Preparation and evaluation of Nano sized ocular drug delivery system for the

management of Glaucoma
Abstract:
It's very challenging for pharmaceutical researchers to deliver medications to the desired
location because of the complex morphology of the eye. The nano-formulations will aid in the
drug distribution at the optimal concentration. Glaucoma is attributed to the increase in
intraoccular pressure in the aqueous humour, which can also result in blindness in the majority of
cases. Anti-Glaucoma medications in the market have either difficulty in accessing the blood-
retinal barrier or have low systemic bioavailability. So it is suggested that, medications with a
lower therapeutic index must be administered more frequently. Administration of these
medications can result in the deposition of concentrated solutions at the ocular site and also
lowering the toxic effects that can cause cellular damage to the eyes. Novel drug delivery
technologies, such as in-situ gels, liposomes, niosomes, hydrogel, dendrimers, nanoparticles,
solid-lipid nanoparticles, Microneedles, or ocular inserts, are critical for improving the
penetration capacity, bioavailability, and the therapeutic efficacy of anti-glaucomic medication.
The significance of current developments in the field of nano carriers, which include recent
patents published in the last few years, existing treatments in terms of drugs used, and the
influence of using the above-mentioned novel drug delivery mechanisms in the treatment of
glaucoma were all clearly emphasized in the present review.
Keywords: Ocular drug delivery system, nano formulations, hydrogels, Solid lipid nanocarriers,
Nano-structured Lipid Carriers, nano emulsion, inorganic nanoparticles.
Introduction:
The human eye is one of the most complex and sensitive organs in the body. Because it is
the most common sense organ, it falls into the category of "human features with remarkable
architecture and physiology." These characteristics, along with a host of others, make the ocular
drug delivery system, one of the most fascinating and hardest to govern. The human eye's
internal structure is separated into two distinctive portions, the anterior and the posterior sections
(Figure 1) [1]. The cornea, conjunctiva, aqueous chamber, iris, ciliary body, and lens are part of
the anterior part. Topical eye drops are widely used to treat anterior eye disorders, due to the
easy accessibility of the front portion of the eye. Topical eye drops have poor ocular absorption
because of corneal barrier, the rapid tear film turnover, and the rapid tear outflow. The choroid,
retina and vitreous body make up the posterior portion [2]. To reach the rear section of the eye,
drugs administered by means of eye drops must travel a extended distance and clear a number of
ocular barriers, resulting in limited drug levels in the posterior segment. The blood–retinal
barrier (BRB) obstructs effective drug delivery to the eye via the systemic route, ensuring
extremely large doses that can cause systemic side effects. Intravitreal (IVT) injections, which
may carry medications which are straight way delivered to the back of the eye, are now widely
used in clinics to treat a number of eye conditions. Because of the vitreous humour turnover, free
medicines can be removed rather act fast after IVT injections, and repeated IVT injections are
required to obtain good therapeutic efficacy (e.g., regular monthly IVT injections of Lucentis®,
the anti-VEGF antibody Fab). IVT injections on a regular basis have been associated to high
costs, poor patient compliance, and also an increased risk of injection-related problems [3]. To
minimize dosage form related problems, the dose frequency, improve therapeutic efficacy, and
patient’s benefit, IVT drug delivery devices with extended drug-release characteristics are
needed.

Figure No 1: The structure of Human Eye

Injecting drugs into the periocular area and/or tissue along the eyeball, such as sub
conjunctival (SCT), sub-tenon, and the peribulbar injections, is less invasive than IVT injections,
but still successfully delivers drugs to the rear portion of the eye (Figure 1). To reach the retina
and vitreous, drugs must pass through the sclera, choroid, and the retinal pigment epithelium
(RPE). These ocular tissue layers act as drug transport barriers, reducing the amount of effective
medication that may be transported to the retina after periocular delivery of the drugs [4]. Supra-
choroidal administration distributes medications to the supra choroidal area beyond the sclera,
bypassing a key diffusion barrier that periocular drug delivery encounters, and is a potential
technique for delivering drugs to the back of the eye [5]. However, because of the supra
choroidal route can cause retinal hemorrhage and detachment, specific equipment (such as
micro-needles) are needed for effective and safe supra choroidal drug delivery.

Figure No 2: Structure of Glaucomic Eye

The anterior and posterior chambers are located in the anterior part of the eye. It's a
straightforward partition of the eyeball's length into its two halves. The anterior chamber is made
up of the space between the Cornea and the Iris, and the posterior chamber is made up of the
space between the Iris and the Lens. Although both chambers are filled with fluid, the anterior
chamber is filled with aqueous humour, whilst the posterior chamber is filled with vitreous
humour due to the closeness to the optic nerves. Aqueous humour, a translucent water fluid
generated by the ciliary epithelium in the anterior chamber, nourishes the lens and cornea [6, 7].
The trabecular meshwork, a spongy structure at the base of the cornea, transports aqueous
humour from the posterior chamber to the anterior chamber, where it empties into the Schlemm
canal. Finally, intrascleral, episcleral, and conjunctival veins discharge the clear fluid into the
venous system [8, 9]. As a result, the entire process forms the eye's drainage system, and if this
drainage system becomes completely or partially clogged, the pressure inside the eye rises.
 The pressure that exists inside the eye is known as intraocular pressure (IOP). Intraocular
pressure (IOP) that is too high might result in a number of eye issues. The apparatus used to
measure eye pressure is called a tonometer [10]. Tonometry is the measurement of eye pressure.
The IOP of a healthy human eye ranges from 10 to 21 mmHg [11]. In a sick state, the range is 5-
40mmHg [12]. One of the primary risk factors for glaucoma is a high IOP (higher than
22mmHg), according to [13]. Glaucoma affects approximately 70 million people worldwide,
with 10% of those who are affected going blind on both sides [14]. In the United States,
glaucoma is the most common cause of blindness [15]. Over 2 million people are thought to have
glaucoma, with roughly 40% of them being completely or partially blind [16]. According to
research, the number of persons suffering from glaucoma in the United States will reach over 3
million by 2020, and 111 million by 2040 [17]. High intraocular pressure causes glaucoma,
which is a group of progressively progressing eye diseases and disorders (IOP). This increase in
IOP is too high for normal eyes to sustain, and it leads to optic nerve damage that worsens over
time. When the optic nerve is injured over time, communication between the retina and the brain
breaks down, leading in irreversible vision loss [18]. Glaucoma is a disease that typically affects
people in their forties and fifties, and it is the second leading cause of vision loss after cataracts.
Glaucoma is divided into different types according on severity and causes. Because open angle
glaucoma has no obvious indications or symptoms, it is regarded as "the silent murderer of
sight." The signs and symptoms, as well as any mild visual loss, are typically overlooked by the
patient. The optic nerve of the eye may be irreparably injured if the diagnosis is not made fast
enough. Figure 2 shows a glaucomatous eye with optic nerve damage caused by an increase in
IOP.
 Figure No 3: Different sustained release drug delivery systems in various stages of
development.
