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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article                                                                                  Review Article

Eye Drops to smart gels: The future of ocular drug delivery

Rajveer Bhaskar , Monika Ola , Vaishnavi Madwe *, Rohini Tikhe , Arun Pawar , Shivani Khade , Sunil Shinde 

Department of Pharmaceutics, R. C. Patel Institute of Pharmacy, Shirpur, Dhule, Maharashtra, India 425405

 

 

The ocular drug delivery system (ODDS) seems to be both necessary and difficult. The eye is the most delicate organ of the body. Furthermore, because of the quick and thorough removal of medications from the pre-corneal lachrymal fluid by solution drainage, lachrymation, and ineffective absorption by the conjunctiva, traditional ophthalmic formulations have a short pre-corneal residence period and poor bioavailability ¹. Most recent studies (ODDS) focus on integrating multiple  drug delivery methods, like a build-up system which prolongs the vehicle’s contact time on the ocular surface and delays  excretion ^{2, 3} . The In-situ gelling system is initially a liquid that is converted into a gel after being instilled into the eye. By exposing it to the ocular environment. This prolongs precorneal residence time and improves ocular bioavailability. The In-situ gelling system depends upon various parameters such as temperature, pH, and ion sensitivity, which allows the drug to be released gradually in a sustained manner. In-situ gelling system involves some advanced drug delivery which includes nanosuspension, nanoparticles, liposomes, niosomes, dendrimers, ocular iontophoresis, collagen shield, minidisc, ocular film, implants, Occusert, and many more examples of innovative dosage forms. 

The human eye is an extremely sensitive and intricate organ. Its anatomy is intriguing and complex. The human eye consists of 2 primary parts: the anterior chamber and Posterior chamber and the posterior chamber ⁴. These two parts are the most important. The anterior part includes the tear film, cornea, pupil, lens, and ciliary body. The posterior area includes the conjunctiva, sclera, choroid, retina, vitreous fluid, and optic nerve. The epithelium layer is composed of several layers of tightly packed cells.  The stroma is the dense layer filled with water, while the endothelium is vital in maintaining the cornea’s transparency. The orbital glands and the secretory epithelial cells regulate the production and composition of tears.  The front surface of the sclera is covered by the conjunctiva, a very thin and transparent membrane that lines the eyelids ⁵. Three layers make up this mucosal membrane: are substanatia propria, which includes blood, lymphatic, and nerve vessels, and the outer  epithelial layers ⁶, which attaches to the sclera, collagen and mucopolysaccharides make up the sclera, a continuous corneal layer. The vascular layer that marks the choroid is located between the sclera and the retina. A thin layer of tissues covers the rear of the eye, called the retina ^{7, 8}, which is made up of glial and neuronal cells ⁹ . It is in charge of producing electrical impulses that go to the brain through the optic nerve.

 

Figure 1: Anatomy of eye

3. Ocular Barriers
4. Precorneal barriers

The cul-de-sac describes the ocular obstacle ¹⁰. It is a shallow pocket-like structure in the lower eyelid which forms in the deeper recess of the upper eyelid, and where the palpebral and bulbar conjunctiva meets. In people, the cul-de-sac maximum capacity is about 30 μL. Although this capacity can be lowered by 70-80% if the lower eyelid reverts  to  its natural   position ¹¹. Furthermore, the cul-de-sac capacity may be further reduced by eye irritation and allergic reactions. Since the effectiveness of any medication is directly connected to its residence length and concentration, the cul-de-sac restricted capacity reduces drug concentration in the eye, which minimizes its therapeutic impact. Drug loss in the precorneal area from the lachrymal gland.   The main obstacles in the pre-corneal space are the drainage of the ocular solution. drug absorption may also be further hampered by protein binding and drug metabolism. To keep the eyes hydrated and stop dust or infection from building up on the surface, tear fluid regeneration is essential.

The cornea behaves as a robust barrier against various chemical and mechanical injuries and plays a vital role in focusing light onto the retina. It consists of layers: Epithelium, Stroma, and Endothelium ⁵.  The epithelium serves as an obstacle to the hydrophilic drugs and large molecules, while the stroma obstructs lipophilic drugs. Several other factors, such as mol wt., charge, degree of ionization, and hydrophobicity, etc., as a result trans transcorneal permeation is a rate-limiting step.

