrapment was high, and the release profile
was sustained, compared with adrug suspension. The permeation study in the cornea
of goat mucosa suggested higher permeation across the cornea than drug suspension.
Further, the higher drug permeation of nanomicelles was confirmed by confocal microscopy.
Overall, the outcomes of the study clearly pointed to higher drug access and enhanced
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bioavailability of everolimus-loaded nanomicelles and revealed that these nanocarriers
could be promisingly employed in the treatment of ocular uveitis [76].
Further, Patel et al. prepared Dex-loaded nanomicelles of polyoxyl 40 stearate and
polysorbate 80 and characterized in vitro for solubility, critical micellar concentration
formation, micelles size, zeta potential, surface morphology, drug release, and efficacy
in an animal model. The ocular drug tolerance and drug distribution in ocular tissue
were investigated in an animal model after single and multiple dosing. The developed
nanomicelles containing Dex (0.1% w/v) showed micelles size of 13.3 ± 0.4 (placebo) and
14.5 ± 0.4 nm (drug-loaded nanomicelles). The TEM image observed a spherical, stable, and
uniform micelle size. The animal testing revealed no inflammation, redness, or irritation
when compared with control. The drug concentration was sufficient to exert a therapeutic
effect in the cul-de-sac cavity after topical use in the rabbit’s eye. The generated novel
nanomicelles enabled the solubilization of 0.1% Dex hydrophobic core and potentially
delivered the drug in the posterior segment of the eye for treatment of posterior uveitis [77].
For active targeting based on peptide transporter-1, Xu et al. designed nanomicellesfor ocular delivery. They prepared chitosan oligosaccharide–valylvaline–stearic acid
(CSO–VV–SA) nanomicelles and castor oil-40/octoxynol-40 (HCO-40/OC-40) mixed nanomicelles. The in vitro cytotoxicity assay produced no significant difference in human
corneal epithelial cells (HCEpiCs) and conjunctival epithelial cells (HConEpiCs). The
inhibitory test confirmed the active transport of CSO–VV–SA nanomicelles through the
chosen transporter. The fluorescence study confirmed the active transport of CSO–VV–SA
nanomicelles by PepT-1 in the posterior segment via the conjunctiva. The animal study
demonstrated precorneal retention of Dex from both nanomicelles of more than 3 h. The
results indicated that CSO–VV–SA nanomicelles could be novel carriers, with promising
testing potential in clinical applications [78].
5.3. Nanoparticles
NPs are colloidal nanoparticulate carriers whose size generally varies in the range
of 10–1000 nm. For ocular drug delivery, NPs comprise a mixture of protein, lipids,
and or polymers derived from synthetics such as PLGA, polylactic acid (PLA), albumin,
alginic acid, chitosan–alginate, and polycaprolactone. NPs improved the ocular passage
of hydrophobic drugs by disrupting superficial ocular barriers and granting systemic
access to medicaments from specific sites [79]. The drug-encapsulated NPs have desirable
biological characteristics related to the enhanced ocular residence time from the dosage
form, reduced toxicity, and increased drug penetration capability deeper to the ocular tissue,
and concomitant with reduced drug loss from the precorneal spaces due to rapid tear fluid
turnover [80]. NPs are promising carriers of drug candidates in ocular delivery, owing to
their small scale, little eye irritation, and prolonged drug release, hence the reduction in
dosing frequency. Due to easy elimination from the precorneal pocket, as seen generally
with aqueous drug solutions, NPs administration is designed with a mucoadhesive feature
likely to aid for more time in the precorneal chamber. For this, chitosan polyethylene glycol
(PEG) and hyaluronic acid are preferably used to increase the pre-corneal residence time of
drug-loaded NPs [81].
NPs with chitosan polymer are widely researched for ameliorating drug concentrations
in the precorneal cavity by improving the ocular residence time. The chitosan is positively
charged, which binds effectively with the negatively charged surface of the cornea and
thus improves corneal residence time and minimizes the precorneal clearance. It was illustrated that natamycin chitosan/lecithin NPs improved ocular bioavailability by 1.47 fold
and reduced precorneal clearance by 7.40 fold, at a low dose, and reduced frequency of
instillation in rabbit’s eye, compared with a marketed suspension [82]. Musumeci et al., reported that melatonin-encapsulated PLGA–PEG NPs were effective in lowering intraocular
pressure (IOP), compared with melatonin PLGA NPs and drug solution of an equivalent
concentration in the rabbit’s eye. It was indicated that the decreased surface charge of
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PLGA–PEG, compared with PLGA alone, well accorded and enhanced interaction of NPs
with eye surface, resulting in better hypotensive outcomes for a prolonged time [34].
Zhang et al., instilled Dex in rabbit’s eye through intravitreal injection and investigated
pharmacokinetics and ocular tolerance of the drug from PLGA NPs. The results concluded
that DEX-encapsulated NPs showed sustained release of the drug for50 days. The vitreous
humor reported constant drug levels (3.85 mg/L) for 30 days. The results implied that Dex
NPs via intravitreal injection provided sustained release in the posterior segment of the
eye [35]. Chi et al., studied hybrid NPs and nanosheets for enhanced cellular uptake in the
ocular tissues, using peptide transporter-1. They prepared and characterized nanocarriers
in vitro. Both nanosheets and hybrid NPs indicated the sustained type of drug release
in vitro and enhanced the precorneal retention in vivo, but hybrid NPs showed higher
permeability in vitro than nanosheets. Furthermore, a cellular uptake study on HCEpiCs
and ARPE-19 cells showed endocytosis based on actively transported PepT-1 and higher
drug internalization, both from hybrid NPs and nanosheets. Thus, it was concluded that
hybrid NPs are promising carriers for ophthalmic instillation in the mid-posterior region,
whereas nanosheets are ideal for ocular diseases [36].
Yu et al., developed several Dex–glycol chitosan (Dex–GCS) conjugate by chemical synthesis and characterized for UV–Visible spectroscopy, infrared spectroscopy, and
X-ray diffraction technology. The conjugate self-assembled into NPs with a size range of
277–289 nm and a positive surface charge of +15 mV. The particles were ascertained as
spherical via transmission electron microscopy (TEM). Moreover, mucoadhesive properties
of Dex-GCS NPs with varying concentrations of mucin were evaluated in vitro. Dex release
in phosphate-buffered saline (PBS, pH = 7.4) expressed progressive drug release till 8 h and
then reached plateau upto 48 h. The cytotoxicity against L929, HCEC, and RAW 264.7 cells
of the formulation was tested after incubation of 24 h and showed similar efficacy to Dex
sodium phosphate (Dexp) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages.
More interestingly, the developed Dex-GCS NPs established effective ocular tolerance
and precorneal retention, compared with an aqueous preparation, indicating that the
self-assembled Dex-GCS NPs appear to be an anticipated system for ocular therapeutic
delivery [83].
5.4. Nanoparticulate Targeting in Retinoblastoma (RB)
Retinoblastoma is encountered during childhood, and the incidence rate is more prevalent in children under the age of 5 years. The survival rate of the cancer is high but may
lead to severe complications such as vision loss and even death if not diagnosed and treated
timely [84]. After detection of cancer, medical intervention relates to chemotherapy, radiotherapy, and or surgery, which are meant to improve patient survival. The NP-based drug
delivery investigated in RB led to improved drug delivery in the posterior eye segment and
also increased the intravitreal half-life (t1/2 ) of chemotherapeutic agents with potential outcomes in retinal cancer [85]. A nanoparticle targeting based on rationale design essentially
incorporates functionalized moieties or ligands for potential cellular uptake, and cellular
internalization of therapeutics has been reported in several publications [86–89]. Several
types of conjugating agents—namely, epithelial growth factor receptor (EGFR), folic acid,
transferrin, cell penetration peptide, and proteins, are used for surface functionalization
processes, depending upon the dominancy of specific receptor to the target site [90]. Further,
it has been observed that the surface alteration of nanocarrier using polyethylene glycol
(PEG) improved the NP uptake due to colloidal stability, reduced protein adsorption, and
less opsonization, thus improving the intravitreal transport to target cells [91]. Sims et al.
designed functionalized melphalan-loaded poly(lactic-co-glycolic acid) (PLGA) NPs to
increase the intravitreal drug delivery through positive cell association and improved
efficacy in retinoblastoma cells. They compared the cell association potential and efficacy
in retinoblastoma cells surface-modified PLGA NPs with unmodified NPs. They observed
prominent cell association, cell internalization, and enhanced efficacy with surface functionalized MPG-NPs after 24 h of administration, compared with unmodified NPs. In another
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study, topotecan-bearing mesoporous silica NPs with folate conjugation had enhanced
drug efficacy in RB treatment. The nanosized particles demonstrated sustained drug release
and superiorcell uptake in Y79 RB cells, compared with nontargeted NPs [92].
5.5. Nanosuspensions
Using conventional techniques to formulate hydrophobic substances is highly challenging. The application of nanotechnology in formulating hydrophobic drug substances
such as nanosuspension is desirable to address the problem associated with drug molecules.
Nanosuspension is a colloidal carrier of dispersed drug substances of submicron particle
size, which are, in turn, stabilized by formulation additives such as surfactants or polymers.
In ocular drug delivery, the method offers many benefits such as ease of sterilization in
formulating the eye drop, minimizing ocular irritation, improving precorneal residence,
as well as enhancing ocular drug absorption. Many studies well reported the improved
glucocorticoids absorption via ocular drug delivery. Glucocorticoids such as Dex, prednisolone, and hydrocortisone have been widely suggested for the therapeutic modality of
inflammatory conditions in ocular tissues of the anterior segment. However, the conventionally established treatment using these drugs needs multiple dosing, resulting in large
cumulative doses that may further lead to complicationssuch as cataracts, optic nerve damage, or glaucoma. Kassem et al. successfully developed glucocorticoids (Dex, prednisolone,
and hydrocortisone) nanosuspension, and the formulation was effective in reducing the
intraocular pressure in rabbit’s eye [37].