Open-angle glaucoma and angle-closure glaucoma are the two primary types. The most
common kind of glaucoma is open-angle glaucoma, which develops gradually. Glaucoma with a
closed angle develops suddenly. Pain and a minor loss of vision are common indications and
symptoms of closed angle glaucoma. When a patient gets medical treatment at the first sign of
discomfort, permanent damage can be avoided [19].
The further divisions include normal tension glaucoma, pigmentary glaucoma, and
uveitic glaucoma. Because it produces optic nerve injury without increasing IOP, normal tension
glaucoma is unusual. Reduced blood supply to the optic nerve could play a role in this type of
glaucoma. Pigmentary glaucoma is a type of open angle glaucoma. It usually begins in
adolescence and lasts till middle age. Pigment cells in the iris spread throughout the eye, causing
an increase in ocular pressure [20]. Uveitic glaucoma is caused by changes in aqueous
production and outflow. Glaucoma produced by uveitis alters the anterior chamber angle's
anatomy. The IOP rises when corticosteroids are given to treat uveitis [21]. The failure of the
trabecular meshwork restricts the outflow of aqueous fluid. Secondary glaucoma is a type of
glaucoma that develops after primary glaucoma has developed. Examples include pseudo-
exfoliative glaucoma, Neo-vascular glaucoma, and Traumatic glaucoma, also known as Blunt
glaucoma. This type of secondary glaucoma can also be caused by faulty surgery [22].
Depending on whether you have primary open angle glaucoma or closed angle glaucoma,
your glaucoma symptoms will vary. Peripheral vision loss is frequent in the early stages of
primary open angle glaucoma, followed by tunnel vision loss in the later stages. Closed angle
glaucoma is characterized by blurred vision, eye discomfort, red eyes, and other visual problems
[23]. Secondary glaucoma can be caused by increasing cataracts, inflammation, tumour, or
diabetes problems. Primary glaucoma has no recognized etiology. Glaucoma has previously been
linked to advanced age, ethnicity, corneal thickness, prior eye injuries, and long-term
corticosteroid use. Other conditions like myopia, diabetes, and hyperthyroidism are also covered
[24]. Drug absorption can occur via two different routes: corneal and non-corneal. The majority
of the drug is supplied and absorbed in the eye by the corneal pathway, with the remainder
absorbed through the nasolacrimal dust [25].
 The main cause of low medicine absorption and bioavailability in the eye is pre-corneal
loss causes. Among these include solution drainage, tear turnover and tear dynamics,
lacrimation, and other factors. Each drop of solution from a regular eye dropper can yield 50-75 l
of solution. By the time the eye returns to its normal resident volume, ie.7l, the bulk of the drug
component has been emptied. Approximately 70 to 80 percent of the medicine is lost in the front
portion of the eye, leaving very little drug to reach the cornea and be absorbed in the inner tissue
of the eye. The anatomy and physiology of the cornea serve as a quick-acting barrier to medicine
absorption. As a result, the residence time is reduced, which might be compensated by repeated
eye drop instillation, resulting in drug dose repetition and poor patient compliance [26]. To be
absorbed systemically, drugs must pass across the blood-retinal barrier (BRB). The drug then
enters anterior ocular tissue after passing through posterior ocular tissue. The absorption of
medications that are weakly fat soluble is hampered by these obstacles. Drugs with a low
therapeutic index must be given frequently to maintain therapeutic concentrations. Repeated
injections of highly concentrated solutions at the ocular region generate toxic effects and cellular
damage to the eye [27]. To increase ophthalmic bioavailability and residence time, several
carriers including as ointments, inserts, solutions, and gels have been created. Ointments, gels,
and suspensions, on the other hand, are not extensively utilized because they cause blurred vision
and ocular irritation, which leads to low patient compliance [28].
It's critical to get around the downsides of traditional eye drops, which can be done by
changing and modifying the dosage type. The dosage form should be made in such a way that it
improves absorption and increases the drug's corneal retention time. Novel drug delivery systems
can be created with beneficial characteristics such as histocompatibility, immunogenicity,
toxicity, and the ability to pass through the corneal barrier [29].
Nanomedicine can improve hydrophobic drug solubility in aqueous solution, provide
longer drug release with reduced toxicity and improved efficacy, increase drug retention time
and improve drug penetration across ocular barriers, and even target specific tissues and cells.
For ocular medication administration, liposomes, polymeric nanoparticles (NPs), micelles, and
dendrimers (Figure 2) have all been developed [30]. Liposomes are lipid vesicles containing an
aqueous phase that contains phospholipids, cholesterol, and other lipid-linked polymers.
Lipophilic pharmaceuticals can be loaded into the lipid bilayers, while hydrophilic drugs can be
loaded into the inner watery core of liposomes [31]. Polymeric NPs can be made to retain a big
amount of medication and release it over a long period of time in a controlled manner.
Dendrimers are well-defined nanostructured globular polymers with low polydispersity (3–20
nm). Drugs could have been entrapped in the core of the dendrimer or conjugated to the
functional groups on the surface. The drug-loading capacity and drug-release profile can be
influenced by dendrimer synthesis, surface chemistry, and conjugation procedure [32]. Micelles
are self-assembled spherical vesicles with a hydrophilic corona and a hydrophobic core that can
solubilize and stabilise hydrophobic medicines. Nanomedicine has showed promise in the
treatment of ocular illnesses, and there are now a plethora of treatments on the market or in
clinical trials. Liposomes, mucus-penetrating particles, polymer NPs, micelles, and dendrimers
are some of the nanomedicines explored in this paper [33].

Figure No 4: Scheme of representative nano medicine platforms for ocular drug delivery.
Drugs used in the treatment of glaucoma
Glaucoma treatment is defined by the causes, risk factors, severity, and type of entry
levels of the disease. Every available treatment has some sort of drawbacks or side effects. When
treating glaucoma, each patient's vulnerability to the condition should be considered. Glaucoma
can be reduced by reducing the increase of intraocular pressure in the eye. A range eye
procedures, including laser treatment, surgery, and medication, can be used to lower intraocular
pressure. Iris-related procedures, filtration procedures, and non-penetrating filtration procedures
are examples of surgical treatments [34]. Argon-based laser trabeculoplasty is one of the major
treatments in iris-related procedures, filtration procedures, and non-penetrating filtration
procedures are examples of surgical treatments. Glaucoma drugs include prostaglandin
analogues, beta blockers, carbonic anhydrase inhibitors, adrenergic agonists, miotics, and
hyperosmotic agents. These drugs either increase the quantity of fluid that leaves the eye or
decrease the amount of fluid that enters the eye [35]. Glaucoma, on the other hand, is a condition
that cannot be completely cured. Because eye drops are effective, they are routinely used to treat
glaucoma instead of surgery. Despite this, because the medicine is absorbed into the conjunctival
blood vessels through the surface layer of the eye, some people do not respond well to standard
eye drops. The active ingredient influences heart rate and respiratory activity once it reaches the
bloodstream. Eye drops may aggravate asthma in people who have had a previous medical
history. Some of the disadvantages include eye irritation, hypotension, cardiac and respiratory
failure, sluggish heart rate, allergic conjunctivitis, asthma exacerbation, and impotence.