This is categorized into two: blood aqueous barrier (BAB) and blood-retinal barrier (BRB). It prevents foreign particles from entering blood bloodstream ¹². BAB is the anterior part that restricts access to many substances from entering the intraocular environment¹³. It only allows lipophilic and small molecular weight drugs, which are eliminated more quickly from the anterior compartment ¹⁴ . Retinal pigment epithelial cells and endothelial cells comprise the BRB, a posterior region that keeps harmful substances, water, and plasma components out of the retina.

 
 

 

Figure 2: Ocular Barriers

 

4. Various routes of administration
5. Topical route 

The topical route is the most common to administer the medicament 95% of marketed formulations follow the route. Although it is a nano-invasive method, its short residence time and inadequate corneal penetration result in a poor bioavailability(<5%) ¹⁵. It results from the nasolacrimal pathways' absorption into the systemic circulation, blinking, and tear drainage ¹⁶. This route requires frequent administration and high concentration, which can have significant side effects. 

Intracameral injection involves directly injecting an antibiotic into the vitreous cavity. It is generally provided after cataract surgery. 

The intravitreal injection delivers the drug directly to the vitreous humor ¹⁷, which is located near to retina ¹⁷. A new treatment approach for glaucoma ¹⁸ Involves a single intravitreal injection of vitamin E/polylactic/polylactic-co-glycolic acid microspheres ¹⁹ containing neurotrophic factor produced from glial cell lines  ²⁰.

Juxta-scleral injections are used ²¹. Conditions include trauma, diabetes-related illnesses, and cystoid macular edema benefit greatly from these injections. New treatment for age-related macular degeneration involves juxta-scleral injection of anecortave cortisone, which has demonstrated prolonged release over six months into the retina and choroid ²² .

The retrobulbar method is administering medicine behind the eyeball into the retrobulbar  space employing injection via the orbital fascia and eyelid ²³. Whenever amphotericin is given by this route, it exhibits more antifungal activity than intravenous injection when administered retrobulbar ²⁴. 

Figure 3: Various Ocular route of administration

Subconjunctival injection is given when topical treatment results in relatively little drug penetration into the anterior chamber of the eye. It is frequently utilized. For at least a month, the PEGylated liposomes have been used to. The administration of brinzolamide-encapsulated PLGA nanoparticles through subconjunctival injection effectively managed intraocular pressure for 10 days ²⁵.

5. Ocular diseases
6. Cataract

Cataracts are the leading cause of vision loss globally, accounting for 40 to 60 percent of blindness worldwide due to complications ²⁶. According to the National Programme for Control of Blindness and Visual Impairment, cataracts cause 62.6% of instances of avoidable blindness in India ²⁷. Cataract develops cloudiness or opacification in the lens. 

Glaucoma

A common optic neuropathy is glaucoma. Blurred vision is the first symptom, and in later stages, it may lead to permanent blindness ²⁸. It causes retinal ganglion cells to die and the optic nerve axons to gradually deteriorate, resulting in blindness. It is frequently linked to an increase in intraocular pressure due to abnormal aqueous fluid production or blockage. Open-angle and closed-angle glaucoma are the two types. Widening optic disc cupping and visual field loss due to increasing resistance to aqueous humor outflow through the trabecular meshwork are characteristic of open-angle glaucoma, which is often asymptomatic ^{29, 30}. 

Age-related Macular degeneration (AMD): 

ADM is one of the main causes of vision loss in affluent countries. After the age of 50, it is more common. ADM causes around 8.7% of blindness globally. In 2020, around 196 million individuals had AMD, and by 2040, that figure is predicted to rise to 288 million³¹. It is a  complicated degenerative disease that affects the posterior part of the eye ³². AMD currently has no known cure, however, appropriate medicine may slow its development ³³. AMD comes in two varieties: Dry (atrophic or non-exudative) and wet (non-vascular or exudative). The primary feature of AMD is irregular angiogenesis, or the formation of new blood vessels, in the retinal epithelium, which leads to Bruch’s membrane separation, atrophy, and drusen, or yellow deposits beneath the retina ^{33, 34}.

Conjunctivitis is characterized by conjunctival irritation, which is very common. This condition can affect individuals of all ages, races, and genders ³³. Conjunctivitis can be classified as Infectious and non-infectious ³⁵. Infectious conjunctivitis occurs due to microbial infections, whereas non-infectious conjunctivitis is caused by allergens and irritants ^{36, 37}. Conjunctivitis symptoms include redness, pain, tears, and excessive eye secretion. the prevalence of allergic conjunctivitis is close to 40% worldwide ³⁸. 

