A Mini-Review On New Developments in Nanocarriers and Polymers For Ophthalmic Drug Delivery Strategies

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Current Drug Delivery, XXXX, XX, 000-000 1
MINI-REVIEW ARTICLE
A Mini-review on New Developments in Nanocarriers and Polymers for

Ophthalmic Drug Delivery Strategies
Yash Sharma1, Preeti Patel2 and Balak Das Kurmi3,*
1
Department of Pharmaceutical Quality Assurance, ISF College Pharmacy, GT Road, Moga-142001, Punjab, India;
2
Department of Pharmaceutical Chemistry, ISF College Pharmacy, GT Road, Moga-142001, Punjab, India;
3
Department of Pharmaceutics, ISF College Pharmacy, GT Road, Moga-142001, Punjab, India
Abstract: The eye is an important and vital organ of the human body consisting of two segments - ante-
rior and posterior segments and these segments are associated with many diseases. This review elabo-
rates upon the various eye-related diseases with their medications and carriers used to deliver them.
Delivery strategies include drugs encapsulated into liposomes, polymeric micelles of drugs, solid lipid
nanoparticles, nanostructured lipid carriers, nano emulsions, and Nanosuspension used to improve pene-
trating properties, bioavailability, and residence time of the drugs as examples available in the literature.
ARTICLE HISTORY
With regard to this, different forms of ocular drug delivery are classified and elaborated. Additionally,
the possibility of addressing the physical and chemical complexities of ocular diseases and how they
could be overcome with environmentally stable nanoformulations are briefly discussed. Enhanced drug
Received: November 01, 2022
Revised: February 20, 2023 delivery efficiency with various novel pharmaceuticals along with enhanced uptake by different
Accepted: March 13, 2023 routes/modes of drug administration. Current advancements in drug carrier systems, i.e., nanocarriers,
DOI: have shown promise for improving the retention time, drug permeation and prolonging the duration of
10.2174/1567201820666230504115446
release of the drug in the ocular site. Bio-degradable polymers investigated for the preparation of
nanocarriers for the entrapment of drugs and to enhance the efficacy through improved adherence of
tissue in the eye, sustained release measures, enhanced bioavailability, lower toxicity, and targeted de-
livery is applicable. This review covers the introduction of various nanocarriers and polymers for ocular
drug delivery with the purpose of enhancing the absorption, retention and bioavailability of medications
in the eye.
Keywords: Ocular drug delivery, biodegradable polymers, nanocarriers, hydrogel, liposomes, nano emulsions, ophthalmology.
1. INTRODUCTION Simultaneously, proper absorption of the drug into the eye

required improved contact time and corneal penetration [5].
The eye is a very sensitive and vital part of our body that
As the third layer of the eye consist of the hydrophilic corne-
promotes the visual system [1]. Many problems are associat- al sheet (stroma) and the corneal epithelium, which act as
ed with drug administration and penetration in the eye; there-
both the barricade for the administration of the drug and the
fore, to increase the topical bioavailability with in the corne-
penetration site for the enhanced delivery of the drug, some
al site, different penetration enhancers and polymers are used
globally spread ocular diseases like glaucoma, cataract, dry
and suggested in the literature [2]. As Ophthalmology is the
eye disease, corneal infections, etc. required the development
root of pharmaceutical sciences which concern with anatom-
of new drug delivery with various drugs to overcome ocular
ical structure and various diseases associated with the func- routes associated problems as the no. of ocular diseases are
tioning of the eye in which, ophthalmic drug delivery could
increasing simultaneously with an increasing population [6,
be considered as very interesting as well as challenging task
7]. To overcome such diseases, different form of ocular de-
for it [3]. Therefore, keeping an eye on to various diseases,
livery of drug is used and one of them is encapsulation of
different formulation parameters are considered for ophthal-
polymers in the formulation in order to increase the contact
mic preparations and their routes for administration of drug
time of drug in the cul-de-sac of the eye which ensures the
delivery with respect to increasing the retention time and better absorbance of drug. Molecular properties of polymers
pharmacokinetics of the drug [4]. The physio-chemical char-
are firstly identified by Hermann Staudinger in 1922, in
acteristics of the drug affect the different absorption path-
which he explained that the polymer has long chains of at-
ways for the permeation of typical drug molecules.
oms bonded by the covalent bond. He explained some of the
significance of polymers, including absorption enhancers,
*Address correspondence to this author at the Department of Pharmaceutics, biodegradation, gelling properties, ocular absorption, vis-
ISF College of Pharmacy, GT Road, Moga-142001, Punjab, India; cosity enhancer, and prolonged drug release [4]. Polymers
Tel: +91-9754275553; E-mail: bdkurmi@gmail.com are commonly employed in the manufacture of healthcare
1567-2018/XX $65.00+.00 © XXXX Bentham Science Publishers