Recently, Yan et al., compared mucus-penetrating particles (MPPs) and cationic NPs
suspension having cyclosporine A (CsA) in terms of ocular bioavailability. This study
further clarified the mucous permeation capacity of MPPs and mucous-retaining capability of cationic NPs, although both preparations were capable of prolonging the ocular
residence time of the drug on the eye surface. Both cationic nanosuspensions and MPP
nanosuspensions (drug core) were prepared by applying an antisolvent precipitation
technique. The X-ray analysis revealed that CsA was in an amorphous state in both formulations. The in vitro mucoadhesion analysis showed that cationic nanosuspensions
interacted 5.0–6.0 times higher with pig mucin, compared with MPP nanosuspensions
(drug core). The permeation study on drug-core MPP nanosuspensions indicated that
apparent permeability (Papp) value was 5.0–10.0 times greater than cationic nanosuspensions. The in vivo ocular bioavailability showed CsA concentration in cationic and MPP
(drug-core) nanosuspensions were 13,641.10 ng/g and 11,436.07 ng/g, respectively, which
was significantly greater than conventional nanosuspension (8310.762 ng/g). These results
indicated that both cationic and MPP nanosuspensions were effective in delivering the CsA
concentration (10–20 µg/g) to the anterior chamber using eye drops. Therefore, cationic
nanosuspensions look promising, as they provided more ocular bioavailability than MPP
nanosuspensions [93].
Boddeda et al., prepared flurbiprofen (FB)-encapsulated polymeric nanosuspension
for enriching the bioavailability in the ocular region. The nanosuspension was developed
by a solvent displacement technique while optimizing the process variables—namely, drug
and polymer ratios and aqueous-to-non aqueous solvent ratio, as well as their impact on
formulation characteristics including size, drug release, and ocular tolerance. The developed nanosuspension showed a spherical particle shape, a particle diameter of around
100 nm to 200 nm, with surface charge ranging from +6.6 ± 2.2 to +19.0 ± 3.1 mV, and drug
encapsulation was recorded between 54.67 ± 3.4 and 90.32 ± 3.2%. The nanosuspension
underwent sustained release of drug (60%) over 12 h, compared with a marketed preparation (Flur eye drops). In vivo study of an animal model reported that it was nonirritant and
safe, based on histopathological studies. The FB-loaded Eudragit nanosuspension proved
to be safe, stable, and suitable for ocular use [38].
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5.6. Liposomes
Liposomes are widely sought drug delivery carriers with vast applications in different
areas of biomedical sciences, including topical applications. They are lipid-based spherical
vesicles that have one or more cell membranes such as phospholipid bilayers encasing the
aqueous phase and proved as promising drug delivery carriers for ocular disease therapy
due to the enhanced ocular residence time for drug absorption. The size of the vesicle
ranges between 10 nm and 1000 nm, depending upon the phospholipid layer:unilamellar
vesicles (10–100 nm), bilamellar vesicles (100–300 nm), and multilamellar vesicles (>300 nm).
In recent times, liposomal drug carrier remains a point of interest for ocular drug delivery.
The liposome is an ideal drug carrier owing to its remarkable biocompatibility, high degradability, flexibility, nonimmunogenicity, nontoxicity, and being mimetic to cell membrane
architect, enabling the encapsulation of both lipophilic and hydrophilic drugs and delivering the medicaments effectively in both anterior and posterior chambers [94]. Various
studies investigated the liposomal drug delivery for improving dissolution, bioavailability,
precorneal penetration, increased residence time, and targeted action [39,95,96].
Age-related macular degeneration (AMD) in the eye is a leading problem associated
with the central region of the retina, i.e., the macula of the eye, which may lead to visual
deficiency and at later stages to blindness. To improve the solubility and bioavailability
of berberine hydrochloride (BBH) and chrysophanol (CHR) for the treatment of ocular
diseases based on active biological response related to anti-inflammatory, antioxidative,
and antiangiogenic effects, Lai et al. developed PAMAM-coated liposomes. The PAMAMcoated liposomes indicated considerable cellular permeability in the corneal cells and
increased bioadhesion on the corneal epithelium of the rabbit model. The coated liposomes
improved drug absorption and acted apparently as protection for the retinal pigment cells
and also protected the rat’s retina after photooxidative injury. The formulation of liposome
pointed to no side effects post investigation of ocular morphology in the rabbit. The
cellular internalization of the developed formulation was investigated in HCEC cells after
incubation of 24 h. As indicated in Figure 8a,b, PAMAM-coated coumarin (Cou) liposome
showed stronger fluorescence intensity, compared with normal liposomal formulations,
after 1 h of topical administration. The study suggests that PAMAM-coated Cou liposomes
may significantly elicit the cell uptake of therapeutics from carrier systems, compared with
normal liposomes [95].
The different preparations—namely, chrysophanol–berberine hydrochloride suspensions (CBs), compound liposomes (CBLs), and PAMAM-coated compound liposomes
(P-CBLs) were used to examine the transcorneal permeability. Each of the formulations can
similarly penetrate the corneal epithelium, as indicated by the fluorescence intensity for
15 min initially after topical instillation. As regards moving time, the concentration of CBLs
and P-CBLs were more detected in the corneal epithelium, shown by high fluorescence
intensity. High drug retention in the ocular tissue was also confirmed because of the lack
of drug in tear fluid. Moreover, for CBs, the fluorescence intensity was diminished in
the corneal endothelium, indicating that they are unable to permeate through the corneal
epithelium (Figure 8c). A pharmacokinetic study was performed using formulation CBs,
CBLs, and P-CBLs in the rabbit’s eye. Notably, the outcome of the study revealed that
Cmax of BBH in the aqueous humor with instillation of P-CBLs and CBLs were 1.719 and
1.23-times greater than CBs. The bioactivity of BBH loaded liposomes was 1.33 times greater
than BBH-Loaded CBs, whereas P-CBLs raised the bioactivity by 1.6343 times vis à vis
CBs. Therefore, the PAMAM-coated liposomal system showed potential utility in treating
complex ocular ailments [95].
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Figure 8. Investigation of liposomal effectiveness in ocular drug delivery: (a) the fluorescence
images of different formulations with Coumarin (Cou) using cell analyzer. The cellular uptake
after 24 h of human corneal epithelial cells (HCECs) (scale bar = 300 µm); (b) formulations intake
count; (c) the Nile red-stained formulation distribution images captured in cornea; the corneal
endothelium indicated by arrow (scale bar = 50 µm); (d) in vivo pharmacokinetic parameters after
topical instillation of different formulations. Permission under Commons Attribution 4.0 International
License [95]. (http://creativecommons.org/licenses/by/4.0/, (accessed on 15 November 2021)).
Moreover, pharmacodynamic studies were conducted to investigate the therapeutic
efficacy in the ocular region, with liposome formulations, in light-induced retinal tissue
damaged rat’s model. The pentobarbital sodium (3%) was injected viathe intraperitoneal
routeinto different groups of animals—normal saline, placebo liposome, CB, CBL, and
P-CBL groups. Among these formulations, P-CBLs induced the highest protection in the
reversal of retinal function in photo-exposed rats. Flash electroretinogram after 14 days
by light damage of retinal tissue indicated a significant increase in b-wave responses in
P-CBLs-treated rats, compared with other formulation groups, as shown in (Figure 9a).
The normal-saline-group-treated rats kept their intact retinal vessels, and the background
of the fundus was clearly seen. The rat vessels treated with the blank liposome group
showed some severe manifestation in the fundus. The P-CBLs had no impact on the retinal
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blood vessels, but they improved the reflection area in the eye, as shown in (Figure 9b).
Compared with the normal saline group, the blank liposome group decreased the numbers
of outer nuclear layer cells and led to the thinning of the layer significantly. Adversely,
histopathological examination of the eye section showed evidence of protective impression
in the retina in P-CBL-instilled rats after ocular cell injury caused by the photo-oxidative
process. The morphological analysis revealed clear layers of retinal structure and wellstained nuclear layers in P-CBL-treated rats (Figure 9c). The antioxidant assay showed
P-CBLs were highly potent in reducing ROS levels as per the relative fluorescence ratio,
compared with CHR and BBH, as shown in Figure 9d,e [95].
Figure 9. Effective drug delivery of liposomes into posterior ocular segment. Protection against
photo-oxidative retinal damage: (a) the b-wave amplitude alteration following topical administration
of different formulations for up to 14days; (b) retinographic images of various formulations treatment;
(c) the protection efficacy of various hematoxylin-and-eosin (H and E)-stained formulations in the
retina (scale bar = 20 µm); (d) images of in vitro anti-ROS efficacy taken with a long-term real-time
dynamic live cell imaging analyzer: (e) ROS levels of various formulations. Data are expressed as
mean ± SD (n = 3). * p < 0.05, ## p < 0.01, ** p < 0.01, *** p < 0.001. Permission under Commons
Attribution 4.0 International License [95]. (http://creativecommons.org/licenses/by/4.0/, (accessed
on 15 November 2021)).
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Moreover, the ocular irritation study in rabbits was performed using the same formulation with equivalent drug doses such as CBs, CBLs, and P-CBLs, and the ocular surface was
analyzed using the Draize eye test. The tissue histology analysis revealed that the cornea,
iris, and conjunctiva were safe, and no tissue damage was seen in thegroup after 14 days of
instillation of P-CBLs (Figure 10a). The stained ocular surface with 0.5% sodium fluorescein
observed under a silt lamp and camera showed no edema or injuries, demonstrating the
safe and protective nature of P-CBLs (Figure 10b) [95].
Figure 10. (a,b) Ocular irritation studies: (a) typical histological image of formulation, P-CBLs after
instillation for 14 successive days (scale bar = 20 µm); (b) ocular surface examination using a silt lamp
and camera, post staining with 0.5 % sodium fluorescein. The ocular irritation studies manifested
no injuries or abnormalities in either part of the cornea, conjunctiva, or iris of the eye (a). The 0.5%
sodium fluorescein stained ocular surface observed under a silt lamp and camera found no edema or
injuries, which further substantiated the safe and protective nature of P-CBLs (b). Permission under
Commons Attribution 4.0 International License [95]. (http://creativecommons.org/licenses/by/4.0/,
(accessed on 15 November 2021)).