 

Diabetes mellitus is a cause of Diabetic Retinopathy. All patients with diabetes type II will develop some degree of retinopathy after 20 years, and about 60% of individuals with type II diabetes will do the same. The main causes of diabetic retinopathy are inflammation and oxidative stress. These are caused by hyperglycemic conditions that cause pro-inflammatory mediators to be   overexpressed ³⁹. Proliferative and non-proliferative diabetic retinopathy are the two primary forms. Both eventually cause the retina to deteriorate more and more. Nowadays, therapies for  diabetic retinopathy include vitrectomy, laser, photocoagulation, and   pharmaceutical measures  ⁴⁰. Although treatment may leave scars, laser photocoagulation can stop blindness by closing leaky blood vessels  ⁴¹. 

Retinoblastoma, a malignant tumor that destroys the retina, mostly affects children under five if left untreated. 99% of cases result in blindness and finally death. Its frequency is about 1 out of 20,000 live births. The occurrence occurs at the same rate in both sexes. A mutation in the tumor suppressor gene RB1, which produces the protein retinoblastoma, is the cause of it. Both unilateral (60%) and bilateral (40%) are possible  ⁴². Retinoblastoma can be treated with radiation, cryotherapy, systemic chemotherapy, and surgery.

Fungal keratitis only develops with corneal damage because a healthy cornea would be impervious to infection by fungus ⁴³. Fungi Such as Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, and Candida parasitosis are the cause of fungal keratitis, which affects 40% of people worldwide. There are two types of risk factors for fungal keratitis: one is systemic and another is the eye.  Leprosy, diabetes, and HIV-positive examples of systemic issues. complications from fungal keratitis include corneal ulceration, poor wound healing, and inflammation seeping into the corneal stroma. The corneal inflammation may alter miRNA expression ⁴⁴. 

6. Dosage Form 
7. Liquid Dosage Forms 
8. Eye Drops: 

More than 95% of marketed eye medications are eye drops  ⁴⁵, which provides medicine to the front region of the eye. Their benefits include strong stability and ease of administration. Their limited retention period, poor bioavailability, and possibly dangerous side effects from regular usage of high concentrations are some of the major disadvantages.

Ocular suspensions are a dispersion of hydrophobic drugs in an aqueous solution. These formulations enhance contact time by retaining the drug in the conjunctival cul-de-sac. Key factors during the preparation process include particle size, solubility, and dissolution rate in tear fluid. Generally, particles larger than 10 µm can cause ocular irritation and increased tearing. However, ocular suspensions have some disadvantages, including poor stability.

An emulsion is a biphasic system maintained in a stable form with the help of surfactants or stabilizing agents ⁴⁶. The capacity to administer hydrophobic medications is one of the benefits of ocular emulsion. In addition, oil-in-water emulsion improves bioavailability, provides longer contact durations, and is less ocular irritating. 

2. Semisolid Dosage Forms
   1. Eye gel: 

Eye gels have a higher water content and are semisolid dose formulations. Their increased viscosity enhances retention time and bioavailability, although they can still cause blurred vision ⁴⁷. Different polymers can be utilized to formulate ocular gels, such as Polyacrylic acid, acrylic acid, hydroxypropyl methylcellulose, and carboxymethyl cellulose ⁴⁸. Curcumin-containing proniosomal gel was prepared  using  the coacervation approach, which resulted in a  notable reduce size of particles  and an increase in anti-inflammatory activity ⁴⁹. Moreover, a phytantriol-based liquid crystalline  gel using a vortex process increased retention time ⁵⁰

Eye ointments are semisolid dosage forms made of mineral oil and white petroleum. Due to their potential to impair eyesight, they are exclusively administered to the lower eyelid at night ⁴⁵. These ointments are frequently used in young patients and are anhydrous, making them appropriate for Drugs that are moisture-sensitive and lipophilic. They also show a longer residence period and greater Bioavailability than solution.

3. Solid dosage forms
   1. Occusert Inserts:

Ocular inserts are solid dosage forms with a zero-order drug release mechanism that are composed of biodegradable polymers  ⁵¹. Longer residence time, continuous medication delivery, steady release rates, and fewer adverse effects are some advantages of these inserts ⁵². Triamcinolone acetonide-infused nanofibers were produced using the electrospinning method. These nanofibers exhibited smaller particle sizes, enhanced systemic absorption, and minimized side effects. 