2 Current Drug Delivery, XXXX, Vol. XX, No. XX Sharma et al.
and pharmaceutical goods. These polymers combined to the drug from the eye and reduces drugs bioavailability. Af-
make stable formulations that are also available in national ter the cornea, light passes along the iris, which manages the
and international markets. Likewise, Sol to gel-forming ocu- light passing through it. The visible shape of the iris, which
lar drug delivery made of different polymers that manifest ranges in size from 11 mm to 13 mm, is controlled by how
improvable phase transformation (sol-gel) and the pseudo- transparent the cornea is [17]. In general, the iris has a coni-
plastic behavioral change is another method to avoid the cal form, and the anterior and posterior are the layers of the
issues associated with the use of conventional eye drops. iris. In a healthy eye, a discontinuity in the anterior layer
This method also benefits in minimizing the blinking inter- allows the viewer to see the posterior layer, which is mani-
ference. With regards to the in situ gel, various advantages fested by crypts in the iris' periphery and a distinct texture in
are associated, such as prolonged and sustained activity the portion of the iris closest to the pupil [18]. The pupillary
when compared to traditional drug-delivery systems [8]. sphincter can be seen as a bright pinkish band close to the
While the synthesis of novel polymers to attain desired func- pupil, behind the posterior layer, in lighter eyes. The dilator
tionalities is conceivable, the substantial safety testing re- cannot be seen because so much of the posterior stroma is
quired for such materials is generally a limiting hurdle to transparent and colorless, and it is actually because so much
their usage in new therapeutic products [9]. Considering the of the posterior stroma is transparent and colorless, and it is
time and money required to gain FDA clearance when a new actually floating freely within it [15]. The ciliary body is
ingredient is to be applied, polymer blends offer an attractive present behind the iris. The choroid is a highly specialized
alternative approach through which to handle various formu- structure and performs different functions [19]. It is a part of
lations and drug delivery difficulties along with drug deliv- uvea. It helps in producing aqueous humor in the ciliary
ery options are discussed and summarized in this review body [20], and the accumulation of aqueous humor in the eye
article, i.e., solutions, emulations, suspensions, in situ gelling increases intra-ocular pressure, which results in glaucoma
system, hydrogel, ointments [10]. and vision loss. The ciliary body consists of ciliary muscles;
when you focus on a near object, the ciliary muscle changes
2. ANATOMICAL AND PHYSIOLOGICAL ASPECTS the shape of the lens. Blood veins that supply and drain the
OF THE EYE
capillary bed make up the loose connective tissue and thick
The human eye is the visual system and highly differenti- melanin pigment that make up the choroidal stroma. the pri-
ated organ having three primary layers [11]. Fibrous tunic is mary means of delivering retinal photoreceptors to a section
the external part of the eye consisting of the sclera and cor- of the choroid [21]. The ciliary body holds the lens of the eye
nea; the center part is the vascular tunic consisting of the in place behind the pupil. Pupil is the round aperture in the
ciliary body, iris, choroid, and retina, forming the neural center of the iris. The iris opening is where light comes be-
layer, which is the anterior eye part [12]. Aqueous humor fore reaching the lens, which focuses on the retina [22]. The
and Vitreous body are surrounded by these coats [13]. A amount of light exposed to the pupil will change the size of
schematic representation of the anatomical view of the eye is the pupil [18]. The width of the pupil is regulated by two
presented in Fig. (1). different iris muscles., Radial dilator pupillae, which dilates
the pupil upon contraction, and Circular sphincter pupillae,
Sclera is formed by the connective tissue (fibroblasts), which constricts the pupil upon contraction. There is a trans-
which is the strong protective external coat of the eye, and it
parent structure present behind the pupil called the lens.
consists of a human eyeball associated with 85% of the outer
Some Elements of the lens are unusual proteins and crystal-
tunic. It helps to maintain the shape and structure of the eye
lin’s (these are the most stable molecules but can be altered
and also balances the intra-ocular pressure with in the eye
by light absorption and the chemical environment) [23]. The
[14]. Thickness of the sclera varies from the anatomical posi-
refractive index of the lens varies from one part of the lens to
tion, i.e., decreasing from the posterior pole to the equator another. As age increases, the thickness and curvature of the
(1-1.3 mm to 0.5 mm respectively), before increasing per-
lens increase except for the lens power. Cataracts and pres-
ilimbal sclera (0.8 mm) again [15]. The constitution of the
byopia are some age-related disorders [24]. The lens work
sclera is similar to other connective tissues in being a priority
jointly with the cornea to focus the light correctly on the
scaffold of fibrous collagen in a hydrated interfibrillar matrix
retina. Retina surrounds the vitreous cavity and covers the
of proteoglycans and glycoproteins. As per metabolic per-
inner surface of the eye [25]. Retina is protected as sur-
spective, the sclera shows little cellularity with temporary rounded by cornea and sclera. The six main kinds of neurons
increase manifest in response to pathology or physical afront.
that make up the neural retina are amacrine cells, photore-
Along with the sclera, the cornea makes up the outer tunic of
ceptors, bipolar cells, horizontal cells, and ganglion cells
the eye. Cornea is a transparent avascular tissue, and several
[26]. The Müllerian glia serves as the structural support sys-
elements, including corneal epithelium, stroma (lamellar
tem for the neural retina. Rods and cones are the two differ-
arrangement of collagen fibers in stroma outcomes in a
ent types of photoreceptors found in the eyes of most verte-
falloff in the retention time of the drug administrated into the brates [27]. Color vision is controlled by cones, which con-
eye), corneal endothelium (strictly regulated hydration of
tain pigments with absorption maxima in the blue, green, or
normal cornea) and corneal avascularity, all contribute to its
yellow regions of the spectrum [28]. The blue-green region
transparency [16]. The cornea is comprised of 5 different
of the spectrum is where the rod pigments' absorption peak is
layers, notably the corneal epithelium, bowman’s layer,
located. Rods do not contribute to color perception and are
stroma, Descemet’s membrane, and endothelium [15]. Cor-
active in low light conditions [29]. After that overlying the
neal epithelial defends the eye from physical, chemical and retina, the vitreous humor is in contact with the vitreous
biological barriers. Maybe due to this, topical administration
membrane. Allowing light to penetrate the retina and main-
of drug like eyedrops become a hurdle; it causes drainage of
taining the structure of the eyeball are the main purposes of
A Mini-review on New Developments in Nanocarriers and Polymers Current Drug Delivery, XXXX, Vol. XX, No. XX 3
Fig. (1). Anatomical structure of the Eye. Many elements of the eye operate with each other to bring things into focus and deliver visual data
to your brain. Several injuries and diseases can cause alterations in eyesight. Some disorders can lead to irreversible visual loss. To maintain
your eyes healthy, have regular eye checkups and stay healthy generally. (A higher resolution / colour version of this figure is available in the
electronic copy of the article).
the vitreous. Collagen and Hyaluronic acid are its primary ocular symptoms of SS can be severe and vision-threatening.
component. Vitreous cortex is the external layer of vitreous Along with these other conditions, SS can cause optic neuri-
which surrounds the structure of the eye. Various reports tis, uveitis, scleritis, retinal vasculitis, and corneal melt/per-
also shown that the vitreous changes with age [30]. foration [36]. The absence of domains evaluating dry eye-
related visual impairment is a significant issue with the SS
3. DISEASE STATES disease activity measurement tools that are now on the mar-
Many eyes related problems have been discussed below, ket [37].
and conventional route for ocular eye drops is shown in Fig.
3.3. Ultraviolet Radiations Oxidative Stress Affecting Eye
(2), and the barriers associated with the administration of the
drug are shown in Fig. (3); also, the benefits and Challenges From the sun when electromagnetic radiation reaches the
regarding the routes of administration for ocular drug deliv- retina, and the radiant energy is converted into impact by
ery is mentioned in Table 1. phototransduction in retinal photoreceptors in the visible
spectrum. The compound interaction between the eye and the
3.1. Thyroid Eye Disease brain (structurally and functionally) depends upon the poten-
It is an autoimmune condition called thyroid eye disease tial to convert electromagnetic radiation into usable visual
(TED) which permanently disfigures the patient's face, data. When the electromagnetic radiation is absorbed on the
which has a bad effect on their daily lifestyle and ability to retina, it shows its Particle Nature.
carry out daily tasks [31]. The condition frequently manifests
3.4. Photokeratitis
unexpectedly, causing a deluge of endocrine and ocular
symptoms that interfere with daily life. An overactive thy- Excessive exposure to UV rays can affect the cornea and
roid gland (also known as Graves' disease) is frequently conjunctiva [25]. Constricted pupils, intense tears, eyelid
linked to TED but is not the actual cause of the condition twitching, and acute pain are some temporary symptoms
[32]. Hypothyroidism, euthyroidism, and, less frequently, [38].
Hashimoto's thyroiditis are other autoimmune thyroid disor-
ders in which it can also manifest. Inflammation and immune 3.5. Cataract
cells invading orbital tissues are signs of active TED (for A cataract is a blurring of the lens in the eye. At elder
example, by T-lymphocytes, mast cells, and B-lymphocytes) age, this may cause the loss of vision. People suffering from
[33]. diabetes can suffer from clouding in the lens. A cataract is
the most common reason behind the blindness. Poor vision,
3.2. Sjogren’s Syndrome (SS)
blurred vision, multiple images, and color looking faded are
About four million Americans suffer from Sjogren’s syn- some symptoms [28].
drome (SS), an autoimmune disorder [34]. Although approx-
imately one in ten individuals with clinically aqueous defi- 3.6. Macular Degeneration
ciency dried eye has basic SS, widespread unnoticed SS Damage to the retina of the eye caused due to the loss of
causes significant misdiagnosed, delays in detection, and muscle mass and blurs your central vision.
subsequently higher anguish and death [35]. Extra glandular
Fig. (2). Potential methods of delivery of drugs to the retina via systemic application eye drop is the most accessible and patient compliance
method of medication administration, especially in the treatment of periapical illnesses. In order to get to the posterior segment of the eye, the
drugs will: (a) Penetrate the conjunctiva to the aqueous chamber, therefore the lens and iris to the vitreous, and ultimately the retina. It is
challenging to get the chemical to the retina using this channel, (b) Diffuse until they reach the retina after passing through the cornea, sclera,
and choroid, (c) Diffuse from the cornea to the conjunctiva in a horizontal direction, (d) To stop medications from entering the systemic
circulation from the eye, pass them through the nasolacrimal drainage, the conjunctival blood vessels, or the choroidal circulation. (A higher
resolution / colour version of this figure is available in the electronic copy of the article).
Fig. (3). Different routes of ocular administrations. Ocular medication distribution is complicated, attributed to the prevalence of physiologi-
cal and anatomic barriers. These barriers can alter drug entrance into the eye following numerous modes of delivery (e.g., topical, systemic,
and injectable) (e.g., topical, systemic, and injectable). Priority is given in the form of drops is, favored for treating periapical illnesses since it
is straightforward and offers local delivery of medications. Major issues with topical administration include poor medication uptake and low
bioavailability. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
Table 1. Benefits regarding routes of administration and facing challenges during ocular delivery.
Route Benefits Challenges References
Eye drops administered Self-administrable, non-invasive, and high patient Higher tear production and turnover, corneal protection,
[57]
topically compliance efflux pumps, and bioavailability (BA) of not more than 5%
Administered systemat- Blood-aqueous barrier (BAB), blood-retinal barrier