Understanding the core mechanisms of these classes is vital and urgent [36]. Each class of
medication has a different method for decreasing IOP in the eye.
Prostaglandin analogues
Prostaglandin analogues are the first-line of treatment for glaucoma in most countries
[37]. The prostaglandin analogues promote aqueous fluid outflow, which lowers intraocular
pressure in the eye. Prostaglandins are hydrophobic prodrugs that imitate prostaglandin in human
bodies for enhancing the fluid drainage through the Schlemm canal. Because they are given at
such a low dose, the prostaglandin families have extremely less negative effects. Prostaglandins,
on the other hand, have ocular adverse effects such as inflammation, redness, and discoloration
of the iris and surrounding skin [38].
Beta blockers
Beta blockers are antagonists of beta adrenergic receptors that reduce aqueous humour
production in the eye, lowering IOP. The two types of beta blockers are non-selective (timolol,
levobunol, etc.) and selective (timolol, levobunol, etc). (betaxolol). After the USFDA approved
the first beta blocker for the treatment of intraocular pressure problem, timolol became the first
choice for glaucoma treatment. As demonstrated in Figure 5 [39], they reduce blood pressure via
blocking the beta adrenoceptor in the ciliary body.
Figure No 5: Mechanism of Glaucoma treatment with Prostaglandins and Beta Blockers
Carbonic anhydrase inhibitor:
Sulphonamide medicines that operate on the ciliary epithelium are the most common
carbonic anhydrase inhibitors (Figure 6). They block the catalytic activity of carbonic anhydrase
isoenzyme II, which is directly responsible for the conversion of CO 2 and H2O to HCO3. The
conversion of CO2 and H2O to HCO3 causes a reduction in aqueous humour production in the eye
[40]. Dorzolamide was the first carbonic anhydrase inhibitor to be approved for use as a topical
eye drop to lower IOP. Dorzolamide can be used as a first-line treatment for glaucoma when the
effects of beta blockers are resisted or disputed. It has also been discovered that the combination
of timolol and Dorzolamide reduces IOP more effectively and act as a synergizer [41].
Alpha adrenergic agonists
Alpha adrenergic medicines reduce ocular pressure by activating the alpha adrenergic system.
The stimulation causes blood vessel constriction, which lowers the formation of aqueous
humour. Alpha adrenergics have a greater influence during the day than at night [42]. Glaucoma
is treated with selective a2 adrenergic agonists such apraclonidine and brominidine, a clonidine
derivative. Initially, a single-use dispenser containing one percent apraclonidine proved
satisfactory for reducing IOP increases, but it was only used in combination with surgical
procedures. For IOP reduction with 0.5 percent apraclonidine, long-term treatment was required.
It has no negative effects on the cardiovascular system, but it does have a number of other
common side effects, such as dry mouth and nose. Both brimonidine and apraclonidine are
similar medicines. According to many patients' complaints, it can cause dry mouth. Unlike
apraclonidine, it crosses the BBB, and there is a moderate risk of systemic hypotension.

Figure No 5: Mechanism of Glaucoma treatment with Carbonic anhydrase, Alpha

Adrenergic Agonist and Miotic/ Cholinergic agonists
Cholinergic or Miotics
As a third line of treatment, miotics, cholinergic agonists, or other para
sympathomimetics are chosen. Pilocarpine and carbacol are two commonly used miotics. It's
given as eye drops to patients on the spot. By restricting the trabecular meshwork fibers, they
help to increase the rate of aqueous humour outflow from the eye (Figure 6) [43]. Combining
two medications in people has been demonstrated to be partially synergistic when used with
latanoprost. Pilocarpine has a synergistic impact because it constricts the ciliary muscle and
reduces uvescleral outflow. When given at high quantities, physostigmine was found to be
beneficial in preventing ocular hypotension produced by latanoprost [44].
Strategies of advanced drug delivery systems
“We are about to construct things that work on the tiniest imaginable length scales, atom
by atom,” said Nobel Laureate in Chemistry Richard E Smalley. “In the scientific and technical
community, there is a rising sense that we are about to enter a golden new era,” he added. He
described nanotechnology as the scientific golden age he spoke of. The term "nanotechnology" is
derived from the Greek word "nano," which means "dwarf." It is defined as a technology based
on engineering and manufacturing processes at the molecular level (nano size). Since then,
nanotechnology has revolutionized a range of industries, including robotics, medicine, and
communications. Nanotechnology has piqued the curiosity of many scientists and researchers.
Nanotechnology in medicine refers to the creation and use of materials for the formation of
intracellular structures and molecules [45].
Nanotechnology breakthroughs have changed the scientific landscape in the healthcare
industry, resulting in a slew of novel medical and medication delivery discoveries. Two new
methods of drug delivery have been discovered: targeted and controlled release drug delivery.
When nanotechnology is applied to ophthalmology, it has resulted in the development of novel
drug delivery techniques such as nanoparticles for the treatment of glaucoma, cataracts,
conjunctivitis, and other infections of the eye. Drugs are delivered to a specific target spot using
nanoparticles as delivery carriers. Drug loading in nanoparticles is straightforward, and any type
of drug can be used [46]. Their ability to load both hydrophilic and lipophilic medications
improves in pharmacological penetration through the eye's ocular barrier. These drug-loaded
nanoparticles are part of an ideal drug delivery system that can bypass ocular physiological
barriers. To route medicines to certain ocular intracellular components, they use passive
diffusion or a ligand targeting approach.
Liposomes
Liposomes are vesicles with one or more phospholipid layers enclosing an aqueous
phase. Liposomes are made up of phospholipids, lipid conjugated polymers, and cholesterol.
Liposomes are classified primarily by the presence of multiple phospholipid layers and their size,
which includes small uni lamellar vesicles with sizes ranging from 10 to 100 nm, large uni
lamellar vesicles with sizes ranging from 100 to 300 nm, and multi lamellar vesicles with more
than a single phospholipid bilayer [47]. Liposomes' unusual shape allows them to carry both
hydrophilic and hydrophobic medicines to the site of action. The presence of a lipid layer on the
outer core of liposomes makes them biodegradable in nature. The presence of charged particles
on the liposome surface is determined by the lipid utilized in the liposome formulation [48].
When penetration-enhancing polymers and bio-adhesives are included into liposomal
formulations for topical distribution, the drug's corneal adherence and penetration are improved
[49]. Due to their unique structure framework, which entraps both lipophilic and hydrophilic
drugs and exerts targeted delivery at the site of action, the liposomal formulation helps in
minimizing various effects such as endophthalmitis, vitreous haemorrhage, and retinal
detachment that are associated with intravitreal instillation of drugs. The drug's reduced
bioavailability after topical instillation is attributed to a shortened precorneal residence period
caused by quick nasolacrimal drainage and tear turnover, which results in decreased absorption
via the conjunctiva. Only a limited fraction of the absorbed drug is able to reach the posterior
tissue because only l-10% or less of the dose is able to diffuse through the anterior segment
tissues of the eye. Liposomes include features such as fluidity of lipid bilayers, charge on the
surface, size, and surface hydration that make them more suitable for ocular medication delivery
and give stability. The interaction of liposomes with the ocular surface is determined by the
presence of charge (positive, negative, or neutral) on their surface. Positively charged liposomes
had higher corneal penetration than negatively charged liposomes or liposomes with no charge
(neutral) [50].