According to recent research, therapeutic contact lenses' prolonged residence duration and close contact with the cornea can increase medication absorption by more than 50%. They have a ten-fold longer residence period than traditional eye drops. These lenses decrease the necessary dosage, the time between dosages, and systemic absorption. There are several methods for encapsulating the medication in contact lenses, such as soaking, ion ligation, molecular imprinting, and the application of nanoparticles ⁵³.  However, several issues, including protein attachment, ion and oxygen permeability, medication loss during production or storage, light transmittance, and lens swelling, make it difficult to employ them clinically ⁵⁴.

7. Benefits of the in-situ gelling method over traditional ocular formulation:
8. Extended Residence time
9. Enhanced bioavailability. 
10. Reduced systemic absorption
11. Accurate drug delivery
12. Improved therapeutic efficacy
13. Disadvantages of in-situ gels:
14. Required an appropriate amount of tear fluid.
15. The drug present in the solution may degrade.
16. Chemical degradation leads to stability issues ⁵⁵.
17. Only a small dose can be administered.
18. Low mechanical strength leads to premature dissolution.
19. Types of In-situ gelling systems
20. pH-sensitive in-situ gelling system:

The physiological environment's pH shift causes the sol-to-gel transition. Pendant acidic or basic groups found in pH-sensitive polymers can either receive or release a proton in response to pH changes. Polyelectrolytes are polymers that contain a lot of ionizable groups. Anionic groups in weakly acidic polymers cause swelling when the pH rises, although edema falls in weakly basic medications. When designing the ophthalmic drops, the buffer is crucial. They have a major impact on clinical response and chemical stability. They also affect the product's safety and comfort. Gelling brought on by a pH shift is one of the possible ophthalmic in situ gels described in the literature ⁵⁶. The polymers that show pH-responsive in-situ gelling are as follows: hydroxypropyl methylcellulose (HPMC), polyacrylic acids, cellulose acetate, etc. These are stable, non-irritating, and offer sustained release of the medication ⁴⁸.

The formulation is liquid at room temperature (20- 250 °C), but when it comes into contact with the application site (35- 37 °C), the temperature rises and it becomes a gel. There is a volume phase transition in temperature-sensitivity hydrogels at certain higher critical solution temperatures (UCST) or lower critical solution temperatures (LCST) ⁵⁷. The sol–to–gel transformation mechanism is based on the progressive desolvation of the polymer with increasing temperature, which causes the polymeric network to become more entangled and aggregate into micellar. The dehydration of the polyoxypropylene block leads to the production of micelles. After coming into contact, the micelles lose their freedom of motion. 

 

 

The ion active gelling system is a solution initially, and when it comes in contact with the tear fluid of the eye instantly converts into a gel. There is a variety of ion-responsive gelling agents as follows: Gellan gum, sodium alginate undergoes cross-linking with the ions, and so that the gel is formed. Ion ion-activated in-situ gelling system provides extended retention time in the ocular, which increases patient compliance ⁵⁸.

Figure 4: Typical Mechanism of ocular in-situ gel

Ocular in-situ nanogels are better than other drug delivery methods for eye diseases. They improve the drug’s bioavailability ⁵⁹. The gel’s nanoparticles ' size makes it easier for drugs to enter the tissues of the eyes, increasing concentrations of medication at the desired place ⁶⁰. Ocular in-situ nanogels are additionally used to regulate drug release medications gradually, extending the therapeutic concentration at a specific location, in contrast to ocular drops, which may remove medications rapidly ⁶¹. A contrast supply of drugs is required for chronic eye disorders.   Ophthalmic in-situ nanogels are easy to use for doctors ⁶². Because they are biocompatible and biodegradable, they do not cause toxicity or unpleasant responses. Ocular in-situ therapy is one potential way to provide medication for eye disorders ⁶³.

11. Types of nanoparticles:
12. Liposomes:

Liposomes provide several benefits, including increased bioavailability, safety, biodegradability, and ease of manufacturing ⁶⁴. One or more concentric lipid bilayers make up these spherical nanocarriers. Liposomes can transport hydrophilic medications in their central core and lipophilic medications in their lipid layer. The formation procedure and composition may be changed to change their temperature responsiveness, surface charge, sensitivity to ions or pH, and ultimately particle size. Since the corneal epithelium typically has a negative charge, using liposomes that are positively charged can improve absorption and extend retention duration. 