Compliance with patient [57]
ically/orally (BRB), hazardous dose, BA 2%
Direct administration avoids BRB, and maintains cataracts, endophthalmitis, intraocular damage, hemor-
Intravitreal [57]
drug levels in the posterior area (vitreous and retina). rhage, retinal detachment, and patient compliance
increases medication levels in the anterior chamber,

does away with topical drops, and lessens systemic TECCDS (toxic endothelial cell destruction syndrome)
Intracameral [58]
and corneal side effects associated with topical ster- and TASS (toxic anterior segment syndrome)
oid therapy.
delivery of depot formulations to the upper and Conjunctival and retina, trans scleral dispersion of the
Subconjunctival [59]
lower segments. medication
3.7. Meibomian Gland Dysfunction tion, and upregulation of proinflammatory cytokines have all
been linked to long-term topical glaucoma medication [46].
When the meibomian gland blocks, it becomes difficult In both animal and human models, a sizable loss of goblet
to secrete enough oil into the tears, which results in faster cells was seen, which can result in dry eye, inflammation,
evaporation of tears. It is amalgamated with blepharitis (a and fibrosis [47].
problem in the eyelid). It may be the cause of dry eye syn-
drome with symptoms like red eyes, grittiness, and itchy 3.10. Dry Eye Disease (DED)
eyes.
It is the most common ocular-related problem; dry eye
3.8. Diabetic And Retinal Vascular Eye Disease disease (DED) affects tens of millions of people worldwide
[48]. Aqueous tear-deficient dry eye (ADDE), which is char-
When retinal capillaries are exposed to high blood sugar acterized by ineffective or failure of the lacrimal glands to
levels for an extended period of time, diabetic retinopathy generate tears, and evaporative dry eye (EDE), which is of-
develops [39]. Although the pathogenesis is still poorly un- ten linked to extra evaporation of the tear fluid, are the two
derstood, it is believed to involve a number of biochemical main subtypes of DED [49]. A number of risk factors, in-
processes, such as an increase in inflammatory oxidative cluding individual, environmental, clinical disorders, drugs,
stress, protein kinase C pathways and advanced glycation and ocular variables, have been related to DED [50]. DED is
end products [40]. Pericyte loss, thickening of the basement more prevalent after menopause and is more likely to affect
membrane, and endothelial damage are the overall effects. women. Dry eye symptoms can be made worse by using
Capillary occlusion and retinal ischemia develop as a result estrogen alone or in combination with progestin, while tes-
of retinal capillary deterioration over time [41]. Furthermore, tosterone therapy relieves these symptoms [51]. Dry eye
retinal edema and serum leaks are brought on by the endo- illness is noticed with the rising amount in patients with au-
thelial barrier being impaired. VEGF, which promotes intra- toimmune, which afflicts around 8 percent of the communi-
ocular neovascularization in late-stage retinopathy, is pro- ty, of whom 78 percent are women. Dry eye disease also
duced by ischemic retinal tissue in the eye. High intraocular impacts postmenopausal women as well as the elderly [52].
pressure and vision loss can result from these aberrant blood Dry eye illness is the most commonly developed diagnosis in
vessels, which are brittle and prone to bleeding inside the eye ophthalmology. In Germany, one in five cases visited an eye
[42]. specialist for the indications of dry eye. Moreover, diurnal
3.9. Glaucoma fluctuations in the kind and degree of symptoms can occur
[53].
The most common reason for irreversible blindness is
glaucoma, which is a multifactorial, developed neurological Tears aid in maintaining the condition of the corneal sur-
disease. Glaucoma is known by the cupping of the optic disc, face in addition to creating a smooth, focused surface for
weakening of the nerve fiber of the retinal layer, and the dis- optimal vision [54]. Tears generate a stratified gradient fluid
appearance of retinal ganglion cells (RGCs) [43]. There are coating over the cornea that serves to preserve the cornea
several different types of glaucoma, each with unique clini- and lubricate eye mechanics. The outer layer is a lipid coat-
cal characteristics, risk factors, and interconnected mecha- ing that is produced by tiny glands, termed meibomian
nisms [44]. The most crucial step in stopping future damage glands (MGs), along the lower and upper eyelids during the
to the optic disc is lowering intraocular pressure (IOP), as blinking process and closes the tear film to prevent tear
long-term topical therapy poses a constant risk to the homeo- evaporation [55]. The intermediate aqueous layer, compris-
stasis of the ocular surface [45]. Conjunctival epithelium ing water, soluble mucins, and other proteins, represents 90
squamous metaplasia, reduced goblet cell density, meibomi- percent of the tear film volume and permits tear spreading;
an gland dysfunction, conjunctival and corneal desquama- this layer is developed by the lacrimal and auxiliary lacrimal
Table 2. Some drugs used in ophthalmic diseases.
S.No. Disease Drugs and Their Associated Mechanism of Action References
Doxycycline (matrix metalloproteases (MMPs) have a critical role in the breakdown of basement
membranes and the proliferation of ECM. Increased production of MMP-2 and MMP-9 happens in
Corneal neovasculariza- CNV. Therefore, Doxycycline inhibits MMPs through a variety of ways, such as transcriptional
1. [62]
tion (CNV) inhibition 5, direct cause on the post-translational level by coordinating with the catalytic site 4, and
indirect cause by affecting endogenous inhibitors) and β-cyclodextrin (HP-b-CD (increase the stabil-
ity of doxycycline in aq. Solution)
Nifedipine (Nifedipine might prevent endothelin-1's vasoconstrictor effect from causing the smooth
2. Glaucoma muscles in the eyes to dilate, which lowers intraocular pressure, it is advantageous to use it to treat [60]
excessive IOP).
Levocarnitine (stimulates the restoration of the integrity and thickness of the central corneal epitheli-
um, as well as the pathological morphology and structure of the tissues of the lacrimal gland and
3. Dry eye [61]
cornea. As well as encouraging conjunctival goblet cell growth. Matrix metalloproteinase MMP-3
and MMP-9 expression levels in corneal epithelial cells are downregulated.)
4. Eye infection (fungal) Fluconazole [62]
Cyclosporine (The anti-inflammatory of choice for treating DED, especially in severe instances, is
5. Dry eye disease (DED) Cyclosporine; it is safe for long-term usage without the side effects typically associated with cortico- [63]
steroids.)
Lutein (Lutein is a type of antioxidant that may quench singlet oxygen and remove free radicals,
protecting the retina from the harm caused by oxidative stress. Additionally, lutein can block the
Age-related Macular
6. retina-damaging blue and ultraviolet radiation. Lutein can be used in the management of AMD in a [64]
degeneration (AMD)
number of methods, including by lowering Reactive oxygen species, raising the macular pigment's
optical density, and lowering the amount of damaging light that reaches the retina.)
choroidal neovasculariza- Nepafenac (Nepafenac, also known as 2- amino-3-benzoylbenzeneacetamide, is a nonsteroidal anti-

7. [65]
tion inflammatory medication (NSAID) with COX-1 and COX-2 inhibitor properties.)
Ciprofloxacin (Broad-spectrum fluoroquinolone antibiotic ciprofloxacin is active against Gram-