For the treatment of glaucoma, Huang Y created a formulation. To address poor ocular
bioavailability, the liposomal formulation included Betaxolol hydrochloride (BH) and
Montmorillonite (Mt) to form (Mt-BH-LP). The designed and refined Mt-BH-LP was found to
be beneficial in lowering intraocular pressure (IOP) and retaining better ocular bioavailability
[51].
Vallejo JC and his colleagues produced a topical formulation by loading triamcinolone
acetonide into liposomes, which was used to transport triamcinolone acetonide into the rabbit's
vitreous cavity and retina. Different formulations were created and labeled as (TA-LF1 to TA-
LF4), and the toxicity and tolerance of TALF2 were assessed using a cell viability assay and an
examination of the rabbit eye, with no increase in intraocular pressure and no changes in the
rabbit eye [52].
Macular edema (ME) is a condition caused by a decrease in the permeability of the
retinal capillaries [53]. Li et al. used the calcium acetate gradient method to manufacture a
liposome formulation loaded with triamcinolone acetonide (TA) medication, which was then
coated with chitosan (TA-CHL) to boost the effectiveness of TA. The drug delivery through the
eyes was confirmed to be safe using the produced formulation. THCHL, the study concluded,
was a more successful new delivery system because of its physical stability, high entrapment
efficiency (EE), long-term drug release, and low toxicity when used as an eye drop [54].
 Because of the eye's particular structure and defense system, the medicine cannot be
retained for a prolonged period of time. Dong et al. studied a liposomal formulation loaded with
ibuprofen for topical delivery of the medicine employing silk fibroin (SF) as a mucoadhesive
substance to increase the duration of drug release in the eye. The produced liposomes were
assessed for drug encapsulation efficiency, in vitro release, and in vitro corneal penetration in a
comparative research between SF-coated liposomes (SLs) and conventional liposomes. The
cytotoxicity of the formulation (SLs) was tested using a human corneal epithelial cell, and no
toxicity was found in the corneal cell. The SF coated liposome was found to be more effective at
delivering the medication to the ocular location [55].
De Sá et al. developed a topical liposomal formulation containing voriconazole (VOR) to
treat fungal keratitis with the help of a coworker. The formulation's characterization properties
included drug entrapment efficiency, average diameter, drug recovery, and polydispersity index
(PDI). Ex vivo permeation investigations, in vitro mucosal interaction, irritancy levels, and in
vitro mucosal interaction were all evaluated. On executing the HET-CAM (hen's egg
chorioallantoic membrane test), the EE was determined to be 80%, and the formulation was
labeled as "non-irritant." According to the findings, VOR liposomes have a lot of potential for
treating fungal keratitis [56].
Fahmy et al. developed liposomes containing latanoprost/thymoquinone (Lt/Ty) loaded in
DPPC for the sub conjunctival approach (1, 2- dipalmitoyl-Sn-glycero-3-phosphocholine). The
drug encapsulation of the Lt/Ty loaded liposomes was found to be high, and they were able to
decrease IOP for more than 84 hours. In glaucomatous rabbits, liposomes were compared to an
usual ocular solution of latanoprost, and it was observed that liposomes could release medicine
for a very long time [57].
Kouchak et al. compared phosphatidyl choline loaded Dorzolamide HCl nanoliposomes
to the conventionally marketed Dorzolamide HCl ophthalmic solution in 20 glaucoma patients
with increased ocular pressure. Patients treated with Dorzolamide HCl nanoliposomes
experienced a significant reduction in IOP when compared to the marketed formulation. Due to a
resemblance between lipid bilayers with positive charge, liposomes are more adherent to corneal
layers, resulting in greater drug absorption [58].
Niosomes
 Niosomes are bilayered primary vesicles made up of non-ionic surfactants with the
unique capacity to capture both hydrophilic (in vesicular bilayer membranes) and lipophilic (in
aqueous compartments) substances [59]. The size of niosomes is typically between 10 nm and 1
m. Because of the functional group present on their hydrophilic heads, niosomes are simple to
manufacture and modify. Niosomes are non-immunogenic and biodegradable. They are chosen
over liposomes for a variety of reasons, including cost and lengthy storage period (shelf-life), as
well as the fact that they do not require particular handling or storage conditions. Niosomes are
recommended as drug carriers because they can lessen drug adverse effects by limiting the drug's
systemic absorption and also improve the drug's therapeutic effectiveness. Niosomes are adept in
delivering drugs to the ocular cavity in a targeted manner. The niosomes' vesicles serve as a
storage facility for the drug, allowing it to be delivered to the site of action over time.
Niosomes can be injected into the eyes as drops, which boosts preocular retention on the
eye's surface attributed to the prevalence of cholesterol, which enhances the durability of the
museums membrane bilayer, reducing systemic drainage and implying precorneal retention. In
comparison to conventional dose forms, niosomes have a better in vitro stability profile.
Niosomes are lipid vesicles that load and transfer drugs over an eye barrier, affecting the
flexibility of the primarily occurs and scleral membranes in the ophthalmic region and so
boosting drug absorption. By slowing ocular metabolism in the lachrymal fluid, niosomes have a
longer duration of action. Ocular hypertension, dry eyes, glaucoma, and eye infection have all
been found to be treated with niosomes [60].
Allam and colleagues created a niosomal formulation to boost vancomycin's therapeutic
effectiveness, which was then placed into a polymeric solution that turned into a gel
(vancomycin niosomal gel) when injected into the eye, extending the duration the antibiotic
spent in the eye. In vitro and in vivo experiments were conducted to investigate vancomycin's
efficacy because it is particularly successful in eradicating methicillin-resistant Staphylococcus
aureus (MRSA) infections. In MRSA-infected rabbits, the new formulation increased
antibacterial activity by 180 times when compared to a vancomycin-free medication solution,
which only increased antibacterial activity by 2.5 times [61].
Nabarawi and his co-workers developed topically applied natamycin (NAT) loaded
niosomes in ketorolac tromethamine (KT) gels enhanced penetration rate, boosting natamycin
effectiveness via ocular tissue by lowering infection associated with fungal keratitis (FK).
During the in vitro testing, created formulation demonstrated up to 57.32 percent hindrance when
compared to commercial preparation. In comparison to other formulations and combined
commercial formulations, the formulation exhibited promising outcomes in the treatment of
candida keratitis (Natacyn and Ketoroline). The niosomal formulation had superior outcomes in
all in vitro, in vivo experimental and histological examinations [62].