A recent study led by Natarajan et al., investigated a latanoprost liposomal preparation for delivery to the anterior segment of the ocular tissues. The instillation of single
liposomal formulation via subconjunctival injection in rabbit’s eye brought forth sustained
lowering effect of IOP for upto 50 days, which is comparable to the conventional eye
drop formulation. Cationic liposomes experienced better drug delivery efficacy in the
posterior ocular segment, compared with anionic or neutral liposomes, by using positively
charged lipid or mucoadhesive, there by improving ocular residence time of the drug. For
instance, stearylamine and didodecyldimethylammonium bromide are generally employed
in designing cationic liposomes [40].
To improve the antibiotic efficacy in topical instillation dos Santos et al., encapsulated
besifloxacin into liposomes with additives as positively charged amines and investigated
the impact of these charges on the drug diffusion process in two approaches—namely, iontophoresis and passive diffusion. The authors hypothesized that the charge present on the
liposome surface could enhance the burst release due to electromigration upon application
of electricity and improve the penetration efficiency and residence time of formulation.
Herein, liposomes prepared by using phosphatidylcholine (LP PC) or phosphatidylcholine
and spermine (LP PC:SPM) were stable, indicating the mucoadhesive property and that
they were compatible withthe ocular tissues. Furthermore, electron resonance spectroscopy
exhibited that drug and excipients incorporated in liposomal preparation did not interfere
with membrane fluidity, structural integrity, and stability in the iontophoretic state. The liposome (LP PC) showed a mean diameter of ~177 nm and zeta potential of −5.7 ± 0.3 mV,
and for liposome (LP PC:SPM),− the mean diameter and surface charge were ~175 nm
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and +19.5 ± 1.0 mV, respectively. The minimum inhibitory concentration (MIC) and the
minimal bactericide concentration (MBC) of the developed liposomes investigated for
P. aeruginosa indicated lower MIC and MBC than the marketed preparation (Besivance).
Both formulations showed the same efficacy, and surface charge incorporation on liposomes was not beneficial in iontophoretic therapy. On the other hand, as investigated in
an ocular model in vitro, passive diffusion/penetration of a drug that simulates the tear
fluid remains challenging in passive delivery of the formulation due to ocular resistance
to the formulation. The result anticipated that liposomes LP PC:SPM expressed higher
drug penetration than the marketed preparation, Besivance. Therefore, besifloxacin-loaded
positive (+) liposomes ameliorated the passive delivery of drug upon topical instillation
and could be considered a novel approach to enhance the ophthalmic disease therapy [39].
Rajala et al. examined the utility of liposome–protamine–DNA complex (LPD) in gene
delivery through a subretinal manner. A biomimetic virus was designed to havemodifications in cellular and signaling peptides for the delivery of retinal pigment epithelium
protein 65 (Rpe65) gene for eye disease treatment in mice. Rpe65 is a key enzyme that
controls the photochemical 11-cis-retinal and helps to see objects. The results indicated
that modified liposome showed effective Rpe65 gene delivery in a specific and further
alleviated long-term expression of the Rpe65 gene in Rpe65 knockout mice, resulting inthe
rectification of blindness in vivo [41].
In another study, acyclovir encapsulated in positively (+) and negatively (−) chargedliposomes were fabricated using stearylamine (cationic) and dicetylphosphate (anionic)
charge-inducing agents. The drug concentration from positively charged liposomes in the
cornea of the rabbit’s eyewas higher than the liposomes of negatively charged vesicle and
plain acyclovir when administeredviatopical instillation after 2.5 h. The observed concentration drug in the cornea for the drug solution, andpositively and negatively charged
liposomes were 253.3 ± 72.0, 1093.3 ± 279.7, and 571.7 ± 105.3 ng/g. The increase in
drug absorption from positively charged liposomes was 2-times higher than negatively
charged liposomes and 5-times higher than drug solution, indicating that positive surface
liposomes havea great affinity with the negatively charged corneal surface, which may be
ascribed to electrostatic interaction, thereby increasing the ocular residence time and drug
absorption [42].
In the posterior segment, drug delivery of liposomal preparation is to be more concentric on elating the t1/2 of the drug by foreshortening the fluid clearance from vitreous
humor and protecting degradable molecules viz., peptides and nucleotides, and furnishing
sustained release of the drug. Referring to this, liposome enabled the increase influconazole
t1/2 in the vitreous humor of rabbit eye approximately 8-times higher than plain drug [97].
In a similar study, a tacrolimus liposome was prepared for effective therapy of uveoretinitis. After i.v. administration of tacrolimus-loaded liposome, the concentration of drug in
the vitreous humor level heightened to >50 ng/mL and showed sustained release behavior
for 14 days. Thus, the tacrolimus liposomal formulation was proved more efficacious in
limiting uveoretinitis, compared with the drug solution and also overcome the toxicity
caused inside the retinal cells [98]. Among alarge number of liposomal formulations in the
preclinical and clinical phases, few of them are commercially available such as Visudyne®
and Tears again® used for the treatment of ocular diseases. Visudyne® , a liposomal preparation having verteporfin as a photosensitizer, is applied in photodynamic therapy for the
growth of new blood vessels in choroidal cellsassociated with macular degeneration (age
related), ocular infection, and myopia [99].
5.7. Dendrimer
Dendrimers are nanoscale, star-shaped multibranched structures comprising polymeric chains. They are accessible in various molecular grades with terminal end positions
of –NH2, OH, and –COOH groups. The end position functional moiety may be used to
functionalize with various ligands or targeting moieties. The multibranched dendrimer
may allow a large number of lipophilic or hydrophilic drug moieties to become entrapped.
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Recently, using dendrimer as a carrier for delivering a drug through different routes in the
ocular cavity has been reported, with a promising outcome of PAMAM dendrimer.
Vandamme et al., employed the utility of PAMAM dendrimers as ocular drug delivery
vehicles of pilocarpine nitrate and tropicamide delivery in glaucoma miotic and mydriatic
activity. The ocular retention time of PAMAM solutions, fluorescein saline, and fluorescein
in carbopol solution (0.2% w/v) was investigated in the rabbit eye. The average ocular
residence period of PAMAM and carbopol solution was accounted higher than the normal
saline. Thus, dendrimers as ocular vehicles were suggested as desirable alternatives for
enriching ophthalmic residence time and improving ocular drug availability, with better
outcomes in the ocular therapy. For instance, pilocarpine nitrate- and tropicamide-loaded
PAMAM dendrimers showed prominent miotic and mydriatic activity when administered
in albino rabbits [43].
To overcome corneal inflammation and reduce dosing frequency, Soibermanet al.,
explored Dex-loaded hyaluronic acid crosslinked G4-PAMAM dendrimer gel for subconjunctival injection as a potential ocular delivery approach for sustained release and
increased absorption of D-Dex. The therapeutic efficacy of the formulation was tested
on a rat model. Herein, the fluorescently labeled dendrimers (D-Cy5) loaded in the gel
were investigated for D-Cy5 release in vivo. The D-Cy5 was specifically released in the
target inflamed tissue and remained confined to the corneal macrophages in the infected
rat. Further, improvement in inflamed tissue of the cornea, corneal clarity, and reduced
neovascularization by subconjunctival application of D-Dex gels were clinically proven
over a period of 2weeksin comparison with the freeDex. The outcomes of the study established that D-Dex dendrimer was more effective in weakening the corneal inflammation
than freeDex, probably through inactivating macrophage and cytokines expression (proinflammatory). The developed injectable gel of D-Dex could have potential as a treatment
of inflammatory disorders in the ocular tissues related to keratitis, dry eye syndrome, as
well as postsurgical problems [100].
Several drugs have been investigated in polyamidoamine dendrimers as novel platforms for ophthalmic drug release in the aqueous solution. Herein, the authors developed
a fast-dissolving dendrimer-based nanofiber (DNF) based on dendrimer as a vehicle for
topical drug delivery of brimonidine tartrate (BT) in glaucoma treatment. The drug release kinetics and safety concerns of the nanofiber were securely investigated both in vitro
and in vivo and showed zero toxicity at therapeutic dose in cultured cells and no irritation caused in the normotensive rat model. The intraocular pressure post administration
of a single dose having equivalent amounts of the drug in DNF and BT solutions was
measured the same. The DNF indicated significant improvement in efficacy, compared
with the BT solution, observed for 3weeks after once-daily dosing suggested that dendrimer nanofibers could act as alternatives for effective drug delivery used as eye drops for
glaucoma therapy [44].
5.8. In Situ Gel
Hydrogel is a crosslinked polymeric system that has wide applications in medical
sciences including drug delivery and tissue engineering. In ocular therapy, hydrogels
are used as promising carriers for drug delivery in a cul-de-sac cavity on account of
biocompatibility and their capability to hold both hydrophilic and lipophilic drug-loaded
systems, protecting them for an adequate amount of time. Hydrogel acts as a drug depot,
on-demand drug release, and tunable cargo could maintain a therapeutic window, thus
enhancing drug absorption [101]. The polymeric structure can hold a large amount of water
and or biological fluid in a swollen state. In situ hydrogel is a polymeric solution in an
aqueous medium that has phase transition characteristics of sol-gel via physicochemical
crosslinking, resulting in the formation of a viscoelastic gel. The gel-forming capacity
can be enhanced by alteration in heat or temperature, medium pH, and ions or may be
developed through UV irradiation. The stimuli-responsive thermosensitive gel is widely
explored for a number of therapeutics in ocular drug delivery [102]. There are several
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thermo-gelling polymers that have been accounted for in the literature for ocular delivery,
including poloxamers, poly (N-isopropylacrylamide), copolymers of polycaprolactone,
polyester block copolymers polyethylene glycol, poly (lactide), and glycolide, as well as
chitosan. The thermogelling polymer at room temperature remains in a liquid state but can
solidify into gel post injection at a physiological temperature [103].