Niosomes are nano-ionic surfactants that self-aggregate in two layers, which are nanocarriers. They can contain both hydrophilic and lipophilic medications without inciting an immunological reaction, and they are biodegradable and biocompatibility ⁶⁵. Niosomes can increase and extend the release of drugs. However, it shows drawbacks, including the possibility for hydrolysis, chemical instability, and drug loss or buildup. Cholesterol or its derivatives are frequently added to niosomes to increase their stiffness and stability.

Nanoemulsions might be used as delivery systems for the eyes. Oil-in-water nanoemulsions are composed of a dispersed oil phase stabilised by surfactants in an aqueous medium ⁶⁶. These nanoemulsion interacts with the lipids in tears and act as a reservoir for lipophilic medications. Provides prolonged release ⁶⁷. Because they interact with the corneal surface and improve medication solubility, surfactants are essential. however, employing Nanoemulsions creates a milky solution, and decreased tolerance to eye irritation brought on by elevated amounts of surfactants might result in impaired vision if the size of the particle exceeds 100nm.

Lipophilic drugs dispersed in a mixture of media maintained by polymer or surfactants make up colloidal nanocarriers. Its advantages are enhanced solubility and bioavailability, longer residence time, and prolonged drug release ⁶⁸. among the most Eudragit® polymers are often used mucoadhesive agents in nanosuspensions  ⁶⁹.

Nanocarriers are anionic, cationic, or zwitterionic surfactants that make up nanocarriers, which can be spherical, cylindrical, or star-shaped, among other shapes. Both hydrophilic and lipophilic medications can be encapsulated in these carriers ⁷⁰. These carriers have simple preparation methods that lead to better drug penetration, higher bioavailability, decreased toxicity, and increased stability ⁷¹. They are capable of delivering drugs to both the anterior and posterior segments of the eye ⁷².

Based on their shape and technique of synthesis, polymeric nanoparticles may be divided into two types: nanospheres and nanocapsules. Small, solid spheres made of a dense network of polymers are called nanospheres. Their matrix-like structure provides a lot of surface area, enabling medications to get trapped inside the particles or absorbed onto their surface. Nano capsules, on the other hand, are made up of tiny liquid cores encapsulated in a polymeric membrane like nanospheres. Medications can be encapsulated within the liquid core of the capsule or adsorbed onto its surface. Because of their tiny particle size, these polymeric nanoparticles may reach both eye segments, improving patient compliance, especially when controlling chronic illness. They provide better penetration, extended drug release, and decreased elimination.

Drugs that are lipophilic and hydrophilic are encapsulated in solid lipid nanoparticles, which are made up of a solid lipid matrix. Triglycerides, fatty acids, steroids, and waxes are common lipids employed to make these nanoparticles ^{73, 74}. One of the SLN's main benefits is that they don’t need surfactant can stabilize lipid dispersion in place of organic solvents. Furthermore, the production of SLNs is economical, safe, biodegradable, and biocompatible. 

Although being a second-generation lipid nanoparticles, which contain around 30% liquid lipids, the final product is solid and does not have a crystalline structure ⁷⁵. The content is higher than with solid lipid nanoparticles because the liquid oil droplets provide the drug with additional space in the lipid matrix. Low toxicity, improved effectiveness, and controlled release are all displayed by these nanoparticles.

The main component of the medication is nanocrystals, which are stabilized and encased by a variety of excipients. Small particle size, simple production methods, strong mucoadhesive qualities, and improved bioavailability are some of the characteristics of these nanocrystals ⁷⁶. Nanocrystals are considered potential nanocarriers deserving of immediate further research ⁷⁷.

Dendrimers are three-dimensional structures of repeating molecular units that surround a central core and are extremely branched, star-shaped, tree-shaped, or tree-shaped ⁷⁸. Because of their many terminal functionalities, they can be used to deliver both hydrophilic and lipophilic medications ⁷⁹. Its benefits include longer residence time, enhanced bioavailability, targeted distribution, extended activity, and antibacterial qualities have all been shown for dendrimers. They can provide drugs to both eye segments.

Lipids are emulsified in water with a stabilizer from bicontinuous cubic liquid crystalline nanocarriers known as cubosomes ⁸⁰. Because of their vast surface area, they can encapsulate a large number of medications and are stable, easy to produce, biodegradable, and generally safe.