The typical and simple procedure for manufacturing Niosomes is thin layer evaporation
(TLE). Soni and Saini used Timolol maleate to evaporate the organic solvent from the lipid and
surfactant solution, resulting in the development of a thin layer lipid-surfactant film. The
resulting film is subsequently hydrated with an aqueous solution to form timolol maleate multi-
lamellar vesicles, or niosomes. Niosomes made utilizing the TLE process had a longer-lasting
drug release in the eye. It enhanced the drug's penetration across the ocular barrier to 65.90
percent in an 8-hour timeframe, which is around 150 percent more than the permeability of a
standard dose. TLE is a simple procedure for laboratory researchers, with the only drawback
being the usage of organic solvents in the formulation [63].
Dehaghi et al. used two approaches to generate a Dorzolamide-loaded niosomes vesicle:
thin film hydration and the phosphate gradient technique. The formulations were examined for
encapsulating efficacy, lipid to drug ratio, cholesterol percentage, and pH to ensure the optimal
release. An increase in cholesterol levels with fat resulted in a gain in encapsulation efficiency,
according to the research. This niosomal formulation [64] should result in much improved drug
release over a longer time period.
Hydrogel
Hydrogels are macromolecular 3-D cross linked polymer networks with covalent or non-
covalent linkages. Crosslinking in the polymer is caused by a variety of interactions, including
van der Waals interactions, covalent bond formation, hydrogen bonding, and physical attractions.
Because of their porous and entangled network structure, these cross linked polymers are useful
for transporting chemicals and medicines. The hydrogel's crosslink structure aids in the
preservation of its structure [65]. Polymerization is used to create the covalent cross-linked
structure. Nano-sized gels are dispersions that retain more water due to their entangled network,
and the structure allows for the addition of various functional group vectors for targeting [66].
By restricting the IOP, hydrogel can control the flow of aqueous humour through the anterior
chamber. The behavior of hydrogel causes restricted outflow through aqueous humour.
 These behaviours can be influenced by the weight of the polymer, the density of cross-
linked polymers, water linkage, and other factors. Water may absorb thousands of times its
weight in hydrogels, causing them to swell without affecting their essential structure. Polymers
with hydrophilic groups, such as amide, hydroxyl, and sulfonic acid, can absorb water. The
presence of these groups can cause the polymer to hydrate to varied degrees, depending on the
composition of the polymer and the surrounding environment [67].
Cheng et al developed a thermo sensitive hydrogel containing latanoprost and curcumin-
loaded nanoparticles in order to assess the adverse effects of repeated dosage of prostaglandin
analogues such as latanoprost. The hydrogel formulation showed sustained release of latanoprost
and curcumin, according to the study. The created hydrogel's adhesion to the precorneal surface
was improved, and it was able to lower IOP within seven days of treatment [68].
Although many studies have been done on anti-glaucomic medications to achieve
sustained release, additional research is needed to achieve more sustained release in order to
lower IOP for longer periods of time. To tackle the problem of standard ophthalmic eye drops,
scientists recently devised a timolol maleate mixture of hydrogels, namely thermo sensitive
elastin and silk elastin. The combination hydrogel was discovered to have a possible effect in
improving drug retention on the cornea and lowering IOP for a longer period of time.
Liu and colleagues developed a degradable microsphere formulation that delivered
aflibercept in a precise manner. They suspended the medication in a thermo responsive poly
(ethylene glycol)-co-(lactic acid) diacrylate/N-isopropyl acrylamide (PEG-PLLA-DA/NIPAA)
hydrogel. They investigated EE and in vitro drug release profiles with radiolabelled aflibercept
Iodine-125 (125I), which also demonstrated variations in dry weight that produced a degradation
profile of hydrogel. Finally, the cytotoxicity of the degraded drug delivery system (DDS)
byproducts was assessed using the LIVE/DEAD® assay technique to determine cell viability. In
comparison to bolus injection loaded hydrogel, the microsphere laden hydrogel system was
found to be safe and efficacious for the treatment of ocular neovascularization [69].
Silva and colleagues created silicone-based imprinted and non-imprinted hydrogels in
which they encapsulated the antibiotic moxifloxacin hydrochloride (MXF) and tested its
therapeutic efficiency as soft contact lenses (SCLs). There were no significant differences in the
release of silicone (3-tris (trimethylsilyloxy) silylpropyl 2-methylprop-2-enoate) hydrogels
between TRIS + D and TRIS/AA hydrogels. TRIS and TRIS/AA + D hydrogels had faster and
longer release times, respectively. As a result, this comparison was beneficial for imprinted
materials used in daily therapy SCLs [70].
Dendrimers
Dendrimer is derived from the Greek words Dendron and meros, which are combined.
The Latin word for "tree" is Dendron, and the Greek word for "portion" is meros. 'Cascade
molecules' is a term used to describe dendrimers. Dendrimers were initially described by Vögtle
in 1978 [71].
Dendrimers are macromolecular 3D shaped structures made up of highly branched
polymeric material with a huge surface area. Dendrimers are distinguished by their high
branching intensity, water solubility, consistent size, constant molecular weight, and the
existence of inner pores that trap medicines for medication delivery. Dendrimers usually have a
globular or ellipsoidal shape. There are three parts to them: a central core, branches, and surface
functional groups, with two reactive functional groups in the central core. The branches are made
up of radially concentric layers. These concentric layers are referred regarded as 'generations.'
The functional groups present on the surface can be used to determine physical properties [72].
The results of the trials were initially much better for lipophilic treatments than for
hydrophilic ones. In such cases, dendrimers have been identified as a viable solution [73]. Poly
(amidoamine) is one of the most widely used polymers in dendrimer manufacturing (PAMAM).
PAMAM dendrimers are polymers with a variety of groups such as carboxylic, amine, and
hydroxyl groups that are either liquid or semi-solid. PAMAM dendrimers have the ability to
solubilize even poorly water-soluble drugs in their zones, which feature cascade tiers in the inner
zone and terminal moieties on the surface region. PAMAM dendrimers have already been shown
to be effective in the delivery of ophthalmic medicines [74].
Lancina et al. looked explored brimonidine tartrate-loaded PAMAM Dendrimers for
glaucoma ocular treatment lately. To make a nano mat, electro spinning was employed to insert
the obtained brimonidine tartrate loaded dendrimers into nano fibers. In normal tension rabbits,
the drug-dendrimer loaded nano mat was tested in vivo and compared to a regular eye drop. The
drug-loaded dendrimer nanometal was found to be non-irritating and well tolerated by the
animals. A single dose of dendrimer-loaded nano fibers could also reduce IOP for a day,
according to the findings [75].
Nano-emulsion
 Nano emulsions are a kinetically stable nano-sized drug delivery method. Nano emulsion
is favored for ocular medication administration because it allows the drug to penetrate deeper
into the ocular tissue by releasing the drug at a steady rate. Nano emulsion has a low formulation
cost and is naturally less viscous [76]. This colloidal dispersion improves ocular residence
duration and increases drug penetration via the cornea. The interaction of nano emulsion with the
lipid layer of the tear film allows the medicine to stay in the conjunctival sac for a longer amount
of time and operate as a drug depot [77].