positive and Gram-negative aerobic bacteria. As a result, it works well to treat a range of bacterial
8. Bacterial endophthalmitis [66]
eye infections. It treats a variety of bacterial eye diseases, including corneal keratitis, endophthalmi-
tis, bacterial and allergic conjunctivitis, and many more.)
glands. The innermost mucous layer, made comprised of solution or suspension form) is to maintain high local con-
membrane-adherent mucins, comes into contact with the centrations for an extended length of time, which outcome in
corneal epithelial cells [56]. With respect to time, this dis- shallow bioavailability (BA), and the instability of the dis-
ease may become severe and can lead to vision loss. There- solved medication are some of its intrinsic drawbacks. Toxic
fore, the management of such a disease is mandatory. Medi- effects might result from additional chemicals like preserva-
cation for all the mentioned above diseases is shown in Table tives [68]. The majority of eye preparations are made up of
2. aqueous medium, buffers, different additives, emulsifiers,
suspending agents, solvents and cosolvents, isotonicity mod-
4. VARIOUS FORMS OF OCULAR DRUG DELIVERY ifiers, preservatives, etc. By increasing the viscosity of the
solution, such as by adding viscosity enhancers such as pol-
Most of the eye-associated disorders are treated through yvinyl acetate or methylcellulose, or by increasing the num-
the topical application of standard preparations solutions,
ber of hydrogen ions, the retention period of solutions in the
suspension, and ointments. These typical preparations have a
eye can be enhanced. Drug wastage from the eye can be de-
less therapeutic impact due to lachrymal drainage and low
creased by either punctual occlusion or by shutting the eye-
penetration. Therefore, formulation researchers are constant-
lids following solution instillation. By using these tech-
ly studying the role of various delivery of drugs, as shown in
niques, systemic absorption is decreased while the interac-
Fig. (4), to optimize the therapeutic efficacy of medications tion time between the medication and tissues is increased
supplied through the eyes.
[69].
4.1. Solutions
4.2. Ointments
Typically, eye drops are delivered intravenously or di-
Ophthalmic ointments are sterile, homogenous formula-
rectly to the eye's surface in pharmaceutical form. They don't
tions that are semi-solid and meant to be applied to the eye
seem to hamper eyesight and are both less costly and simple
[70]. The four different kinds of the ointments-oleaginous
to use [67]. The difficulty in such formulations (eye drops in
Fig. (4). Schematic depiction of different Nano-carriers and their focused ability. The penetration of nanotechnology over the ocular mem-
brane on topical treatment for eye disease treatment. The symbols next to the nanoparticles in each of the eye's levels indicate the targeting or
penetration capabilities of the particular nanocarriers. (A higher resolution / colour version of this figure is available in the electronic copy of
the article).
base, absorption base, water-removable base, and water- change in environmental conditions [75]. The function of gel
soluble base-are discussed. As compared to eye drops, this formation is enhanced by warmth, ions, and solvent [75].
formulation reduces the drug's wastage through the flow of The gelling system should influence the features like stubby
tears and lengthens the surface time residence to extend cor- viscosity, free-flowing fluid that permits repeatable delivery
neal residence time [71]. Most of the time, Semisolid paraf- within the eye as solution form, i.e., drops and phase separa-
fin or white petrolatum makes up the majority of ointments tion just robust to endure the pressures in the cul-de-sac and
and may be extracted using organic solvents while also being confirm longer retention periods in the eye [76]. The ther-
heated to the white petrolatum's melting point [72]. This pro- mally sensitive gel forming technique for the efficient ad-
cess is simple, efficient, and dependable. It may take many ministration of the medication uses Pluronic polymers. The
extraction cycles to get consistent results because it is chal- formation of an appealing formulation that transforms into a
lenging to extract the medication from oleaginous ointments transparent polymeric gel inside the body at physiological
[73]. temperature using the 20% solution of Pluronic F127 is
achieved [77]. Many antibiotics were explored in gelling
4.3. In situ Gel systems over the two decades to promote treatment adher-
These gels are viscous liquids that exhibit the capability ence by extending and controlling the release of drugs, de-
to go sol-to-gel phase change when impacted by outside var- laying corneal contact and enhancing ocular absorption. Dif-
iables, including the right pH, temperature, and in ionic ferent in situ gelling strategies are applied in ocular drug
form, as displayed in Fig. (5) [74]. This characteristic effect administration as that of the thermosensitive, the ion-
of the in situ gel slows medication drainage from the plane of activated and the pH-sensitive gelling system. Different ex-
the eye and increases the pharmacokinetics of the active cipients are employed in the manufacture of in-gelling sys-
component [69]. Examples of possible ocular droppable gels tems in situ in order to adjust the mucoadhesion forces and
mentioned in the review include those that gel when there is the fluidity of the formulation. HPMC is a viscosity booster
a switch in pH, such as CAP latex cross-linked polyacrylic mainly applied in gel form. The mixture of alginate as a sol-
acid and derivatives, such as carbomers and polycarbophil, gel agent and HPMC with gatifloxacin revealed a greater
when the transition takes place by a change in the state of effect than alginate itself. The mixture is utilized as an in situ
temperature, such as poloxamers, methylcellulose, and Smart forming method to promote adherence of patients and boost
Hydrogel, and transition take place when there is a change in ocular bioavailability [78].
the ionic strength, such as Gelrite and alginate [69]. Also, in
4.4. Emulsions and Nano-Emulsion
situ generating hydrogels are the polymerization solutions
supplied in the form of fluid implants. This illustrates the The solubility and bioavailability of the encapsulated
phase transformation in the cul-de-sac of the eye and results pharmaceuticals are the two factors by which emulsion for-
in the creation of a gel, which serves to offer a reaction to the mulations aim to improve. Two forms of emulsions-oil-in-
Fig. (5). In situ gelling mechanism. Sol-to-gel phase change takes place when there is a change in the environmental condition. (A higher
resolution / colour version of this figure is available in the electronic copy of the article).
water (O/W] and water-in-oil (W/O), are the foundation of ered to be in vitro biocompatible with the produced
the main formulating process that produces this design. O/W nanoemulsion, and as a result, the author found that G/W
emulsions are preferred over W/O emulsions for use in the (gel in water) nanoemulsions have the ability to deliver topi-
administration of medications to ocular tissues, primarily due cal medications with the highest therapeutic efficacy in the
to their positive properties, like slight irritation of the target posterior eye segment [82].
tissues and enhanced eye tolerance to O/W emulsions [79].
The water-insoluble medication is solubilized in the internal 4.5. Advantages
oil phase of the oil-in-water emulsion and rests in the desira- Simultaneously improve and enhance the bioavailability
ble solution state. By maintaining the medication in solution, of drug, therefore lowering dosing frequency. The presence
the problem of possible absorption due to the slow break- of a surfactant and co-surfactant improves the ocular mem-
down of solid drug particles are not used. Additionally, the brane permeability. Clear, stable polycrystalline with a parti-
water in the exterior phase reduces the amount of eyesight cle size of 100 nm.
blur brought on by oils. Additionally, the medication concen-
tration in the oil phase may be changed to enhance thermo- 4.6. Disadvantages
dynamic activity, improving drug penetration [80]. Because Stabilization of microdroplets demands considerable
of the smaller particle diameter and a larger surface area concentrations of surfactant and co-surfactant so possibilities
when compared to traditional emulsifiers, Nanoemulsions of eye irritation.
(NE) are frequently more stable and permeable. They are
formed up of drops that have the size of a nanometer which 4.7. Suspension and Nano-Suspension
are stabilized by emulsifiers, as shown in Fig. (6). Due to Ocular suspensions are insoluble drugs that finely divide
their intrinsic antibacterial activities, ability to increase drug and are suspended in an aqueous medium with solubilizing
solubility, stability, and bioavailability, the possibility for and dispersion agents. The precorneal cavity maintains drug
part of the body and cellular targeting, ability to aim bio- particles in suspension, extending the time that the drug is in
films, and potentials to overcome antibiotic resistance, NE contact with the eye. The medicine's bioavailability is ulti-
has already been considered as a potential method of antibac- mately influenced by the drug's particle size, which regulates
terial delivery. Also studied were essential oil-based NEs how rapidly the molecules of the drug are absorbed in corne-
without pharmacological payloads that can exert antibacterial tissue [83]. Chemically, these pharmaceutical forms are
al effects primarily through physical or biological processes. characterized as drug dispersions made by a hydrophilic sol-
We also discuss drug-loaded NE, which increases the vent that contains a dispersion agent or suspension to devel-
strength of already-existing antibiotics to improve antibacte- op a final saturated solution. Precorneal tissue absorbs the
rial efficacy. We emphasize NE's adaptability to be adminis- suspension's particles, increasing the amount of time the
tered via a variety of different methods [81]. medicine is in contact with the tissues and the amount of
For a viable alternative for treating disorders of the poste- time it is therapeutically active [84]. Corticosteroids are fre-
rior ocular region, nano gel emulsion was developed as a quently used to treat the sight-threatening consequence of
safe delivery. The PDI (polydispersity index) and particle macular edema brought on by noninfectious uveitis. For pa-
sizes of the monodispersed nano gel emulsion were roughly tients who have non-infectious uveitis-related macular ede-
0.2 and 200 nm, accordingly. The zeta potential having -8.1 ma, triamcinolone acetonide injection suspension for supra-
mV indicated that the nanoparticles had better stability and choroidal usage (XipereTM) is an alternate therapy option.
retinal permeability. Hepatocytes and HUVECs were discov- The FDA has approved an injectable suspension of triamcin-
Fig. (6). Schematic Representation showing Tear film stabilization by NEs via the inhibition of nasolacrimal production and tear outflow and
NE also disperse by the epithelium of the corneal via the paracellular pathway and through the transcellular route. (A higher resolution / col-
our version of this figure is available in the electronic copy of the article).
olone acetonide for use in the suprachoroidal region. The 4.10. Liposomes
suprachoroidal region is the physiological void that exists
between the choroid and the sclera. Studies with quasi- The microscopic vesicles known as liposomes are made
uveitis-associated macular edema have revealed improve- up of one or more lipid bilayers that are concentric and are
ment in sight and irritation with a suprachoroidal infusion of surrounded by water or aqueous buffer compartments [86].
triamcinolone. Head-to-head trials are necessary for further The likelihood of ocular absorption of the drug is increased
evaluation of the effectiveness and safety of this innovative by liposomes' capacity to make strong interactions with the
delivery technique, which raises the likelihood that it may conjunctival and corneal surfaces [87]. A drug's poor absorp-
lessen anterior segments exposed side effects like glaucoma tion, low diffusion coefficient, poor solubility, or medium to
and cataract. Furthermore, there are active prospective trials high molecular weight are all factors that make this capabil-
that show promise for using the suprachoroidal region to ity particularly desirable [88]. These carriers' biocompatibil-
treat ocular malignancies, diabetic macular edema, and mac- ity, biodegradability, amphiphilic characteristics, and relative
ular degeneration [85]. toxicity have been highlighted as benefits [89]. It is also un-
derlined that their stability is lower than that of therapeutic
4.8. Advantage systems that utilize polymers and that the amount of medi-
cine that may be included in them is constrained [90]. In
Colloidal dispersion technique of water-insoluble medi-
addition, it is costly and technically challenging to produce
cations in a dispersion medium which would be remained
them on a wide scale. Their usage in ocular pharmaceutical
stable by surfactant and polymeric materials to size ranging
formulations enhances the absorption of the materials that
from 10 nm to 1000 nm, tends to increase solubility, thus
working to improve the absorption of eye medications. It are produced and protects them from enzymes that reside on
the site of the corneal endothelium [91]. It should be men-
also enhances the permanent resident moment in the cul-de-
tioned that the efficacy of liposomes in delivering the active
sac and enriches the release of drugs owing to its possibility
component depends on a variety of parameters, such as en-
to enhance the intrinsic consistency of poorly water-soluble
capsulation efficiency, liposome size and charge, durability
prescription drugs in the lacrimal fluid.
of liposomes in anterior chamber, or affinity to ocular sur-
4.9. Disadvantages face. The nature of liposomes as an eye medication delivery
mechanism has discovered to be, in part, attributable to their
Physical stability, deposition.
zeta potential. Ionized liposomes appear to preferred trapped
at the opposite charges corneal surface as comparison with are built of reusable block copolymers, in which the hydro-
neutral or charged negatively liposomes [92]. It is droppable, philic element serves as that of the shell and the repellent
harmless, and recyclable in nature. It reduces the potency of component as the building's core. By encapsulating several
the medicine. It gives the sustained drug release and site- medications with low solubility, such as celecoxib, sparflox-
specific administration. Liposomes are tough to generate in acin, cyclosporine, etc., the nanoparticles improve drug solu-
sterile preparation. It has restriction similar medications with bility. The system also benefits from the medication, which
light load and inadequate stability. Likewise, for dry eye has regulated and prolonged release over a longer duration of
disease, Despite being a potentially effective therapeutic time [64].
agent, lactoferrin (LF) has poor water stability and signifi-
cant nasolacrimal duct drainage. In this study, we use the 4.14. Advantage
lipid film approach to insert lactoferrin into hyaluronic acid Particles with a size range generally <400 nm are good
covered liposomes, followed by homogenization under high for ocular usage. Intended medication administration to the
pressure. The average size of LF-loaded liposomes was 90 surface of the eye avoids non-specific dispersion and pro-
nm, and they had a monomodal population, a positive sur- motes therapeutic efficacy. Protects medicine from deteriora-
face charge, and a 53% encapsulation rate for high- tion. Elevates intracellular penetration, therefore enhancing
molecular-weight proteins. The nanocarrier improved bio- medication absorption.
pharmaceutical behavior, and any harmful effects were in-
vestigated in human corneal epithelial. Developed liposomes 4.15. Disadvantages
demonstrated anti-inflammatory activity and the potential to Drugs with low loading and particle agglomeration, burst
restore the symptoms of dry eyes without causing ocular discharge of medicines owing to the large surface area, lack
discomfort. As a result, lactoferrin-loaded liposomes may of scale-up methods, and cytotoxicity issues.
present a novel nanocarrier that is appropriate for the treat-
ment of DED [93]. 4.16. Hydrogel
4.11. Advantage Different sorts of drug delivery systems and procedures