Phua et al., rationally developed a preparation to outweigh the limitation of poor
bioavailability in ophthalmic treatments. The preparation comprised thermosensitive hydrogels of pluronicF-127 meant, to strategically enhance the bioavailability by improving
ocular residence of drug-encapsulated nanoliposomes dispersed in thermosensitive hydrogels. They prepared a depot preparation of nanoliposomes for subconjunctival injections.
Senicapoc-loaded nanoliposomes showed sustained release from nanoliposome and hydrogel preparations. The in vivo study in Sprague Dawley rats showed a 12-fold increase in
ocular residence time, with 24% hydrogel preparation for 1 h, compared with 5 min for free
liposomes, observed with fluorescence measurement. A pharmacokinetic study on flushed
tears revealed that hydrogels enabled drug retention for a long time, compared with a
viscous preparation (1 h), and drug concentration could also be detected in conjunctival
tissues within 24 h post injection [45].
Tacrolimus (TAC) is a hydrophobic drug. The marketed formulation of TAC as eye
drop causes poor drug retention in precorneal space, low aqueous stability, and pulse
kinetic pattern, overall leading to less drug absorption. Sun and Hu developed TAC-loaded
SLN in situ gel (TAC-SLNs ISG) for ocular drug delivery. The optimized formulation was
characterized for in vitro performances including drug release properties. The pharmacokinetic and pharmacodynamic studies were also performed, to investigate the impact
of formulation in comparison with a drug suspension. The probe sonicated particle of
TAC-SLNs ISG had a particle size of 122.3 ± 4.3 nm, and the same was changed nonsignificantly in situ gel. The viscosity of the formulation resulted in pseudoplastic flow.
The gelation temperature of the developed gel was 32 ◦ C, and a marked rise in viscosity
was observed and formed a rigid gel at a higher temperature. In vitro study illustrated
the sustained release of the drug from TAC-SLNs ISG. An in vivo pharmacokinetic study
showed that eye drops achieved Cmax 4657.7 ng/mL within 30 min; on the other hand,
TAC-SLNs achieved Cmax 1892.6 ng/mL in 30 min, and TAC-SLNs-ISG had the highest
concentration of 2132.3 ng/mL within 2 h. The lower concentration early on from such
formulation was probably due to the sustained release effect. The AUC0–t of TAC-SLNs-ISG
and TAC eye drops were 590,355.9 and 222,382.5 ng·min/mL, i.e., 2.65-folds higher for
TAC-SLNs-ISG than for TAC eye drops. The data clearly point to the superiority of TAC
SLNs-ISG, compared with eye drops [46].
In 2020, Noriakiet al., developed tranilast NPs (ophthalmic TL-NPs formulations) for
enhanced drug penetration into the ocular tissues. They designed in situgel, integrating TLNPs with methylcellulose (MC, 0.5–3%), to improve the ocular residence time of the drug.
TL-NPs preparation was fabricated using the bead mill method, and the resulting particle
size was ~93 nm. An animal study using rats showed that the concentration of drug in the
lacrimal fluid was enhanced when the preparation was developed using the MC (0.5–1.5%)
concentration. The drug deposition in the cornea and conjunctiva and the anti-inflammatory
effects of TL were observed in rats post instillation, with an ophthalmic TL-NP preparation.
The optimized formulations of TL-NPs gel with MC (0.5–1.5%) ensured a long residence
and improved contact time in the conjunctiva, compared with a formulation using TL-NPs
with 3% MC [47].
5.9. Nanocapsules and Nanospheres
Depending upon the structural integrity of polymer NP, this is categorized as nanocapsules or nanospheres. Polymeric nanocapsule has been widely examined and interest in its
use as a drug delivery carrier has increased in recent years due to unique nanostructure that
comprises an outer part of a polymeric shell and inner part as a liquid or solid core [104].
Katzer et al., prepared prednisolone-containing nanocapsules (NCs) by interfacial depo-
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sition technique using polycaprolactone or Eudragit® RS100. The prepared NCs were
subjected to physicochemical characterization in vitro for particle size distribution using
laser-based spectroscopy and size-tracking analysis. Furthermore, cytotoxicity and ocular
irritation were determined on the epithelial cell line of the cornea and chorioallantoic
membrane of a rabbit model. NCs were reported to have mean sizes between 100 nm and
300 nm, and prednisolone entrapment was 50%. The NCs showed controlled prednisolone
biexponential release for upto 5 h. Both formulations were safe in the CAM test due to
being nonirritant and showed no cytotoxicity in corneal epithelial cells in the rabbit. The
prednisolone nanocapsule was successfully developed for the first time, for application as
eye drops in the treatment of eye inflammation [105].
Rebibo et al., (2021) used tacrolimus as a model drug to treat eye inflammation.
Bearing in mind the rapid drug expulsion from the carrier system, a critical challenge in
ocular drug instillation, they developed tacrolimus-encapsulated nanocapsules (NCs) for
ocular instillation. The developed formulation was assessed for stability and efficacy under
different experimental conditions. The characterization of the NCs showed the uniform size,
and encapsulation efficiency was high, upto 80%. Furthermore, the lyophilized product
showed good stability as per ICH guidelines for 18 and 3 months under long-term and
accelerated stability conditions. Moreover, drug-loaded NCs did not show any irritation
in the rabbit eye post single and multiple-dose schedules. In addition, ex vivo study of
drug penetration on the porcine cornea, as well as pharmacokinetics analyses in various
eye compartments of the rabbit, showcased the high retention and permeation of drug
from NCs into the anterior chamber of the eye, compared with plain drugs present in the
base. An animal study in rats also revealed high tacrolimus concentration in the eye. The
designed tacrolimus NC system tested on a murine model of keratitis showed a significant
reduction in several inflammatory markers, leading to reduced inflammation in the anterior
chamber. The outcomes of the study showed that NCs as eye drops provided clinical and
histological effectiveness, chiefly in the inflammation of the posterior eye chamber in the
murine model and experimental auto-immune uveitis [48].
Bevacizumab has been employed in ocular therapy in age-related macular degeneration (AMD) in many countries, and due to their short biological t1/2 , multiple intravitreal
injections are required. Li et al., prepared PLGA and PEGylated nano- and microspheres
using bevacizumab, with an aim to improve the drug retention time in the ocular cavity.
The release profile of the developed formulation evaluated in vitro showed bevacizumab
release in a sustained fashion over a period of 3 months [106].
Robinson et al. prepared and evaluated epidermal growth factor receptor (EGFR),
tyrosine kinase inhibitor (TKI), and AG1478-loaded PLGA microspheres and nanospheres
meant for intravitreal injection in rats through an optical nerve crush injury model. In vitro
characterization of microspheres and nanospheres revealed particle sizes of ~2.6 µm and
~360 nm. After intravitreal injection, the optic nerve regenerated within two weeks. Moreover, the nanospheres were found to be superior to microspheres in regrowth of the optic
nerve. The authors came to the conclusion that nanospheres’ intravitreal installation was
more efficacious than microspheres due to delivering the therapeutics in the vitreous
humor [49,107].
Giannavola et al., formulated acyclovir-loaded PLA nanosphere colloidal suspensions
via a nanoprecipitation technique for ophthalmic drug delivery. They investigated the effect
of molecular weight and type of polymer, as well as surfactants concentration used in the
formulation on in vitro characteristics of nanosphere. The acyclovir-loaded nanospheres
were tested in vivo for ocular drug absorption and the results were compared with a
free-drug suspension. Moreover, PLA nanospheres were modified with the PEGylation
technique to improve retention of formulation in the aqueous humor. The ocular tolerance
test of PLA nanospheres was estimated by a modified Draize test. The drug concentration in the aqueous humor was monitored for 6 h to determined absorption and ocular
bioavailability from different formulations. The higher molecular weight polymer led to
reduced nanosphere size, whereas the PEGylated formulation showed sustained release,
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improved pharmacokinetics, and well toleration in the eye. The efficacy of PEGylated PLA
nanospheres was reported significantly higher than plain PLA nanospheres [50].
5.10. Solid Lipid NPs (SLNPs)
This method is an emerging surrogate to colloidal drug delivery having the advantage
of incorporating lipid and polymer NPs into a single system. A patent by Muller and
Lucks disclosed SLNPs as stable solutions with a solid lipid core that have the potential for
encapsulating medicaments stabilized by a layer of surfactant [108]. The SLNs differ from
emulsions and liposomal systems in having high-melting lipids. They are free from chronic
and acute toxicity, are biocompatible, and could provide a controlled and targeted release
to a specific site. The lipid matrix plays an important role in controlling drug release and
protecting the drug from degradable enzymes [109,110].
Fungal eye infection caused by fungal keratitis (FK) is a severe pathogenic condition
that may lead to ocular morbidity. In this perspective, Natamycin (NAT)-loaded solid
lipid NPs (NAT-SLNs), as first-line treatment of FK, has been designed to combat poor
corneal permeation and improve residence time, bioavailability, and efficacy in the ocular
tissue by Khames et al., The NAT-SLNs were developed by employing the emulsification–
ultrasonication technique. The designed experiment was used to optimize the formulation,
and the impacts of concentration of chosen factors, i.e., lipid, surfactant, and sonication
time, were studied on particle size, surface charge, and drug encapsulation as responses.
The optimized formulation was investigated in vitro for drug release, corneal permeation,
and antifungal efficacy, as well as cytotoxicity studies. The outcomes of the optimized
preparation reported a mean size of 42 nm and a surface charge of 26 mV, and drug entrapment was ~85%. NAT-SLNs expressed sustained drug release upto 10 h. In addition,
NAT-SLNs improved corneal permeation, with a steady-state flux of 11.59 × 10−2 cm h−1
and permeability coefficient of 3.94 mol h−1 , compared with plain drug, with a flux and
permeability coefficient of 7.28 × 10−2 cm h−1 and 2.48 mol h−1 , respectively. The antifungal activity revealed the enhanced zone of inhibition, 8 mm and 6 mm against Aspergillus
fumigatus (ATCC 1022) and a clinical isolate of Candida albicans, respectively. The minimum inhibitory concentration (MIC) value was reduced to 2.5 times against each strain of
fungus. Furthermore, the developed NAT-SLN formulation was nonirritant to the corneal
tissue. The formulation NAT-SLNs resulted in extended drug release, enhanced corneal
permeation, higher antifungal efficacy, and no toxic effects on the corneal tissues. Therefore, NAT-SLNs are among the anticipated ocular therapeutic systems for the treatment of
corneal keratitis [51].