Mahboobian and colleagues developed a brinzolamide (BZ) formulation loaded in nano
emulsions for the treatment of glaucoma (NE). When compared to a commercially available
ocular suspension, the novel formulation exhibited two to three times better corneal penetration
(Azopt). Ex vivo and in vivo studies showed that the generated formulation was safe and had a
strong penetrating effect when compared to Azopt [78]. Because it serves to boost the medicine's
bioavailability, NE is regarded to be beneficial in ocular drug delivery. Shah et al. created a nano
emulsion formulation to boost the therapeutic efficacy of Moxifloxacin. In this study, the drug
concentration at the target site was found to be higher. After the irritation study was finished, the
formulation was found to be well tolerated. Following the discovery of this delivery system's
beneficial effect, it was discovered that the drug may produce a therapeutic effect even at low
doses [79].
Conclusion
This article summarizes the development of many Nano medicines that helped bypass
ocular obstacles. Improved medicine residence length, bioavailability, bio distribution, and
biocompatibility have all been proven in several trials. Liposomes, nano suspensions, hydrogels,
NLC (nanostructured lipid carrier), SLN (solid lipid nanoparticles), and polymeric micelles are
just a few of the systems that have been studied for delivering therapeutic dosages at a controlled
rate while also improving drug bioavailability [80]. Drugs included in different nanocarriers have
been proven to help ARMD (Age-Related Macular Degeneration), dry eye, uveitis, choroidal
neovascularization, conjunctivitis, and glaucoma. In the era of conventional and Nanomedicine
drug delivery systems, various research activities with promising outcomes will continue to
emerge [81].
Glaucoma is a disorder in which the intraocular pressure (IOP) in the eye rises to the
point where the ocular nerves are irreversibly damaged. If left untreated, glaucoma can result in
permanent vision loss. The current treatments are available as eye drops, which have the
drawbacks of frequent dosage and a shorter precorneal retention time. In this review, the
pharmacological characteristics of numerous common glaucoma drugs were examined, as well as
how these therapies can be improved in efficacy by being manufactured as various new drug
delivery systems. Various attempts to produce a prolonged or regulated delivery of the drug to
the eye have been made over the years. These new medication delivery technologies have the
potential to increase patient compliance, therapeutic efficacy and effectiveness, reduce side
effects, and, ultimately, maintain the eyesight of glaucoma patients.
References:
1. O.A. Bamiro, R. V. Ubale, R.T. Addo, Background of Ocular Drug Delivery, in: Ocul.
Drug Deliv. Adv. Challenges Appl. (2016)1–9.
2. Kels BD, Grzybowski A, Grant-Kels JM. Human ocular anatomy. Clin Dermatol. 2015
Mar-Apr;33(2):140-6.
3. Jonas JB, Spandau UH, Schlichtenbrede F. Short-term complications of intravitreal
injections of triamcinolone and bevacizumab. Eye (Lond). 2008 Apr; 22(4):590-1.
4. Bochot, A. and Fattal, E. (2012) Liposomes for intravitreal drug delivery: a state of the
art. J. Control. Release 161, 628–634.
5. Chiang B, Jung JH, Prausnitz MR. The suprachoroidal space as a route of administration
to the posterior segment of the eye. Adv Drug Deliv Rev. 2018 Feb 15; 126:58-66.
6. H. Noma, H. Funatsu, M. Yamasaki, H. Tsukamoto, T. Mimura, T. Sone, T. Hirayama,
H. Tamura, H. Yamashita, A. Minamoto, H.K. Mishima, Aqueous humour levels of
cytokines are correlated to vitreous levels and severity of macular oedema in branch
retinal vein occlusion, Eye. 22 (2008) 42-48.
7. N. Perumal, C. Manicam, M. Steinicke, S. Funke, N. Pfeiffer, F.H. Grus,
Characterization of the human aqueous humour proteome: A comparison of the genders,
PloS one. 12 (2017) e0172481.
8. G.Baerveldt, pharmacia and Upjohn Co US, Method and apparatus for inserting a
glaucoma implant in an anterior and posterior segment of the eye, US Patent (2000)
Patent 6050970.
9. P.C. Ng, J.J. Oliver, Anatomy of the Eye, In Handbook of Emergency Ophthalmology
(2018) 1-12.
10. N.M. Farandos, A.K. Yetisen, M.J. Monteiro, C.R. Lowe, S.H. Yun, Contact Lens
Sensors in Ocular Diagnostics, Adv. Healthc. Mater. 4 (2015) 792–810.
11. C.O. Timothy, R.O. Nneli, The effects of cigarette smoking on intraocular pressure and
arterial blood pressure of normotensive young Nigerian male adults, Niger. J. Physiol.
Sci. 22 (2007) 1-2.
12. G.Z. Chen, I.S. Chan, D.C. Lam, Capacitive contact lens sensor for continuous
noninvasive intraocular pressure monitoring, Sens. Actuators A. Phys. 203 (2013) 112-
118.
13. A. Heijl, M.C.Leske, B. Bengtsson,L.Hyman, M. Hussein, Reduction of intraocular
pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial,Arch
Ophthalmol. 120 (2002) 1268-1279
14. H.A. Quigley, A.T. Broman, The number of people with glaucoma worldwide in 2010
and 2020, Br. J. Ophthalmol. 90 (2006) 262-267.
15. J.L. Wiggs, J. Hee Kang, B.L. Yaspan, D.B. Mirel, C. Laurie, A. Crenshaw, W. Brodeur,
S. Gogarten, L.M. Olson, W. Abdrabou, E. DelBono, Common variants near CAV1 and
CAV2 are associated with primary open-angle glaucoma in Caucasians from the USA,
Hum. Mol. Genet. 20 (2011) 4707-4713.
16. M.J. Martin, A. Summer, E.B. Gold, Race and primary open-angle glaucoma, Am. J.
Ophthalmol. 99 (1985) 383-387.
17. D.S. Friedman, R.C. Wolfs, B.J.O’Colmain, B.E. Klein, H.R Taylor, S. West, M.C.
Leske, P. Mitchell, N. Congdon, J. Kempen, Prevalence of open-angle glaucoma among
adults in the United States, Arch. Ophthalmol. (2004) 532-538.
18. L.H. Hertzog, K.G. Albrecht, L. LaBree, P. Lee, Glaucoma care and conformance with
preferred practice patterns: examination of the private, community-based
ophthalmologist, Ophthalmology. 103 (1996) 1009-1013.
19. L. Ciulla, A. Harris, J. Geng, C. Ip, P. Serrano, J. Gross, B. Siesky, The role of
hypertension in retinal blood flow alterations in open‐ angle glaucoma patients, Acta.
Ophthalmol. 95 (2017) e794-e795.
20. J. Kountouras, C. Zavos, D. Chatzopoulos, Primary open-angle glaucoma:
pathophysiology and treatment, Lancet. 364 (2004) 1311–1312
21. A. Da Mata, S.E. Burk, P.A. Netland, S. Baltatzis, W. Christen, C.S. Foster, Management
of uveitic glaucoma with Ahmed glaucoma valve implantation. Ophthalmology. 106
(1999) 2168-2172.