should be developed to prolong the concentration of oph-
Liposomes range is approximately 0.08 to 10.00 mm. It thalmic medications within the front and/or posterior areas of
can incorporate both polar and lipophilic medicines. Bio- them; hydrogels really have excellent therapeutic benefits.
compatible and non-toxic. Increases corneal permeability. Hydrogels are of three types, namely Thermosensitive, pH-
Decreases dosage frequency. sensitive and ion-sensitive, as shown in Table 3, which may
4.12. Disadvantage deliver pharmaceuticals to various action sites via diverse
modes of administration, such as topical management, acces-
Lack of expansion ability owing to its limited stability. sory organs and ocular injection [98]. The interaction of the
Leakage of encapsulated medication. Manufacturing costs medicine on the retina cells is somewhat short (1–2 min)
are extremely high. because of the continual tear generation (0.5–2.2 µL/min)
and tear switching. Hydrogels are able to withstand the
4.13. Micro and Nanoparticulate System
blinking and flush of tears; hence increasing medication res-
Because of decreased bioavailability of the medication ident lifetime on the corneal surface to allow more medica-
via the ocular route, the traditional delivery method has a tions to locally act on mucous membranes or to permeate
larger quantity of drug in the vehicle system. This greater into the deeper corneal surface. Hydrogels not only lengthen
dosage of the medicine may have negative and harmful ef- the drug resident period on the cornea, but they may also
fects on the tissues of the eyes [94]. Beyond toxicity-related sustain the release of pharmaceuticals in the ocular tissue,
difficulties, the old approach can also have low bioavailabil- particularly watery fluid and the retinal cavity [99, 100].
ity problems, which are caused by inadequate corneal per- Aqueous humour is the liquid that is generated by the eyes'
meability, lachrymation, tears evaporation, metabolic, tear ciliary muscle. The formation of the aqueous humour is
protein, etc. The regulated and sustained release of the phar- roughly 2–3 µL/min with a cycle duration of 1.5–2 h [30].
maceuticals is a benefit of nanoparticulate delivery systems, Frequent administration will compromise patient compli-
in which the particles have a size range of 1-200 m [95]. The ance. Hydrogels can deliver a continuous release of medica-
medicine's harmful effects result from the delivery systems' tions in the aqueous humour and create an efficient concen-
continual drug supply to the site of action [79]. The erosion tration [101].
process gradually releases the medication, which is then fol-
lowed by the diffusion process. The systems' polymers ex- 4.17. Solid Lipid Nanoparticles
hibit bio-adhesive qualities that lengthen drug retention and Solid lipid nanoparticles (SLNs) have a particle size
make it easier to transfer the medication to the inner chamber range of 10 nm to 500 nm and are colloidal drug delivery
of the eye [96]. When compared to larger size particulate systems thought up of lipids dispersion in an aqueous surfac-
systems, the smaller particles show improved patient com- tant solution. They are well-suited for hydrophobic drug de-
pliance and greater therapeutic efficacy. For adherence with livery. It has been demonstrated that SLNs have better pene-
the ocular surface, several mucoadhesive microparticles that tration and longer-lasting sustained drug release at the ocular
display delayed medication release over time have been cre- location. They can lessen the toxicity brought on by adminis-
ated [97]. The drug delivery methods in the nano-size range tering a high dose repeatedly [103]. To treat retinal disorders,
are known as nanoparticulate systems, and they include lipo- Ahmed et al. created etoposide-loaded SLNs using a melt
somal and polymeric nanoparticles. Polymeric nanoparticles emulsifying agent and ultrasonication approach [103]. The
Table 3. Polymers used for types of hydrogels.
Type of Hydrogel Polymers Used References
Poly and Pluronic (N-isopropyl acrylamide)

Thermosensitive gel Poly (acrylic acid), polyacrylamide, and [71]
Poloxamer, chitosan, and hydroxyl propyl methyl cellulose are reversible materials.
pH-sensitive gel Acetate and compounds of cellulose Pseudo latex, carbomer, macrogol, and poly methacrylic acid [72]
Ion sensitive gel Alginate sodium, gellan gum (Gelrite) [102)
Fig. (7). Schematic illustration of polymeric micelles entering the transscleral route following topical treatment. (A higher resolution / colour
version of this figure is available in the electronic copy of the article).
synthesized SLNs had a particle size of 239.43 ± 2.35 nm