SLNPs have been widely explored as ocular nanocarrier systems to enhance drug
absorption and improve the ocular bioavailability of both hydrophilic and lipophilic drugs.
One study investigated the future of clarithromycin encapsulated SLNs in improving
the permeation and penetration of drugs in topical ocular therapy. The formulation was
developed using high-speed magnetic stirring, followed by the sonication technique. Solubility of the drug with different formulating components—namely, lipid former, surfactant
(Tween 80), cosurfactant as transcutol P, and stearic acid was studied. The formulation
of clarithromycin SLNs was optimized by statistical design and investigated in vitro for
particle size, morphology, stability, ocular permeation, irritation, and pharmacokinetics
studies. The drug from SLNs indicated ~80% release in 8 h and was complied with the
Weibull kinetic release model. The optimized SLNs revealed a higher drug permeation of
30.45 µg/cm2 /h, compared with the drug solution. The in vivo studies demonstrated that
SLNs had 150% higher Cmax (~1066 ng/mL) and a 2.8-fold enhanced AUC (5736 ng h/mL),
compared with the drug solution (Cmax ; 655 ng/mL and AUC; 2067 ng h/mL). The result obtained concluded that SLNs serve as potential drug delivery carriers for enriching drug concentration in topical ocular delivery and could be efficacious in treating
endophthalmitis [111].
Despite the application of statins in cardiovascular disease, it is largely explored in the
management of age-related macular degeneration. To improve poor aqueous absorption
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in the ocular region, Yadav et al., investigated atorvastatin (ATS)-loaded SLNs as eye
drops for self-use. They developed ATS-SLNs by hot, high-pressure homogenization and
characterized in vitro in the ocular application. Their findings revealed that ATS-SLNs
were 12-times more bioavailable in the ocular tissues than the conventional eye drop. The
stability of the formulation was established as 13.62-times higher, including photostability.
The fluorescein-labeled SLNs (F-SLNs) confirmed effective uptake of F-SLNs and prolonged
ocular residence upto 7 h [52].
6. Inorganic NPs
6.1. Mesoporous Silica NP
The silica particle is a highly porous structure that is widely used as a drug delivery
carrier in various routes; nevertheless, ocular delivery of silica NP is limited, owing to the
toxicity of degraded product of silica as silicic acid, which causes an inflammatory reaction
when implanted in the conjunctiva, although silicic acid is naturally present in the human
body. To investigate the toxicity, safety, and biocompatibility of silica particles, Paiva et al.,
developed tacrolimus (TAC)-loaded mesoporous silica NPs functionalized with aminopropyltriethoxysilane (MSNAPTES). They evaluated the cell viability of MSNAPTES and
TAC-loaded MSNAPTES (MSNAPTES-TAC) in the ARPE-19, and further, a chorioallantoic
membrane (CAM) assay model was employed to show the biocompatibility and safety after
intravitreal injection in vivo. Moreover, it was clinically examined based on measurement
of intraocular pressure, ERG, and histopathological studies in rats’ eyes [53].
The in vitro characterization investigated that the NPs were tagged with functional
moiety. The drug-free MSNAPTES and MSNAPTES TAC NPs reported a lack of in vitro
cytotoxicity. After the application of NP, no sign ofretinal abnormalities, vitreous hemorrhage in the eye, neovascularization, and retinal detachment were observed during
in vivo study. However, follow-up studies on ERGs indicated no changes in the retina cell
function after 15 days of intravitreal injection, which were also proved by histopathologic
examination, further supporting the biocompatibility, safety, and efficacy of the developed
nanocarrier system in ocular therapy. Thus, the findings affirmed the considerable potential
of MSNAPTES TAC to transport therapeutics in the ocular delivery for the treatment of eye
diseases [53].
Furthermore, another author pointed to safety concerns of intravitreal injection of
mesoporous silica NPs in guinea pigs’ and rabbits’ eyes. They establish in vitro cytotoxicity
using silicic acid from sol–gel particles on EA.hy926 cells and found dose-dependent
cytotoxic effects. They prepared various sizes of silica NPs, out of which 15 µm silica
particles with 10 nm pore size were found to be safe in animals’ eyes and were retained
there for >2 months. The other preparation of larger pores established a localized, depot
formation of sol–gel particles with a variable glassy overcast around them in the aqueous
humor, with few inflammatory cells. The inflammatory responses trends were higher with
greater pore size particles. The developed sol–gel mesoporous silica particles acquired
consistent particle sizes and distinct pores, beneficial for implantation through a fine needle.
The optimum formulations could be exploited as nanocarriers in intraocular therapeutic
systems, ensuring appropriate drug loading and encapsulation [112].
6.2. Gold NPs
Gold NPs typically comprise an inert core of gold and an outer active layer. The
particle size distribution is narrow, varying from 1nm to 150 nm. The outer layer of gold
NPs could be tuned for the desired ligation with proteins and peptide molecules for sitespecific receptor-based targeting of therapeutics, whereas the inner layer of gold particles
can safely encapsulate drug molecules [113]. It has been shown that i.v. instillation of gold
NPs of appropriate size can cross the blood–retinal barriers and be uniformly distributed
end-to-end retinal layers without toxic effect to the cells.
In view of this, Kim et al., demonstrated that i.v. administration of 20 nm size of
gold NPs into C57Bl/6 mice enabled passing the blood–retinal barrier, which was well
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detected around the retinal layers. It was importantly noted that NPs accumulation at the
site of retinal cells did not cause any defect in the cell or cell death, compared with the cells
lacking NPs. The results indicated that small-sized gold NPs (20 nm) could possibly be
employed in the ocular drug delivery and can efficiently penetrate blood–retinal barriers
in the ocular disease [54]. Gold NPs as theranostic applications are well discussed in the
literature, especially in different cancers in the human body. Mitra et al., designed gold
NPs (AuNPs) covered with polyethyleneimine (PEI) and thereby ligated with epithelial
cell adhesion molecule (EpCAM) antibody and siRNA molecules. They stated that the
gene delivery system was prominently internalized by retinal cells, probably due to the
overexpressed receptor cells ensuring significant cytotoxicity to cancer cells. Regardless
of significant efforts made on the intraocular cancer therapy, the study relied on in vitro
characterization constraints, as well as on mature intraocular cancer animal models [55].
Qiong et al., incorporated bimatoprost-loaded gold NPs, and their uptakeinto contact lens
from a soaking solution was investigated; the authors showed improved release kinetics
both in vitro and in vivo due to high uptake from soaking solution without causing any
alteration in the contact lens, indicating therapeutic efficacy in ocular diseases [114].
7. Contact Lenses
To increase the drug contact time in the ocular tissue, ocular lenses are designed with
polymeric materials that encapsulate the drug molecules to prolong the therapeutic effect
in the local ocular tissues. Contact lenses are thin, curved-like polymeric disks, which
are designed in such a way that can comfortably fit into the cornea. Upon insertion into
the cornea, the contact lens clings to the cornea due to physical adherence or surface
tension. Contact-lens-incorporating drugs have been explicated in the ocular delivery of
antihypertensive drugs, antimicrobials, and antihistamines. The contact lens improved
the drug residence time in the ocular tissue and tear film, which successively increased
drug absorption in the cornea and minimized drug loss via nasolacrimal duct. Usually, the
drug is loaded into contact lenses by soaking them in drug solutions. These soaked contact
lenses demonstrated higher efficiency in delivering drugs, compared with conventional
eye drops [115].
To overcome the challenges of drug loss from precorneal surface especially in the
treatment of corneal conjunctivitis and keratitis, moxifloxacin (MF) with Dex was designed
in a drug-eluting polymeric contact lens for effective drug delivery. The contact lens
comprised polymer chitosan, polyethylene glycol, and glycerol. The polymer contact lens
was prepared in a combination drug as well as separately. The dual drug-loaded contact
lenses were characterized in vitro for surface characteristics, swelling index, thickness, and
mucoadhesive property. Furthermore, in vitro release was conducted to investigate release
profile behavior, corneal permeation ex vivo, and antimicrobial activity both in vivo and
in vitro. The contact-lens-loaded therapeutics was compared with pure drug solutions
and commercially available products. The results indicate that drug-loaded contact lenses
exhibited higher corneal drug distribution 24 h post incubation, compared with pure drug
solutions. Further, in vitro and in vivo investigations showed drug-loaded contact lenses
were superior to pure drug solutions. The drug biodistribution indicated adequate drug
concentrations in the cornea, aqueous humor, and the sclera using contact lenses, compared
with drug solutions. These findings showed that the drug-eluting polymeric contact lens
was effective in delivering both the drug MF and DM in the precorneal area and could
achieve therapeutic concentrations, suggesting their preferred applications in post ocular
operations and eye infections [56].
Kim and Chauhan observed that contact lenses made up of poly (hydroxyethyl
methacrylate) exhibited higher Dex absorption, compared with eye drops. However,
the developed contact lens had limitations such as poor drug loading and burst release. To
further improve the drug release characteristics, particle-laden contact lenses with molecular imprints have been explicated. Particle-laden contact lenses are prepared by dispersing
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the drug entrapped vesicles—namely, liposomes, NPs, or ME, as well as the material base
of the contact lens [57].
In a subsequent attempt, Gulsen et al., designed particle-laden contact lenses for
lidocaine delivery in the ocular tissue. They developed lidocaine-loaded ME drops and
liposome in a different study and dispersed them in particle-laden contact lenses, which
comprised poly-2-hydroxyethyl methacrylate (p-HEMA) gels. Their findings conveyed
that lidocaine showed sustained release for upto a period of 8 days. Thus, particle-laden
contact lenses are expected to deliver therapeutics for an extended period in the ocular
region [58].