22. D.A. Lee, E.J. Higginbotham, Glaucoma and its treatment: a review, Am. J. Health. Syst.
Pharm. 62 (2005) 691-699.
23. M.C. Leske, The epidemiology of open-angle glaucoma: a review, Am. J. Epidemiol. 118
(1983) 166–91.
24. A.L. Coleman, S. Miglior, Risk factors for glaucoma onset and progression, Surv.
Ophthalmol. 53 (2008) S3-S10.
25. T. Yasukawa, Y. Ogura, Y. Tabata, H. Kimura, Intraocular sustained drug delivery using
implantable polymeric devices, Adv. Drug Deliv. Rev. 57 (2006) 2033-2046.
26. J.R. Robinson, G.M. Mlynek, Bioadhesive and phase-change polymers for ocular drug
delivery. Adv. Drug Deliv. Rev. 16 (1995) 45-50.
27. J. Barar, A.R. Javadzadeh, Y. Omidi, Ocular novel drug delivery: impacts of membranes
and barriers. Expert. Opin. Drug. Deliv. 5 (2008) 567-581.
28. E. Dimitrova, S. Bogdanova, M.Mitcheva, I.Tanev, E.Minkov, M.Tanev, E. Minkov,
Development of model aqueous ophthalmic solution of Indomethacin, Drug DevInd.
Pharm. 26 (2000) 1297-1301.
29. S. Yu, Q.M. Wang, X. Wang, D. Liu, W. Zhang, T. Ye, X. Yang, W. Pan, Liposome
incorporated ion sensitive in-situ gels for opthalmic delivery of timolol maleate, Int. J.
Pharm. 480 (2015) 128-136.
30. Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for
treatment of ocular disease. Acta Pharm Sin B. 2017 May;7(3):281-291.
31. Lalu L, Tambe V, Pradhan D, Nayak K, Bagchi S, Maheshwari R, Kalia K, Tekade RK.
Novel nanosystems for the treatment of ocular inflammation: Current paradigms and
future research directions. J Control Release. 2017 Dec 28; 268:19-39.
32. Rodríguez Villanueva J, Navarro MG, Rodríguez Villanueva L. Dendrimers as a
promising tool in ocular therapeutics: Latest advances and perspectives. Int J Pharm.
2016 Sep 10; 511(1):359-366.
33. Mandal A, Bisht R, Rupenthal ID, Mitra AK. Polymeric micelles for ocular drug
delivery: From structural frameworks to recent preclinical studies. J Control Release.
2017 Feb 28; 248:96-116.
34. M.M. Abdull, J. McCambridge, J. Evans, F. Muazu, C. Gilbert, Can Adapted
Motivational Interviewing Improve Uptake of Surgical or Laser Treatment for Glaucoma
in Nigeria: Randomized Controlled Trial. J. glaucoma, 26 (2017) 822-828.
35. C. McAlinden, Selective laser trabeculoplasty (SLT) vs other treatment modalities for
glaucoma: systematic review, Eye. 28 (2014) 249.
36. J. Gault, J. F. Vander, Ophthalmology Secrets in Color E-Book, Elsevier Health
Sciences.(2015).
37. C.B. Toris, A. Alm, C.B. Camras, Latanoprost and Cholinergic Agonists in Combination,
Surv. Ophthalmol. 47 (2002) S141–S147.
38. G. Soni, K.S. Yadav, Applications of nanoparticles in treatment and diagnosis of
leukemia, Mater. Sci. Eng. C, 47 (2015) 156-164.
39. Bhattacharjee A, Das PJ, Adhikari P. Novel drug delivery systems for ocular therapy:
With special reference to liposomal ocular delivery. Eur J Ophthalmol 2019; 29(1): 113-
26.
40. 4. Yadav KS, Rajpurohit R, Sharma S. Glaucoma: Current treatment and impact of
advanced drug delivery systems. Life Sci 2019; 221: 362-76.
41. Mishra GP, Bagui M, Tamboli V, Mitra AK. Recent applications of liposomes in
ophthalmic drug delivery. J Drug Deliv 2011; 2011863734.
42. Geroski DH, Edelhauser HF. Drug delivery for posterior segment eye disease. Invest
Ophthalmol Vis Sci 2000; 41(5): 961-4.
43. T.R. Thrimawithana, S. Young, C.R. Bunt, C. Green, R.G. Alany, Drug delivery to the
posterior segment of the eye, Drug Discov. Today. 16 (2011) 270–277.
44. J. Jiang, J.S. Moore, H.F. Edelhauser, M.R. Prausnitz, Intrascleral Drug Delivery to the
Eye Using Hollow Microneedles, Pharm. Res. 26 (2009) 395–403.
45. J. Jiang, H.S. Gill, D.Ghate, B.E.McCarey, S.R. Patel, H.F. Edelhauser, M.R. Prausnitz,
Coated microneedles for drug delivery to the eye, Invest. Ophthalmol. Vis. Sci. 48
(2007)4038-4043.
46. C. Liu, Q. Lan, He, C. Nie, C. Zhang, T. Xu, T. Jiang, S. Wang, Octa-arginine modified
lipid emulsions as a potential ocular delivery system for disulfiram: A study of the
corneal permeation, transcorneal mechanism and anti-cataract effect, Colloids Surf. B.
Biointerfaces. 160 (2017) 305-314.
47. A.S. Mundada, B.K. Shrikhande, Formulation and Evaluation of Ciprofloxacin
Hydrochloride Soluble Ocular Drug Insert, Curr. Eye Res. 33 (2008) 469–475.
48. L.P. Jervis, A Summary of Recent Advances in Ocular Inserts and Implants, J. Bioequiv.
Availab. 9 (2017) 320-323.
49. A. Kumari, P.K. Sharma, V.K. Garg, G. Garg, Ocular inserts—Advancement in therapy
of eye diseases, J. Adv. Pharm. Technol. Res. 1 (2010) 291-296.
50. De Souza, F. Júlio, N.M. Kamila , P.S.D.O. Patrício, G. M.Fernandes-Cunha, M. G. Da
Silva, C.E.D.M. Jensen, G.R. Da Silva, Ocular inserts based on chitosan and brimonidine
tartrate: Development, characterization and biocompatibility, J. Drug Deliv. Sci. Technol.
32 (2016) 21-30.
51. Huang Y, Tao Q, Hou D. A novel ion-exchange carrier based upon liposome-
encapsulated montmorillonite for ophthalmic delivery of betaxolol hydrochloride. Int J
Nanomedicine 2017; 12: 1731-45
52. Altamirano-Vallejo JC, Navarro-Partida J, Gonzalez-De la Rosa A. Characterization and
pharmacokinetics of triamcinolone acetonide- loaded liposomes topical formulations for
vitreoretinal drug delivery. J Ocul Pharmacol Ther 2018; 34(5): 416-25.