4.18. Polymeric Micelles
and an entrapment effectiveness of 80.96 ± 2.21%. The de-
veloped formulation demonstrated two phases of drug re- Amphoteric self-assembling nano micelles have a size
lease in the vitreous region-an initial rapid release and a sus- between 10 and 100 nm. In order to provide transparent
tained release for seven days [104]. Reduced toxicity was aqueous formulations, the Nano micelles can dissolve hy-
found in the retina region according to histopathological drophobic medicines in the hydrophobic core, as displayed in
tests. Poor impact strength, drug evacuation via lipid crystal- Fig. (7) [107]. Drugs that are hydrophobic are encapsulated
line structure, and transition of alpha to beta configuration in these polymeric micelles, which can increase medication
upon storing are some of the limitations of SLN-based stability and prevent drug degradation. To treat ocular prob-
nanocarriers. In order to improve medication loading and lems brought on by diabetes, Alvarez-Rivera et al. created
stability, next-generation lipid nanocarriers called lipid na- polymeric nanomicelles containing alpha-lipoic acid in So-
noparticles carriers (NLCs) have been studied [105]. Liquid luplus® [108, 159]. When compared to commercial eye
and solid lipids are combined to create NLCs in a nanoparti- drops, the developed nanomicelles showed a 10-fold increase
cle system. Due to the asymmetric nature of NLCs, the re- in the absorption of alpha lipoic acid and improved corneal
lease of the drug is comparatively sluggish, and drug ejection residence time. In another study, polyvinyl caprolactam-
is inhibited. Due to their lipid composition, efficient drug- polyvinyl acetate-polyethylene glycol was used to make cur-
loading capability, and good stability, NLCs are a great drug- cumin-loaded nanomicelles to treat ocular inflammation
delivery strategy for the posterior area of the eye [106]. [109]. Curcumin solubility, as well as chemical stability,
cellular absorption in vitro, and ocular function in vivo, were gelation process works by the hydrophobic interactions be-
increased in the developed nanomicellesas compared to a tween molecules with methoxy substitution leads to the gela-
free curcumin solution [110]. tion of cellulose solutions. Low temperatures result in less
interaction between polymers because the macromolecules
5. TYPES OF DIFFERENT POLYMERS USED FOR are hydrated. The polymers will slowly lose their hydration
OCULAR DELIVERY as the temperature rises. Relative viscosity declines as a re-
Polymers are utilized to increase the solubility of oph- sult of this circumstance [114].
thalmic procedures. It is essential to produce drug products
5.2. pH-Responsive Polymer
that not only lengthen the vehicle's contact duration with the
corneal surface but also delay the drug's clearance in order to Amazing pH variations throughout the human body
challenge the limits of conventional drug products. Various might help to target therapeutic medicines to a particular
approaches have been devised to optimize the bioavailability organ, tissue, or cell compartment. Due to the significant pH
of ocular medications by prolonging the contact period be- differences, the pH of the aqueous systems and pH-induced
tween the ophthalmic formulations as well as the eye tissues, sol-gel transition changes appear to be the best strategy for
and the addition of polymer induced in the drug is one of the improving the pharmaceutical effectiveness of topical medi-
strategies mentioned in Table 4 and marketed formulations cation administration, particularly for ophthalmic as well as
of the polymer-induced drug are shown in Table 5. intravaginal treatments. pH-sensitive materials include those
polyelectrolytes whose structures contain an acid (carboxylic
5.1. Thermo-responsive Polymer or basic units (ammonium salts) or sulfonic) that receive
Gels that execute sol-gel phase transition induced by a or emit protons in response to environmental pH fluctua-
temperature change are known as thermos-sensitive in situ tions environment. The most popular pH-responsive materi-
gelling systems [111]. Such gels have been extensively ex- als isCS, cellulose phthalate acetate (CAP), PAA, and poly-
plored as temperature-responsive material for invertible carbophil are examples of ophthalmic preparations [115].
thermosensitive gelation at particular temperatures. Some Polymer chain networks that have been crosslinked to-
examples are smart hydrogel and methylcellulose [111]. gether make up pH-sensitive hydrogels, which are encased in
HPMC and poloxamer are two frequently applied excipients a salt solution. A physical phenomenon, either by gel swell-
in the synthesis of in situ gel, mainly for the thermal kind ing or deswelling, will be triggered by a variation in the pH
[112]. The utilization of natural polymers that disturbs the value of the solution enclosing the gel. The physical process
process of transition forms sol to gel form is begun by a is typically not instantaneous; therefore modelling the gel
temperature change is an exciting way to manufacture in situ swelling/deswelling rate aids in our ability to fully compre-
formation. Physiologic temperature with no need for an outer hend the dynamics of the gel [115]. This is crucial for using
heat source other than from the body for gelation is the best hydrogels in controlled drug delivery systems because the
phase transition temp for this type of system. Temperature- drugs are released as the hydrogel swells. The most known
sensitive in situ gels can be categorized as negatively ther- polymers with thixotropic qualities are PAA, which has less
mosensitive, positively thermo-sensitive, and thermal re- viscous and acidic by nature aqueous solutions that become
versible gels [60]. The most often utilized polymer in the gels when the pH is raised. Many ionizable acid units, such
creation of thermosensitive in situ gels is poloxamer (also as carboxylic or sulfonic acid, are found in the architectures
known as Pluronic). Chitosan, xyloglucan, and naturally of pH-sensitive polymers known as poly acids and polyan-
found cellulose derivatives are additional polymers that are ions, including PAA (Carbopol) and poly(methacrylic) acid
frequently employed. The polymer class of cellulose deriva- (PMAA). The carboxylic groups take protons at low pH lev-
tives includes HPMC and MC. A water-soluble three-block els and release ions at high pH values. Because the opposite
copolymer called poloxamer was composed of two polyeth- charges groups on the polymer repel each other electrostati-
ylene oxide and one polypropylene oxide core arranged in an cally when the pH rises, the polymer expands and releases
ABA configuration. Commonly available poloxamer, also the drug molecules into the environment. However, at low
known as Pluronic, has an extended drug residence duration pH values, the pendant carboxylic acid groups are not ion-
and good thermal setting properties. It functions as a solubilized and keep the drug inside of them. In contrast, drug de-
izing and gelling agent. Poloxamer produces a clear, color- livery happens, which results in the ionization of the pendant
less gel. The following describes how poloxamer works: It carboxylic acid groups, which causes the polymer to swell
operates as a viscous liquid at room temperature (25°C), [116].
changing to a translucent gel at higher temperatures (37°C).
It produces a small micellar subunit in solution at low tem- 5.3. Ion Activated Polymer
peratures, and as the temperature rises, the viscosity increas-
When various electrolytes are present, these sorts of pol-
es, causing swelling that results in the formation of a large
ymers can go through a phase change. The tear fluid contains
micellar internetwork [112]. During the phase transition,
a variety of electrolytes that support the sol-gel transition of
HPMC is used as a viscosity enhancer. HPMC is a –semi- some polymers, lengthening the drug's residence duration
synthetic derivative, inert, viscoelastic polymer that is
and boosting its absorption on the ocular surface. Gellan
nonionic harmless, an excellent carrier for absorption of
gum and sodium alginates are two ion-activated polymers
drugs which demonstrates significant swelling capacity.
utilized in ophthalmic formulations the most frequently.
Methylcellulose solutions change into a thick gel around 40-
50°C, whereas HPMC exhibits a phase change around 75-90 Gellan gum (GG) incorporates the utilization of anion
°C. These phase transition temperatures may be decreased by exchange water-soluble polysaccharides generated by the
either physical or chemical adjustments [113]. The HPMC bacteria Sphingomonas elodea that comprises a repeating
Table 4. Some polymer induced drugs.
S.No. Polymer Use Drug Disease References
Carbopol 940-extremely effective rheology

modification capable of producing high
Carbopol-940, HPMC- viscosity and creating dazzling clear gel or Norfloxacin
1. E50LV, HPMC E4M Conjunctivitis [120, 121]
hydro-alcoholic ointments and cream. (pH-triggered)
and HPMC K4M
HPMC - is then used to treat irritation to
the skin caused by diminished tear flow.
HPMC and PVA PVA - They increase strength and are used
(Penetration enhancer – as a water-soluble protective coating as Acetazolamide
2. Glaucoma [121]
EDTA, BAC) well as an ingredient in adhesives and (Ion-activated)
Benzalkonium chloride emulsifiers.
The rapid gelling capacity of alginate per-