The primary constituents of the olaminosomes are a surfactant, oleic acid, and Oleylamine. A common option for manufacturing ocular nanocarriers is oleic acid, a naturally occurring unsaturated fatty acid that is safe and biodegradable. Oleic acid is the source of Oleylamine, an unsaturated fatty amine that is widely utilized as a surfactant or co-stabilizer. It includes tiny particles, high drug entrapment capabilities, improved corneal penetration, and general safety and efficiency.

Bilayered nanocarriers called bilosomes are made up of bile salts. They feature a tiny particle

 

size, sufficient zeta potential, favourable safety profiles, greater corneal penetration, higher activity, and high drug entrapment capabilities ⁸¹.  Abdelbary and associates create terconazole-infused edge activators, span 60, and cholesterol to create bilosomes.  Superior drug entrapment, higher activity, and better permeability we all displayed by the final formulation ⁸².

 

 

 

 

Figure 5: Various types of Nanoparticles

Table 1: Characterization of nanoparticles loaded in-situ gelling system:

Parameter	Description	Procedure
pH Measurement	pH impacts drug stability, permeation, and ocular comfort. Formulations with very low (<4) or high (>10) pH can irritate the eye.	Ideal pH range: 4–8 (enhances permeation, avoids irritation). Measured using a digital pH meter. Ocular formulation pH typically falls between 3.50 and 8.50 83.
Visual Appearance	Influenced by particle size, oil type, and surfactant. Important for product appeal and user compliance.	Nano formulations may appear transparent, translucent, or turbid. % Transmittance measured using UV spectroscopy to assess clarity 84.
Gelling Ability	Indicates the ability of sol to transform into gel in a lachrymal fluid.	A drop of formulation is added to 2 mL of simulated tear fluid. Gelation is visually observed 58.
Osmolarity	Important for ocular comfort. Osmolarity imbalances can cause irritation or damage.	Normal tear osmolarity: 231–446 mOsm/kg. Values <100 or >640 mOsm/kg may cause discomfort. Takes into account vapor pressure, freezing/boiling point, and osmotic pressure 85.
Rheological Studies	Determines viscosity and flow behaviour before and after gelation, critical for in-situ gels.	Measured using a Brookfield viscometer. Before gelation: 5–1000 mPa·s After gelation: 50–50000 mPa·s At Temperature: 25°C (before), 37±0.05°C (after) 86
In Vitro Drug Release	Simulates drug release into the eye to evaluate performance.	Conducted using a Franz diffusion cell with dialysis membrane (0.22 µm pore). Receptor: Simulated tear fluid Donor: Formulation Assembly kept at 37±0.5°C on magnetic stirrer. Sample analyzed by UV spectrophotometer 87.
Texture Analysis	Determines gel’s mechanical properties, indicating patient acceptability.	Done using Texture Analyzer to assess cohesion, stiffness, and consistency. High adhesiveness indicates better contact with the eye surface 88.
Isotonicity Testing	Ensures osmotic balance with tears to prevent irritation or cell damage.	Formulations are mixed with drops of blood and observed under a 45x microscope. Compared with commercial ophthalmic products for isotonic behaviour 89
Compatibility & Melting Point Studies	Detects drug-polymer interactions and thermal properties.	FTIR (Fourier Transform Infrared Spectroscopy): for interaction via the KBr pellet method. DSC (Differential Scanning Calorimetry): for phase transition/thermal shifts. TGA (Thermogravimetric Analysis): for water content determination 90.
Stability Studies	Checks shelf-life, formulation robustness under storage.	Short-term accelerated stability (ICH guidelines)  Storage: 40±2°C, 75±5% RH Parameters: drug release, drug content, viscosity, clarity, pH, gelling capacity, tested weekly 91.
Size and Uniformity Analysis	Determines nanoparticle size and distribution uniformity.	Conducted through Dynamic Light Scattering (DLS) using instruments like Zetasizer. Particle size (PS) and Polydispersity Index (PDI) were measured. PDI = 0 (uniform), PDI = 1 (non-uniform) 92.
Zeta Potential (ZP)	Indicates physical stability and ability to interact with the ocular surface.	Measured through electrophoretic mobility. ZP: ±20 mV is considered to be ideal and leads to stability 93.
Drug Distribution	Determines how well the drug is incorporated and retained in the system.	% Entrapment Efficiency (%EE): Drug entrapped relative to total drug used. % Drug Loading (%DL): Drug mass relative to system mass. Affected by the drug's hydrophobicity, MW, and carrier material properties 94.
Ocular Biocompatibility (Hen's Egg Test)	Evaluates the irritation potential of the formulation.	Uses Hen’s Egg Chorioallantois Membrane (HET-CAM) assay. Fertilized eggs were incubated at 37±0.5°C, 67±5% RH for 10 days. Observed for hemorrhage, clotting, hyperemia. Confirms ocular safety 95.