8. Implants
Ocular implants are fabricated to provide localized controlled release of therapeutics
for a prolonged period. The problem arises due to frequent intraocular injection, and related
complications can be generally replaced with using intraocular implants. This device is
placed intravitreally with a minor incision at pars plana situated between lens and retina.
The intraocular implants receive overwhelming interest due to sustained and localized drug
release in the ocular disease tissues to attain therapeutic levels, reduce unwanted effects,
and also overcome the blood–retina barrier [59]. Many devices to implant in the ocular
cavity have been designed and formulated as ocular therapeutic systems for vitreoretinal
chronic therapy.
Sheshala et al. developed an investigational implant of biodegradable poly-lactic-coglycolic acid (PLGA)-injectable, phase inversion, in situ forming system for controlled drug
delivery of TA. The implant developed with variable concentrations of TA that ranged from
0.5% to 2.5% w/w was dissolved in a solvent and subsequently incorporated into 30% w/w of
polymer, PLGA (50/50 and 75/25); the resulting solution formed a homogenous injectable
preparation. The formulation was evaluated in vitro for the measurement of various
parameters. The formulation showed a viscosity of 0.19–3.06 Pa.s, good syringeability,
and shear thinning behavior. The microscopic examination indicated that the thickness of
the implant depended on time and rate of implant formation, further demonstrating the
fast phase inversion. The implant showed 42 days of sustained drug release in the ocular
environment. These findings concluded that the PLGA/solvent-based, phase inversion,
in situ forming implants can ameliorate the therapeutic treatment outcome in the ocular
disease by sustaining the drug release for an extended period of time, thus reducing the
dosing frequency of injections [61].
Both biodegradable and nonbiodegradable ocular implants are available as drugreleasing devices. Biodegradable implants are developed using FDA-approved polymers, e.g., polylactic acid (PLA), polycaprolactones (PCLs), PLGA, and polyglycolic acid
(PGA) [116]. The polymers used in designing the nonbiodegradable implants are silicone
composite, polyvinyl alcohol (PVA), and ethylene-vinyl acetate (EVA). Compared with
bio-degradable implants, nonbiodegradable implants lengthen drug release via zero-order
release kinetics.
Nonbiodegradable Implants
Vitrasert® (Bausch and Lomb Inc., Rochester, NY, USA) is FDA-approved ganciclovir
containing Vitrasert® for intraocular implants, with controlled release characteristics used in
cytomegalovirus retinitis therapy. The implant is composed of 4.5 mg tablet of ganciclovir
encircled by PVA/EVA, which releases drugs for an extended period of 7 months, is
available at low cost, and without systemic toxicity.
Retisert® (Bausch and Lomb Inc., Rochester, NY, USA) is an FDA-approved nonbiodegradable implant applied for chronic uveitis therapy and also affects the posterior
segment of the eye, bearing silicone-laminated PVA. Fluocinolone acetonide was released
from Retisert® in a sustained manner for up to 3 years. The implant had a better effect in
reducing the inflammation, preventing recurrences of uveitis, and improvingvisual acuity
as well [59,60].
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In contrast, another class of implants is largely explored due to the implants’ biodegradable and biocompatible features, apart from showing sustained drug release characteristics.
The biodegradable nature of the implant required no surgery for removal, which preferably
degrades in the biological milieu, compared with nonbiodegradable implants. PGAs, PLAs,
PLGAs, and polycaprolactones are commonly employed polymers for the fabrication of
such implants.
For instance, Surodex™ and Ozurdex® are biodegradable implants designed for intraocular Dex-sustained delivery in the ocular inflammation and macular edema (ME) of
the eye. Surodex™ (Allergan, Inc., Irvine, CA, USA) has active ingredients including Dex
in PLGA and hydroxypropyl methylcellulose. In postcataract-surgery-linked inflammation, the implant is inserted in the anterior chamber of the eye to control the release of
medicaments for a week and to curb inflammation and related problems [59].
Ozurdex® (Allergan Inc., Irvine, CA, USA) was approved by the FDA in June 2009 as
another biodegradable intravitreal implant for the treatment of ME. It is based on Allergan’s
NOVADUR® technology used in the ocular delivery of Dex. The NOVADUR® system
comprises a polymeric PLGA matrix that tardily degrades into lactic acid and glycolic acid
and accommodates Dex release for upto 6 months. The clinical trials investigated their
efficacy in reversing vision loss in patients and observed improvedsharp vision in eyes
associated with ME, i.e., vein occlusion in the retina [59].
The role of small molecules in ocular therapy is apprehended due to the advantages
of specificity, transportability, scalability, and efficacy. Ocular drug implants (ODIs) wererecently demonstrated by Sun et al., for the sustained effect of medicine in the ocular cavity.
The methodology was based on intravitreal injection of the implant into the small eyes of
genetically modified mice. They used biodegradable PLGA as polymer and small molecule
cyanine 5.5 as an active entity, in the weight ratio of 95 to 5, and formed Cy5.5-PLGA that
showed sustained drug release. Further, the authors investigated the efficacy and ocular
bioavailability of ODIs and thereby developed a robust, economic, and minimally invasive
technique known as “mouse implant intravitreal injection” (MI3) into the mouse eyes. This
procedure could be clinically translated into the treatment of human eye diseases [117].
9. Recent Advancements in Ocular Delivery
9.1. Nanofiber Inserts
The large surface-area-to-volume ratio is an important feature that draws attention to
nanofiber-based ocular drug delivery. The nanocarrier system can be effectively administered into the conjunctival sac and contacts well with the ocular segment. Nanofibers
could overcome the limitation of eye drops with respect to cul-de-sac volume (∼30 µL).
Many researchers designed multilayered nanofibers inserted with an intermittent layer of
therapeutics using various polymers including Eudragit RL 100 [118].
Mirzaeeiet al., prepared a nanofiber insert with a modified electrospinning technique,
to improve ocular residence time and prolong drug delivery of ofloxacin (OFX) from the
nanofiber insert. The chitosan/polyvinyl alcohol (CS/PVA) nanofiber layered in Eudragit
RL100 was fabricated by crosslinking technique intended for conjunctivitis. Firstly, the
electron microscopy showed that the average fiber diameter of 123 ± 23 nm for a single electrospun nanofiber lacked crosslinking. Secondly, a crosslinked single electrospun nanofiber
hadan average diameter of 159 ± 30 nm. Antimicrobial efficacy in bothsingle-spun and
multispun nanofibers demonstrated a potential zone of inhibition against S. aureus and
E. coli. The ofloxacin release from nanofiber inserts on the rabbit eye affirmed a sustained
release behavior for up to 96 h. It is further found that the crosslinked nanofibers could
reduce the burst release of drugs in single- and multi-layered nanofibers. The animal study
exhibited that the nanofibers showed a 9–20-fold increase in bioavailability, compared with
drug solutions. Thus, the demonstrated potentiality of the electrospun nanofiber approach
to prolong the drug release in ocular segments was evidently promising [62].
Electrospinning is a diversified technique mainly formed by electrostatic repulsion
charge surface, which draws nanofiber from a viscoelastic liquid.It is composed of poly-
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mers, ceramic nanomaterials, and nanosized molecules in this combination. This technique
successfully developed nanofibers in vitro. The nanofiber produced by the electrospinning
technique is characterized by a solid smooth surface with a number of branches as secondary structures. It has a hollow- or core-sheath-like structure with numerous pores. The
existing large surface area on both the outer surface and anterior part can be modified by
a number of molecular species, proteins, ligands, or NPs during the processing of such
technique [63].
Researchers’ interest in the use of electrospun nanofibers in ocular therapeutic platforms is tremendously increasing, as the system may accommodate the eye surface and
provide controlled drug release. Exploring this technique, Gimaudo et al., designed a novel
ocular insert consisting of hyaluronan (HA) nanofibers in a combined delivery of ferulic
acid (FA), an antioxidant, and an antimicrobial peptide (ε-polylysine, ε-PL). The designed
fibers were obtained with diameters of ~100 nm, containing PVP 5%, HA 0.8% w/v, PVP
10%, and HA 0.5% w/v in an organic and aqueous mixture. The increase in PVP concentration led to an increased thickness of ~1 µm. Nanofibers crosslinking with ε-PL, blank,
and FA-loaded inserts demonstrated average thicknesses of 270 ± 21 µm and 273 ± 41 µm,
respectively. The insert enabled the complete release of ε-PL, both from blank and drugencapsulated inserts, within half an hour under dissolution medium. The FA-loaded inserts
showed considerable antimicrobial efficacy against P. aeruginosa and S. aureus [119].
Khalil et al. developed an alternative to conventional eye drop for the first time.
They designed a single-dose mucoadhesive biodegradable polymeric-multilayered NPsin-nanofibers (NPs-in-NFs) matrix as an ocular insert of azithromycin. The ocularinsert
was prepared with electrospinning technique using polyvinylpyrrolidone and investigated
their efficacy in vitro against bacterial infection in the eye. The drug release and permeation
profile established that ocular insert could render controlled drug release upto 10 days. The
authors concluded that the incorporation of NPs into NFs could achieve many advantages
such as increased ocular residence due to better contact with conjunctiva, accurate dosage,
prolonged drug release, reduced dosing frequency, reduced systemic side effects, and
improved bioavailability [64].
Taghe et al., developed azithromycin Eudragit® L100 NPs for sustained drug release
and improved ocular performance. The NPs were prepared by solvent diffusion method
with sonication technique. The drug-loaded Eudragit® L100 NPs were plasticized using
polyvinyl alcohol (PVA) solutions and investigated in vitro. Moreover, azithromycin ocular
insert (film) was developed using a solvent casting method by applying a solution of
cellulose derivates hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose
(HEC). The final preparation of NPs had entrapment of 62.167 ± 0.07%, a particle size
of 78.06 ± 2.3 nm, a surface charge of −2.45 ± 0.69 mV, and a polydispersity index of
0.179 ± 0.007. The developed inserts expressed antimicrobial effects on S. aureus and E. coli
cultures. The release profile of the drug was initially immediate, followed by sustained
release, and thus significantly prolonged the release of drug from inserts, compared with
the drug solution. This trans-corneal ex vivo study demonstrated higher corneal drug
permeation, compared with the drug solution. Therefore, the ocular insert offered a
promising method for the delivery of azithromycin in the ocular chamber as treatment of
eye inflammation and infections [65].