Sod. Alginate (mucoad- mits it to enhance the ocular residence Ciprofloxacin hydrochloride Corneal ulcer of ocular
3. hesive polymer) and period and boosts the ocular medication [122]
(PH – triggered) infection
HPMC bioavailability minimizing the demand for
frequent drug administration.
They exhibit amphiphilic behavior because

they are triblock copolymer that is struc- Optimisation and
tured like PEO-PPO-PEO (hydrophobic analysis of Pluronic
Carbopol, sodium hya- Thermoresponsive Diclo-
4. polypropylene oxide-PPO and hydrophilic F127-based ther- [123]
luronate, Pluronic fenac Sodium
polyethylene oxide-PEO). They could moresponsive NSAIDs
extend the time of drug release and provide ocular in situ gels
adequate inertia for eye tissue.
Poloxamer F127 and Drug-controlled release over 8 hours in a Brinzolamide

5. Glaucoma [124]
Carbopol 934P sol-gel at 33.2 1.1°C. (Thermosensitive)
Pluronic (PF-127 and In vivo, testing on rabbits revealed Pluronic Ofloxacin

6. PF-68) and sodium F127 to have 20% (w/w) better retention Bacterial infection [84]
alginate performance than Pluronic F68. (Thermosensitive)
Pluronic F-127 HPMC extended its stay and increased its ocular Ketorolac tromethamine
7. Fungal infection [125]
K4M availability. (Thermosensitive)
Pluronic F127, Pluronic Lomefloxacin

8. F68 and sodium algi- Revealed a sustained release profile of 8 h. Bacterial infection [126]
(Thermosensitive)
nate
Poloxamer 407 and Had better medication retention than the Methazolamide
9. Glaucoma [127]
poloxamer p188 eye drops. (Thermosensitive)
Compared to either the medication solu-

Poloxamer 407 and tions or the market product, a better phar- Dorzolamide hydrochloride
10. Glaucoma [128]
Poloxamer 188 macological effect with a quicker beginning (Thermosensitive)
of action and a longer-lasting effect.
Compared to the generic baicalin artificial

Carbopol 974P with tears, this treatment has good robustness,
11. Baicalin (PH-triggered) Bacterial infection [129]
HPMC E4M ocular absorption, and sustained release of
drugs.
Carbopol and chitosan Displayed a managed release across

Timolol maleate brimoni-
24-hour periods. Brimonidine tartrate's dine
12. Carbopol 974 P and Glaucoma [130]
effectiveness has increased, and its system-
HPMC E4M ic absorption has decreased. (PH-triggered)
(Table 4) contd….
S.No. Polymer Use Drug Disease References
Carbopol 940 combined Gatifloxacin

Supplied sustained release over for an 8-
13. with HPMC and HPMC Conjunctivitis [129]
hour period. (PH-triggered)
K15M
Showed enhanced precorneal holding time, Moxifloxacin

14. Carbopol/HPMC Bacterial infection [131]
and ocular bioavailability. (PH-triggered)
HPBCD complexed Showed excellent management of flucona- Fluconazole

15. gellan gum and κ- zole administration and great bio-adhesive Fungal infection [132]
(Ion-activated)
carrageenan qualities.
Greater the C max, prolonged t max, and Terbinafine hydrochloride

16. Gellan gum longer mean retention time and enhanced Anti-fungal [133]
(ion-activated)
the bioavailability.
Antisense oligodeoxynucle-
Gellan gum and carra- The biggest decrease in wound size, the otide
17. Muscular dystrophy [134]
geenan lowest stromal edema and hypercellularity.
(ion-activated)
Rapid gel formation by increasing pH to Sparfloxacin

Sodium alginate and 7.4, in vitro maintained drug release
18. (Multiple stimuli-ion and Bacterial infection [80]
methylcellulose throughout 24 h of the period, greatly in-
creased corneal penetration. PH sensitive)
Nepafenac (multiple stimu-

Carboxymethyl chi- The gelling temp of 32–33 °C and retarding
19. li- PH-induced and thermo- Anti-inflammatory [135]
tosan and poloxamer the drug dispersion rate were found.
sensitive)
Improved trans corneal drug permeability Timolol (multiple stimuli –

20. Chitosan and prolonged the storage at the corneal PH sensitive and ion acti- Glaucoma [136]
site. vated)
Table 5. Ocular insitu gel approved in the market.
Product Polymer In situ Gelling System Company References