 

Table 2: Ocular in-situ Gels approved for market

Product name	Polymers used	Types of in-situ gel systems	Company name
Akten	Hydroxypropyl methyl cellulose	Temperature active 96	Akorn Operating Company
Azasite	Poloxamer407	Temperature active 97	InSite Vision
Pilocarpine-HS	Poloxamer407	pH active 97

 

Table 3: Patents of Ocular in-situ gels 

Patent no.	Patent Title	Gelling agents
US 2011/0082 128 A1	Ocular medication delivery system using in-situ gel	Deacetylated gellan gum 98
US 2002/0 114 778 A1	Reversible gelling technique	Propylene oxide, ethylene oxide with Hydroxy propyl methyl cellulose 120.
WO 2 011 018 800 A3	In-situ gel for ocular delivery	A blend of Thermoreversible natural polysaccharide polymer 99, 100.
US 6 703 039 B2	Reversible gelling technique	Propylene oxide and ethylene oxide with hydroxy propyl methyl cellulose US 6 703 039 B2 101

Table 4: Reported nanoparticles loaded in-situ gelling system

APIs	Polymer	Type of stimuli	Major Findings
Curcumin	Kolliphor 188 and 407	Thermo-active nanostructured lipid carriers	Noticeably improved preocular retention time. 97
Dorzolamide	Pluronic 407	Thermo-active nanoemulsion	Non-irritating and extremely therapeutically effective. 102
Ketorolac	Poloxamer@F-127 and hydroxypropyl methylcellulose	Thermo-active nanoemulsion	Enhanced drug release, ocular bioavailability, and no irritation 103
Loteprednol	Pluronic-407and 188	Ion-Active nanoemulsion	Increase residence time,2,54 times bioavailability. 104
Timolol	Gelerite	Ion-Active Liposomes	Low intraocular pressure and more effective. 105

 

Table 5: Reported multi-stimuli responsive in-situ gels

API	Polymers	Response	Results
Ciprofloxacin	Carbomer	pH and thermo-responsive	Increased effectiveness of treatment and provides 8 hr of prolonged-release 100
Levofloxacin	Algin and chitin	Ions and pH-responsive	Retention time was improved 106
Nepafenac	Chitosan N-(carboxymethyl) and pluronic	pH and thermo-responsive	Gellation was on 32-33°C 107
Sparfloxacin	Algin and Chitin	Ion and pH-responsive	Rapid gelation occurs at pH 7.4 and prolonged release for 24 hrs 106
Timolol	Chitin with gellan gum	pH and ion-responsive	Improved corneal penetration and prolonged drug release.105

 

 

Effective drug delivery to the eyes is the most challenging due to various natural barriers, like tear drainage and limited absorption. Traditional methods like drops and injections have limitations, such as short retention time and potential side effects. To overcome these issues, advanced drug delivery systems like in-situ gels, nanoparticles, and nanocarriers have been developed. These modern approaches improve drug retention, bioavailability, and patient comfort by promising controlled and sustained release. In-situ gels are particularly promising as they transform into a gel upon contact with the eye, extending drug retention and minimizing the need for frequent dosing. With continuous advancements in nanotechnology and smart drug delivery systems, the future of ocular drug treatment looks promising, offering efficiency and improved patient care.

Acknowledgements: We thank Dr. Monika Ola Ma’am for her advice and immense insights while writing this review article. 

Authors' contributions: Vaishnavi D. Madwe – draft writing, Rohini P. Tikhe – draft writing, Arun A. Pawar– draft writing, Shivani M. Khade– draft writing, Sunil D. Shinde– draft writing, Rajveer Bhaskar – Supervision, Monika Ola – Supervision.

Funding source: There is no funding source. 

Conflict of interest: The authors reported no conflict of interest. Ethical Approval: Not applicable

Ethical Approval: Not applicable

 

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