9.2. Microneedles (MNs)
MNs offer a minimally invasive drug delivery approach in localized targeting to the
posterior ocular tissue, with high precision and accuracy, compared with hypodermic
needles. The MN-based drug administration may repress complications that arise in
intravitreal injections, which may lead to retinal breakups, hemorrhage, cataracts, eye
inflammation, and infection. This technique has the potential to improve vision jeopardized
by posterior ocular diseases linked to age-related macular degeneration, posterior uveitis,
and diabetic retinopathy [66]. The strategic drug delivery approach using MNs may
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overcome the blood–retinal barrier and prominently deliver therapeutics inside the retina
or choroid.
MNs have traditional designs and are capable of penetrating the limited depth of the
sclera, thereby preventing major damage to the deep ocular tissues. Using this needle, it is
easy to deposit therapeutics or drug delivery systems into the sclera or in between sclera
and choroid spaces, the so-called suprachoroidal space. Micropuncturing the sclera layer
may facilitate higher deposition of drug molecules or drug carriers in the sclera, and more
drug diffusion into the deeper ocular tissues may result [120]. Jiang et al. investigated the
surface-coated MNs with drugs in cadaver eyes to study the sclera surface penetration by
MNs, sulforhodamine dissolution, and release behavior from MNs into the intrascleral
region. The results showed that the surface layered drug instantaneously dissolves in the
sclera tissue, intimating high sulforhodamine deposition in the sclera via MNs hole [67].
In another attempt, Jiang et al., prepared and evaluated MNs’ performance as complements to drug solution infusion from nanocarriers into the sclera tissues. Using MNs,
the authors enabled the infusion of ~10–35 µL fluid directly into the sclera tissues. They
further investigated MNs for delivery of nanosuspensions and microparticles in the sclera
layer. The outcome of their study revealed that the vacuous MNs loaded with micro/NPs
are better routes for drug delivery into the sclera with minimal invasiveness [68].
In 2016, Thakur et al., studied the dissolving nature of MNs for increasing the bioavailability of the macromolecules in the ocular tissue. The fabricated MNs comprised polymers and PVPs of different molecular weights (MWs), with three molecules of high MW
fluorescein sodium and fluorescein isothiocyanate–dextrans (MW ranges between 70 k
and 150 k Da). The dimension of MNs was a height of 800 µm and a base diameter of
300 µm, with model drugs, which were prepared and characterized in vitro in terms of
braking forces, insertion forces (in the sclera and the cornea region), penetration depth
using OCT and confocal imaging, drug release time, and permeation studies. The results
showed that the high-MW PVP-fabricated MNs could withstand greater forces with a petty
reduction in needle height. Polymer MNs showed fast dissolution within 180 s depending upon PVP’s MW. In vitro studies demonstrated high permeation of macromolecule
across the scleral and corneal tissues, compared with aqueous solutions. Interestingly,
macromolecules formed depots inside the ocular tissue, as indicated by confocal images,
and helped in sustained permeation. Biomaterials used in the fabrication of MNs were
biocompatible and had the potential for drug retention in specific ocular tissues. The collective outcomes showed that the designed MNs are minimally invasive, rapidly dissolving
devices that have high insertion forces to deliver macromolecules through the transscleral
route in eye diseases [121].
Considering the critical challenges imposed by the ocular barrier in overcoming
ocular diseases and injuries in eyes resulting in significant clinical impairment, Thanet al.
strategically developed an eye patch furnished with a layout of detachable microneedles.
The developed microneedles could enable deeper penetration into the ocular surface tissue
and had a controlled drug release from these microimplanted reservoirs. The biphasic
drug release pattern from multilayer microreservoirs enhanced therapeutic efficacy. The
corneal neovascularization model associated with eye disease indicated antiangiogenic
characteristics of the monoclonal antibody (DC101) microneedle, which can reduce ~90%
of the neovascular region. Moreover, the onset of diclofenac, an anti-inflammatory agent
followed by a sustained release of DC101, provided synergistic therapeutic efficacy. The
application of microneedle as an eye patch is minimally or noninvasive, easy to administer,
and ensures patient compliance. Thus, the intraocular therapeutic delivery approach could
be promisingly efficacious against several eye diseases [69]. A brief summary of recent
patents on ocular disease therapy is included in Table 2.
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Table 2. Recent patents on ocular disease therapeutics.
Patent Application
US Patent No. 11,000,509
US Patent No. 10,993,932
US7795203B2
KR20200000395A
Title and Year
Description
Clinical Use
References
Methods and compositions for daily
ophthalmic administration of
phentolamine to improve visual
performance (2021)
The invention providedthe composition, methods, and
phentolamine in kits for ameliorating visual operation such
as visual acuity by the routine administration of ophthalmic
phentolamine solution in the patient eye at bedtime for
broad time, which minimizes the appearance of redness in
the eye during daytime or waking time. The composition of
invention benefitted the patients enduring poor visual
performance both during the day and night time.
Visual impairment
[122]
Methods and compositions for
treatment of presbyopia, mydriasis,
and other ocular disorders (2021)
The invention relates to the composition and method for the
preparation, and kits of phentolamine, an alpha-adrenergic
antagonist intended for monotherapy or used as a
combination therapy in the treatment of patients having
presbyopia, mydriasis, and/or other ocular complications.
The phentolamine, instilled topically, preferably is supplied
as aqueous ophthalmic preparation.
Presbyopia, mydriasis,
and other ocular problem
[123]
Method for topical treatment of eye
disease, composition, and device for
said treatment (2010)
The invention pertaining to aqueous ophthalmic
preparation comprised of a N-acetylcarnosine derivative or
a pharmacologically acceptable salt of N-acetylcarnosine
with cellulose imparting intraocular absorption of the said
compound. The patent further disclosed a hydrogel contact
lens, an ocular insert made of polymer for topical instillation
containing N-acetylcarnosine
and N-acetylcarnosine derivatives.
Eye diseases (corneal problems,
glaucoma, presbyopia,
and blurred vision)
[124]
Eye composition containing
cyclosporine and a method of
preparing the same (2020)
The current invention disclosed a composition of an
ophthalmic nanoemulsion that contained cyclosporine, in a
highly solubilized state as an active ingredient, and their
stability improved by incorporating drug in a nonaqueous
vehicle, an emulsifier, and an aqueous vehicle. The
nanoemulsion established desired particle size of 100 nm
and narrow particle distribution.
Dry eye syndrome, Conjunctivitis,
and tingling sensation in the eye
[125]
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Table 2. Cont.
Patent Application
Title and Year
Description
Clinical Use
References
Ophthalmic nanoemulsion
composition containing cyclosporin
for the treatment of
dryeyesyndrome (2011)
An ophthalmic composition having cyclosporine
(0.01–0.1%), propylene glycol monocarprylate (0.1–2.5%).
poloxamer (0.5–15%) glycerine, (0.1–10%), chitosan or
carbomer (0.1–5%) and purified water (67.4–98.5%). The
method for preparing the composition Follows dissolving
the drug in a propylene glycol monocarprylate gradeI
solution, thereafter dissolving poloxamer, glycerin, and
chitosan or carbomer in purified water to obtain a grade II
solution, and finally mixing the I and II step solution while
adjusting pH by 7.2–7.6.
Dryeyesyndrome
[126]
KR20200053205A
A surfactant-free type ophthalmic
nanoemulsion composition and the
manufacturing method thereof
This invention provides a composition of eye drop
nanoemulsion and their manufacturing aspects thereof. The
composition hascyclosporine, a solubilizing agent, a
stabilizer, and a solvent. The solubilizing agent established a
nanoemulsion with a droplet size of 20 nm or less. The
invention of nanoemulsion eye drop improves stability
and patient compliance.
Dry eye syndrome
[127]
US6956057B2
EP4 agonists as agents for lowering
intraocular pressure (2005)
The invention relates to an active compound, EP4 agonist
meant for the treatment of ocular hypertension or glaucoma.
The efficacy of the invention was proved by administering in
animal models possessing ocular hypertension or glaucoma.
Ocular hypertension or glaucoma
[128]
Topical aqueous nanomicellar,
ophthalmic solutions and uses
thereof (2015)
The invention disclosed herein a method and composition of
formulations for topical instillation. The composition of the
formulation may include a polyoxyl lipid (fatty acid) and/or
a polyalkoxylated alcohol and nanomicelles. In a further
embodiment, methods herein describe the treatment
procedures for preventing ocular diseases.
Ocular diseases
[129]
Liposome eye drops (1999)
The present invention of liposomal eye drops having
taurine, glucose, and inorganic salts, with adjusted pH
ranging 5.5–8.0. The osmotic pressure of formulation is
maintained in between 250 and 450 mOsm. Further, the
taurine and inorganic salts are entrapped in lipid vesicles
viz., the liposomes.
Mitigation of dry eye problem
[130]
KR101008189B1
US8980839B2
US5945121A
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Table 2. Cont.
Patent Application
Title and Year
Description
Clinical Use
References
WO2017152129A2
Treatment of glaucoma and/or
retinal diseases (2017)
The invention provided herein is an ophthalmic
formulationand methods of its use. The embodiments of the
formulations may include a polyoxyl lipid or fatty acid,
and/or a polyalkoxylated alcohol in nanomicelles. It also
includes the method of treating or preventing ocular
diseases or conditions.
Glaucoma and retinal diseases
[131]
WO2018095429A1
Use of gold cluster or
gold-cluster-containing substance in
preparation of drugs for preventing
and/or treating glaucoma (2018)
The disclosed invention relates to the application of
gold-cluster-bearing substances in the drug composition for
the treatment and mitigation of glaucoma.