®
Timoptic-XE (Timolol maleate oph- Gallen gum Ion induced Merck Pharmaceuticals, USA [137]
thalmic gel forming solution)
Pilopine HS® (pilocarpine hydrochloride Carbopol 940 PH-triggered Alcon laboratories, inc. USA [138]
ophthalmic gel)
Akten® (Lidocaine hydrochloride) HPMC and poloxamer 407 Temp. triggered Akorn Inc., Lake Forest, IL InSite [139]
vision
unit of tetrasaccharide made up of 2 residues of -d-glucose, the source of SA, a naturally occurring anionic polymer that is
one repeat of β - d acid, and one residue of -l-rhamnose. When water-soluble, nontoxic, and biodegradable. SA possesses
GG gets into touch with dimers and divalent ions, it possesses hydroxyl and carboxyl groups that can attach to the buccal
the ability to transform from such a liquid to a gel [117]. The mucosa's mucin. The pharmaceutical and food and beverage
combination of Na+, K+, Magnesium+, and Calcium ions+ in industries both use SA. It is frequently utilized as a coating
tears fluid would induce GG-based formulation to gel [117]. material, excipient for polymer film formation, and excipient
for stabilizing gel and emulsion in the pharmaceutical sector.
The most extensively studied alginate type in the pharma-
The above characteristics allow SA to be used in buccal mu-
cological and biomedical fields is sodium alginate (NaALG)
coadhesive films [119].
(NaC6H7O). For the encapsulation and immobilization of vari-
ous cell types for immunological isolation and biochemical 6. FUTURE OF THE NANOMEDICINE MARKET
processing, NaALG has a wide range of uses. Additionally, AND THE FUTURE OUTLOOK OF NANO DRUG
numerous studies demonstrate how easily NaALG degrades, DELIVERY SYSTEMS IN THE OPHTHALMOLOGY
how simple it is to manufacture, and how it may be used to
immobilize cells. Yet, there is little evidence that ALG gel is Scientists are looking more and more into nanomedicines
an effective substrate for cell growth [118]. Brown seeds are for various medical uses. They include more effective drug
targeting and administration as well as individualized nano- tears, and nasolacrimal outflow all work in concert to block
medicine, in which a patient is given a drug according to topical drugs from entering the eye. Significantly, with the
their genetic composition [140]. As the topical method is emergence of a novel topic-nanotechnology, the area of oph-
convenient, non-invasive, and self-administrable, but it is thalmic drug delivery has taken a significant stride forward.
difficult to administer medications effectively because of a Nanotechnology has been proven incredibly potent, effec-
number of anatomical and physiological obstacles that pre- tive, and promising in terms of therapy and detection of ocu-
vent therapeutic molecules from entering the tissues of the lar illnesses. In general, nanotechnology can improve the
eye. To prevent topical medications from entering the eye, bioavailability and efficacy of drugs, as well as their compli-
reflex blinking, tear production, and nasolacrimal outflow all ance and safety. Together with better solubilization, na-
act together. Moreover, the multilayered corneal structure nosized drug delivery systems have enhanced ophthalmic
serves as a crucial structural barrier to ocular medications medicines' targeting, stability, permeability, and interactions
that are applied topically [141]. Moreover, the ineffective with ocular tissues. Several nanotechnology-based transport
systemic absorption through the choroid, uveal tract, and systems are being developed and explored in massive in-
conjunctiva also restricts medication availability to the ante- stances, including nanoparticles, liposomes, nano micelles,
rior segment. As a result, often less than 5% of treatments nanosuspensions, polymeric nanoparticles, hydrogels, and
applied topically enter the aqueous humor. To help transport implantable materials to produce more effective and less
or target pharmaceuticals more effectively, new nanocarriers destructive therapies for eye illnesses. These nanocarriers
such as Liposomes, Niosomes, Hydrogel, in situ gel, Nano- can circumvent all obstacles in the eye, leading to sustained
emulsion, and Nano-suspension are being developed [140, and controlled drug release, targeted drug delivery, improved
142]. They could get the medication to the target spot despite specificity, and higher bioavailability. In addition, these
ocular obstacles. Certain nanotechnology-based ocular deliv- unique ways aid the patients by reducing the necessity of
ery systems (NODS) improve the feasibility of administering frequent medicine administration. The nanocarriers made
poorly soluble ocular medications as eye drops by increasing with different polymers are used to enhance the contact time
their biphasic composition. NODS interface with the corneal and improve the drug's bioavailability. All in all, additional
surface to extend the ocular retention period because of their research will enhance the future of nanotechnology and
large surface area [143]. Furthermore, their formulation ele- nanocarriers, which have powerful application opportunities
ments, like chitosan, hyaluronic acid, and cationic lipids, in the ophthalmology field and might modernize standard
may lengthen the time of retention on the ocular surface. In drug delivery systems and treatments.
addition, several surfactants added to the formulations of
these methods improve drug bioavailability in intraocular LIST OF ABBREVIATIONS
tissues by enhancing trans-corneal permeability [144]. AMD = Age-related Macular degeneration
NODS also serve as drug reservoirs, resulting in prolonged
BA = Bioavailability
drug delivery, reduced frequency of administration, and im-
proved patient compliance. Moreover, nanocarriers guard BAB = Blood-aqueous Barrier
against the enzymatic and metabolic destruction of the active BRB = Blood-retinal Barrier
substances that are trapped [145]. NODS may be used to
deliver genes and drugs to the ocular tissues. The treatment CAP = Cellulose Phthalate Acetate
efficacy can be increased and off-target toxicity decreased by CNV = Corneal Neovascularization
functionalizing them with proteins and peptides and specifi-
cally targeting the damaged ocular tissues [146]. In order to COX = Cyclooxygenase
overcome ocular barriers, increase drug contact time with the CS = Chitosan
ocular surface, improve trans corneal permeation, reduce
drug degradation, accomplish sustained/controlled release, DED = Dry Eye Disease
drug targeting, and gene delivery, the use of nanocarriers in EDE = Evaporative Dry Eye
the treatment of Anterior Segment Eye Disease (ASED) of-
fers several benefits. As a result, there is a decrease in the GG = Gellan Gum
regularity of administration, a reduction in side effects, and HPMC = Hydroxypropyl Methylcellulose
improvements in clinical outcomes and patient compliance
IOP = Intraocular Pressure
[147].
MC = Methylcellulose
CONCLUSION
MG = Meibomian Glands
Currently, enormous attempts are being put into ocular
studies toward creating safe and patient-compliant new drug MMP = Matrix Metalloproteases
delivery approaches. All ophthalmic drug delivery methods NE = Nanoemulsion
aim to improve ocular residence duration, provide sustained
medication activity, and enhance the bioavailability, conse- NLC = Nanostructured Lipid Nanocarriers
quently minimizing adverse effects and improving patient NSAID = Nonsteroidal Anti-inflammatory Medica-
safety. Although the topical technique is convenient, non- tion
invasive, and self-administrable, it is challenging to give
drugs successfully due to a variety of anatomical and physio- PAA = Polyacrylic Acid
logical barriers that prevent therapeutic molecules from ac- PDI = Polydispersity Index
cessing the tissues of the eye. Reflex blinking, generation of
PMAA = Poly(methacrylic) Acid [8] Almeida, H.; Amaral, M.H.; Lobão, P.; Lobo, J.M.S. In situ gelling
systems: A strategy to improve the bioavailability of ophthalmic
RGC = Retinal Ganglion Cells pharmaceutical formulations. Drug Discov. Today, 2014, 19(4),
400-412.
SA = Sodium Alginate http://dx.doi.org/10.1016/j.drudis.2013.10.001 PMID: 24120893
SLN = Solid Lipid Nanoparticles [9] Muench, S.; Roellig, M.; Balzani, D. A new method for the in vivo
identification of degenerated material property ranges of the human
SS = Sjogren’s Syndrome eye: feasibility analysis based on synthetic data. Biomech. Model.
Mechanobiol., 2022, 21(2), 401-418.
TASS = Toxic Anterior Segment Syndrome http://dx.doi.org/10.1007/s10237-021-01541-6 PMID: 34928468
[10] Singhvi, M.S.; Zinjarde, S.S.; Gokhale, D.V. Polylactic acid: Syn-
TECCDS = Toxic Endothelial Cell Destruction Syn- thesis and biomedical applications. J. Appl. Microbiol., 2019,
drome 127(6), 1612-1626.
http://dx.doi.org/10.1111/jam.14290 PMID: 31021482
TED = Thyroid Eye Disease [11] Rahman, M.A.; Rabbani, M.; Maruf, M.H.; Islam, A.; Shihavuddin,
UV = Ultraviolet A.S.M. Characterizing the aging process of the human eye: Tear
evaporation, fluid dynamics, blood flow, and metabolism-based
VEGF = Vascular Endothelial Growth Factor comparative study. BioMed Res. Int., 2022, 2022, 2805402.
http://dx.doi.org/10.1155/2022/2805402 PMID: 35372570
CONSENT FOR PUBLICATION [12] Lopes, T.J.A.; Simic, M.; Myer, G.D.; Ford, K.R.; Hewett, T.E.;
Pappas, E. The effects of injury prevention programs on the biome-
Not applicable. chanics of landing tasks: A systematic review with meta-analysis.
Am. J. Sports Med., 2018, 46(6), 1492-1499.
FUNDING http://dx.doi.org/10.1177/0363546517716930 PMID: 28759729
The author BDK and PP thankful to the Indian Council [13] Álvarez-Barrios, A.; Álvarez, L.; García, M.; Artime, E.; Pereiro,
R.; González-Iglesias, H. Antioxidant defenses in the human eye: A
of Medical Research (ICMR), New Delhi, India, for Adhoc focus on metallothioneins. Antioxidants, 2021, 10(1), 89.
Research Grant No. 2021-10799). http://dx.doi.org/10.3390/antiox10010089 PMID: 33440661
[14] Bonilla, L.; Espina, M.; Severino, P.; Cano, A.; Ettcheto, M.;
CONFLICT OF INTEREST Camins, A.; García, M.L.; Souto, E.B.; Sánchez-López, E. Lipid
nanoparticles for the posterior eye segment. Pharmaceutics, 2021,
The authors confirm that this article's content has no con- 14(1), 90.
flict of interest. http://dx.doi.org/10.3390/pharmaceutics14010090 PMID:
35056986
ACKNOWLEDGEMENTS [15] Boote, C.; Sigal, I.A.; Grytz, R.; Hua, Y.; Nguyen, T.D.; Girard,
Declared none. M.J.A. Scleral structure and biomechanics. Prog. Retin. Eye Res.,
2020, 74, 100773.
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A Mini-review on New Developments in Nanocarriers and Polymers for

1. INTRODUCTION Simultaneously, proper absorption of the drug into the eye

1567-2018/XX $65.00+.00 © XXXX Bentham Science Publishers

Route Benefits Challenges References

Administered systemat- Blood-aqueous barrier (BAB), blood-retinal barrier

increases medication levels in the anterior chamber,

Table 2. Some drugs used in ophthalmic diseases.

S.No. Disease Drugs and Their Associated Mechanism of Action References

4. Eye infection (fungal) Fluconazole [62]

choroidal neovasculariza- Nepafenac (Nepafenac, also known as 2- amino-3-benzoylbenzeneacetamide, is a nonsteroidal anti-

Ciprofloxacin (Broad-spectrum fluoroquinolone antibiotic ciprofloxacin is active against Gram-

4.11. Advantage Different sorts of drug delivery systems and procedures

Table 3. Polymers used for types of hydrogels.

Type of Hydrogel Polymers Used References

Poly and Pluronic (N-isopropyl acrylamide)

Ion sensitive gel Alginate sodium, gellan gum (Gelrite) [102)

synthesized SLNs had a particle size of 239.43 ± 2.35 nm

Table 4. Some polymer induced drugs.

S.No. Polymer Use Drug Disease References

Carbopol 940-extremely effective rheology

The rapid gelling capacity of alginate per-

They exhibit amphiphilic behavior because

Poloxamer F127 and Drug-controlled release over 8 hours in a Brinzolamide

Pluronic (PF-127 and In vivo, testing on rabbits revealed Pluronic Ofloxacin

Pluronic F127, Pluronic Lomefloxacin

Compared to either the medication solu-

Compared to the generic baicalin artificial

Carbopol and chitosan Displayed a managed release across

S.No. Polymer Use Drug Disease References

Carbopol 940 combined Gatifloxacin

Showed enhanced precorneal holding time, Moxifloxacin

HPBCD complexed Showed excellent management of flucona- Fluconazole

Greater the C max, prolonged t max, and Terbinafine hydrochloride

Rapid gel formation by increasing pH to Sparfloxacin

Nepafenac (multiple stimu-

Improved trans corneal drug permeability Timolol (multiple stimuli –

Table 5. Ocular insitu gel approved in the market.

Product Polymer In situ Gelling System Company References

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