53. Li J, Cheng T, Tian Q. A more efficient ocular delivery system of triamcinolone
acetonide as eye drop to the posterior segment of the eye. Drug Deliv 2019; 26(1): 188-
98.
54. Sahoo SK, Dilnawaz F, Krishnakumar S. Nanotechnology in ocular drug delivery. Drug
Discov Today 2008; 13(3-4): 144-51.
55. Dong Y, Dong P, Huang D. Fabrication and characterization of silk fibroin-coated
liposomes for ocular drug delivery. Eur J Pharm Biopharm 2015; 91: 82-90.
56. de Sá FAP, Taveira SF, Gelfuso GM, Lima EM, Gratieri T. Liposomal voriconazole
(VOR) formulation for improved ocular delivery. Colloids Surf B Biointerfaces 2015;
133: 331-8.
57. H.M. Fahmy, E.A.E.M.S. Saad, N.M. Sabra, A.A. El-Gohary, F.F. Mohamed, M.H.
Gaber, Treatment merits of Latanoprost/Thymoquinone–Encapsulated liposome for
glaucomatus rabbits. Int. J. Pharm. 548 (2018) 597-608.
58. M. Kouchak, M. Malekahmadi, N. Bavarsad, A. Saki Malehi, L. Andishmand,
Dorzolamidenanoliposome as a long action ophthalmic delivery system in open angle
glaucoma and ocular hypertension patients, Drug Dev. Ind. Pharm. 44 (2018) 1239–
1242.
59. Sharma R, Dua JS, Prasad DN, Hira S. Advancement in NovelDrug Delivery System:
Niosomes. J Drug Deliv Ther 2019; 9(3-s): 995-1001.
60. Biswas GR, Majee SB. Niosomes in ocular drug delivery. Eur J Pharm Med Res 2017;
4(7): 813-9.
61. Allam A, El-Mokhtar MA, Elsabahy M. Vancomycin-loaded niosomes integrated within
pH-sensitive in-situ forming gel for treatment of ocular infections while minimizing drug
irritation. J Pharm Pharmacol 2019; 71(8): 1209-21.
62. El-Nabarawi MA, Abd El Rehem RT, Teaima M. Natamycin niosomes as a promising
ocular nanosized delivery system with ketorolac tromethamine for dual effects for
treatment of candida rabbit keratitis; in vitro/in vivo and histopathological studies. Drug
Dev Ind Pharm 2019; 45(6): 922-36.
63. M.N. Azmin, A.T. Florence, R.M. Handjani-Vila, J.F.B. Stuart, G. Vanlerberghe, J.S.
Whittaker, The effect of non-ionic surfactant vesicle (niosome) entrapment on the
absorption and distribution of methotrexate in mice, J. Pharm. Pharmacol. 37 (1985) 237–
242.
64. M.H. Dehaghi, A. Haeri, H. Keshvari, Z. Abbasian, S. Dadashzadeh, Dorzolamide loaded
niosomal vesicles: comparison of passive and remote loading methods, Iran J. Pharm.
Res. 16 (2017) 413-422.
65. G. Soni, K.S. Yadav, High encapsulation efficiency of poloxamer-based injectable
thermo responsive hydrogels of etoposide, Pharm. Dev. Technol. 19 (2014) 651–661.
66. G. Soni, K. S. Yadav, Communication of Drug Loaded Nanogels with Cancer Cell
Receptors for Targeted Delivery. In: Suzuki J., Nakano T., Moore M. (eds) Modeling,
Methodologies and Tools for Molecular and Nano-scale Communications. 2017 pp. 503-
515. Springer, Cham.
67. N.A.Peppas, A.R. Khare, Preparation, structure and diffusional behavior of hydrogels in
controlled release, Adv. Drug Deliv. Rev. 11 (1993) 1-35.
68. C.H. Lee, V. Moturi, Y. Lee, Thixotropic property in pharmaceutical formulations, J.
Control. Release. 136 (2009) 88-98.
69. Liu W, Lee BS, Mieler WF, Kang-Mieler JJ. Biodegradable microsphere- hydrogel
ocular drug delivery system for controlled and extended release of bioactive aflibercept in
vitro. Curr Eye Res 2019; 44(3): 264-74.
70. Silva D, de Sousa HC, Helena Gil M. Moxifloxacin imprinted silicon based hydrogels for
sustained ocular release. Ann Med 2019; 51: 103-4.
71. A.M. Caminade, R. Laurent, J.P. Majoral, Characterization of Dendrimers, Adv. Drug
Deliv. Rev. 57 (2005)2130-2146.
72. G. Spataro, F. Malecaze, C.O. Turrin, V. Soler, C. Duhayon, P.P. Elena, J.P. Majoral,
A.M. Caminade, Designing dendrimers for ocular drug delivery, Eur. J. Med. Chem. 45
(2010) 326–34.
73. B.K. Nanjwade, H.M. Bechra, G.K. Derkar, F.V. Manvi, V.K. Nanjwade, Dendrimers:
emerging polymers for drug-delivery systems, Eur. J. Pharm. Sci. 38 (2009) 185-196.
74. T.F. Vandamme, L. Brobeck, Poly (amidoamine) dendrimers as ophthalmic vehicles for
ocular delivery of pilocarpine nitrate and tropicamide, J. Control. Release. 102 (2005)23-
38.
75. M.G. Lancina III, S. Singh, U.B. Kompella, S. Husain, H. Yang, Fast Dissolving
DendrimerNanofiber Mats as Alternative to Eye Drops for More Efficient Antiglaucoma
Drug Delivery, ACS. Biomater. Sci. Eng. 3 (2017) 1861–1868.
76. Anton N, Benoit JP, Saulnier P. Design and production of nanoparticles formulated from
nano-emulsion templates-a review. J Control Release 2008; 128(3): 185-99.
77. Ammar HO, Salama HA, Ghorab M, Mahmoud AA. Development of dorzolamide
hydrochloride in situ gel nanoemulsion for ocular delivery. Drug Dev Ind Pharm 2010;
36(11): 1330-9.
78. Mahboobian MM, Seyfoddin A, Aboofazeli R, Foroutan SM, Rupenthal ID.
Brinzolamide-loaded nanoemulsions: ex vivo transcorneal permeation, cell viability and
ocular irritation tests. Pharm Dev Technol 2019; 24(5): 600-6.
79. Shah J, Nair AB, Jacob S. Nanoemulsion based vehicle for effective ocular delivery of
moxifloxacin using experimental design and pharmacokinetic study in rabbits.
Pharmaceutics 2019; 11(5): 230.
80. G. Soni, K.S. Yadav, Nanogels as potential nanomedicine carrier for treatment of cancer:
A mini review of the state of the art, Saudi. Pharm. J. 24 (2016) 133-139. Doi:
10.1016/j.jsps.2014.04.001
81. H. Almeida, M.H. Amaral, P. Lobao, J.M.S. Lobo, In-situ gelling systems: a strategy to
improve the bioavailability of ophthalmic pharmaceutical formulations, Drug Discov
Today, 19(2014), 400-412.