Glaucoma
[132]
Nanocrystalline eye drop,
preparation method, and
application thereof (2020)
The invention provides preparation of nanocrystalline eye
drop and their application. The composition of eye drop is
single soluble (chitosan or hyaluronic acid) and double
(poloxamer and tween) soluble macromolecule, and a drug
targeting on endothelial growth factor receptor or a platelet
growth factor receptor. The interaction among double and
single soluble macromolecule encloses the target drug as
nanocrystal and preserves the nanocrystal stability. The
medicament enabled the penetration of various barriers in
the eye and entered the vitreous humor by permeation or
passive targeting via intercellular space/pinocytosis and
could achieve effective drug concentration
in the cul-de-sac cavity.
Congenital macular degeneration
[133]
Bifunctional copolymer use for
ophthalmic and other topical and
local applications (2016)
This invention studied a water-soluble graft copolymer
poly(L-Lysine)-graft-poly(ethylene glycol) with good surface
featuresin terms of biological surfaces. The composition was
further sterically stabilized with PEG coatings and made
compatible with biological surfaces. The composition is
useful in dry eye syndrome and contact lens
intolerance therapy.
Dry eye syndrome
[134]
CN110664757A
US9295693B2
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Table 2. Cont.
Patent Application
Title and Year
Description
Clinical Use
References
US20200237925A1
Polypeptide eye absorption
enhancer and use thereof
This pharmaceutical preparation relates to synthetic cell
penetration, i.e., peptides. The peptide has the potential
ability to permeate the ocular tissues, with no ocular toxicity
reported. The peptides actas absorption enhancers and are
delivered through a noninvasive route for intraocular
delivery and thus improve ocular drug bioavailability. The
invention is a promised alternative to intraocular injection
and patient compliance for
the treatment of intraocular diseases.
Intraocular and fundus diseases.
[135]
CN109906075A
Liposome corticosteroid for the
locally injecting in inflammation
lesion or region (2019)
Thisinvention relates to corticosteroid liposome for local use
and inflammatory region on ocular tissues. The composition
of liposomes having uncharged lipid or Pegylated liposome
for the treatment of inflammation lesion with the one-time
applicationin two weeks.
Inflammatory lesion in eye
[136]
Olopatadine formulations for
topical administration
Topical formulations of olopatadine for the treatment of
allergic or inflammatory disorders of the eye and nose are
disclosed. The aqueous formulations contain approximately
0.17–0.62% (w/v) of olopatadine and an amount of
polyvinylpyrrolidone or polystyrene sulfonic acid sufficient
to enhance the physical stability of the formulations.
Inflammatory eye disorder
[137]
US6995186B2
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10. Recent Patents on Ocular Disease Therapy
US Patent No. 11,000,509 disclosed the composition and methods of formulation of
phentolamine in kits for ameliorating visual operation. The routine instillation of ophthalmic phentolamine solution improvedvisual acuity and minimized the appearance of
redness in the eye. The composition of invention benefitted the patients enduring miserable
visual performance both during the day and night time [122]. Another patent by the same
inventor disclosed the composition and method for the preparation and kits of phentolamine, an alpha-adrenergic antagonist intended for monotherapy or used as a combination
therapy in the treatment of presbyopia, mydriasis, and/or other ocular complications [123].
A similar patent on an aqueous ophthalmic solution of phentolamine was mentioned in
application number 11090261, credited to Ocuphire Pharma, Inc. The inventor of the patent,
Alan Meyer, disclosed the ophthalmic solutions of phentolaminemesylate in combination
with pharmaceutically acceptable additives such asmannitol, sodium acetate, and water as
a medical kit for improving visual performance [138].
Babizhayevet al. invented a patent to treat eye diseases with an aqueous ophthalmic
preparation of N-acetylcarnosine, a N-acetylcarnosine derivative or a pharmacologically
acceptable salt of N-acetylcarnosine, with cellulose imparting the intraocular absorption of
the said compound. The therapeutics were incorporated into a polymeric hydrogel contact
lens, and ocular insert for topical instillation, for effective therapy of corneal problems
associated with glaucoma and blurred vision [124]. Application KR20200000395A disclosed
the composition of a nanoemulsion comprising an active ingredient cyclosporine in a highly
dissolve state and an emulsifier in an aqueous vehicle. The nanoemulsion established
desired particle size of 100 nm and narrow particle distribution. The preparation showed
efficacy against ocular problems such asdry eye syndrome, conjunctivitis, and tingling
sensation [125].
Moreover, a patent disclosed a composition of ophthalmic nanoemulsion having cyclosporine (0.01–0.1%), propylene glycol monocarprylate (0.1–2.5%), poloxamer (0.5–15%)
glycerine, (0.1–10%), and chitosan or carbomer (0.1–5%). The preparation technique involves drug dissolution in propylene glycol monocarprylate leveled as a solution I, followed
by dissolving the poloxamer, glycerin, and chitosan or carbomer in purified water to obtain
solution II, and ultimately, mixed both solutions I and II whileadjusting pH by 7.2–7.6. This
invention was used for dry eye syndrome [126].
A patent disclosed a composition of eye drops of a nanoemulsion and their manufacturing aspects. The composition consists of cyclosporine, a solubilizing agent, a stabilizer,
and a solvent. The droplet size of the nanoemulsion was established at 20 nm or less.
The nanoemulsion eye drop improves stability and patient compliance, used in dry eye
syndrome [127]. Novel active compound EP4 agonists havebeen successfully invented
for lowering intraocular pressure, glaucoma, and ocular hypertension, and their efficacy
clearly proved in animal models is mentioned in [128].
Further, a nanomicelles preparation credited to Mitra and Weiss consisting of polyoxyl lipid (fatty acid) and/or a polyalkoxylated alcohol has been disclosed in the patent
US8980839B2 [129]. Similarly, a liposomal preparation of eye drops was invented by
Kato et al. for the treatment of dry eye syndrome [130]. An invention provided herein is an
ophthalmic formulation having a polyoxyl lipid or fatty acid, and/or a polyalkoxylated alcohol in nanomicelles. It also includes the method of treating or preventing ocular diseases
or conditions. The preparation is used in glaucoma and retinal diseases [131].
The use of gold cluster or gold-cluster-containing substance in the preparation of drugs
for preventing and/or treating glaucoma has been disclosed in WO2018095429A1 [132]. A
chitosan- or hyaluronic-acid-based nanocrystalline eye drop and its application in congenital macular degeneration has been revealed in a patent CN110664757A. The developed
formulation may work based on the designed targeting approach to endothelial growth
factor or a platelet growth factor receptor. The medicament could manage the penetration of
the ocular barriers through passive targeting or intercellular pinocytosis approach, thereby
providing effective drug concentration in the cul-de-sac cavity [133].
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US patent US9295693B2 disclosed a composition of water-soluble graft copolymer
poly(L-Lysine)-graft-poly(ethylene glycol) coated with sterically stabilized PEG coatings,
which is good for binding with biological surfaces. The composition is used in dry eye
syndrome and contact lens intolerance therapy [134]. A pharmaceutical composition of
cell-penetrating peptides has potential permeation ability in the ocular tissues without observing any toxicity. The peptide is a good absorption enhancer and is givennoninvasively
in the ocular chamber, therefore improving the ocular bioavailability. Furthermore, the invention is suggested as an alternative to ocular injection and improved patient compliance
in intraocular diseases treatment [135].
A liposomal preparation of corticosteroid is given locally in the inflammatory lesion in
the ocular tissue. Further, the composition of liposome with uncharged lipid or Pegylated
liposome is used for the treatment of inflammation lesion with the application of once in two
weeks [136]. The topical formulations of olopatadine for allergic or inflammatory disorders
of the eye and nose are disclosed in another patent. The composition of formulation
has olopatadine (0.17–0.62% w/v) with a sufficient quantity of polyvinylpyrrolidone or
polystyrene sulfonic acid as a stabilizer [137].
11. Conclusions and Future Prospects
Drug delivery challenges due to the various ocular barriers confoundpotential setbacks
for scientists working on targeted drug delivery in the ocular tissues. Nevertheless, considerable efforts have been made so far, and the trends still continue in seeking ocular drug
delivery, seeking efficacious, safe, and biocompatible therapeutic drug delivery approaches.
At present, researchers working in this domain strive to enhance the performance of the
conventional formulation in vivo. Many drug delivery carrier systems with nanotechnology applications are being designed and formulated at a large scale, including polymer
NPs, solid lipid NP, lipidic vesicles, micelles, micro- and nanoemulsions, nanosuspensions,
microneedles, and dendrimers. For instance, several ocular drug delivery studies are only
limited to in vitro performances, and explorations of in vivo studies using ocular models
of cell lines may further facilitate the development of precise data at the preclinical and
clinical stages.
Nanotechnology-based drug delivery systems so far have been useful in reducing
toxicities, multiple dosing, dose-related undesired effects, and fluctuations in drug plasma
concentration, associated with a traditional drug delivery system. However, research
on ocular therapeutic systems still suffers from a large gap, and the design process of
a novel carrier that could be nontoxic, biodegradable, biocompatible, and efficacious in
mitigating both the posterior and anterior segments of the eye disease is underway. The
current attempts and prospects made by scientists regarding ocular therapeutic systems
may translate nanomedicine into clinics with promising precorneal residence time and high
drug accumulation in targeted ocular tissues, reduced frequency of administration, and
good bioavailability. Finally, combining both the therapeutic and diagnostic agents in one
nanocarrier system may bring better visual acuity in ocular therapy.
Author Contributions: Conceptualization, M.H.A. and I.A.; Literature search, M.H.A., I.A., H.K.,
A.O., S.N.M.N.U. and S.K.; Data analysis, M.Y.A., A.I.A.-H., H.K., O.A. and S.N.M.N.U., Drafting,
M.H.A., I.A., A.S.A.A., A.O. and S.K., Revision of work, M.H.A., H.K., O.A. and S.N.M.N.U. All
authors have read and agreed to the published version of the manuscript.
Funding: This review work received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors are grateful to Scientific Research Deanship at King Khalid University, Abha, Saudi Arabia, for their financial support through the Small Research Group Project under
Grant Number (RGP.01-48-42). The authors also thank M. Khurana for the kind support.
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Conflicts of Interest: The authors declare no conflict of interest.
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