Wet age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population worldwide. The hallmark feature of wet AMD is the abnormal growth of choroidal neovascularization (CNV) beneath the macula, leading to retinal edema, hemorrhage, and fibrosis. Current treatment options primarily involve intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, such as ranibizumab and aflibercept. Although effective in reducing disease progression and improving visual outcomes, frequent injections are required to maintain therapeutic levels, posing challenges related to patient compliance, treatment burden, and potential complications such as endophthalmitis and retinal detachment².

Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. Eye drops are conventional ophthalmic delivery systems often result in poor bioavailability and therapeutic response, because high tear fluid turnover and dynamics cause rapid precorneal elimination of the drug. A high frequency of eye drop instillation is associated with patient non-compliance. Inclusion of excess drug in the formulation is an attempt to overcome bioavailability problem is potentially dangerous if the drug solution drained from the eye is systemically absorbed from the Nasolachrymal duct. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the appropriate duration¹⁴.

The balance between the free radicals and antioxidants is crucial for good health. The risk of free radicals in health has been increasing gradually. Many of the degenerative disease like atherosclerosis, cancer inflammatory joint disease, asthma, diabetes, dementia and degenerative eye disorder are the result of imbalance of free radicals and antioxidants. In case of eye, free radicals are responsible for the pathogenesis of the majority of serious ocular diseases such as cataract, primary open angle glaucoma and age-related macular degeneration. The process of biological ageing might also have a free radical basis. Most free radical damage to cells involves oxygen free radicals or reactive oxygen species (ROS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals¹⁵.

In the present scenario there has been growing interest in deciphering the impact of oxidative reactions in human disease. Oxygen free radicals play major role in many physiological and pathological conditions associated with human health and disease including age related diseases as a biological phenomenon. A free radical is any atom or molecule that has a single unpaired electron in an outer shellwhereas normally electrons exist in pairs in specific orbitals in atoms or molecule^. It includes molecular oxygen, since ground-state oxygen has two unpaired electrons^16,17.

TYPES OF OCULAR DISEASES:

Age Related Macular Degeneration:

The neovascular age-related macular degeneration is related to oxidative stress involving the macular retinal pigment epithelium. In a study, the function of age, levels of enzymes which defend tissues against oxidative stress in the macular retinal pigment epithelium of human eyes with this disease was investigated. The surgical specimens of macular choroidal neovascular membranes from eyes with age-related macular degeneration and the macular regions of whole donor eyes with neovascular age-related macular degeneration or without evident ocular disease were studied by quantitative electron microscopic immunocyto-chemistry with colloidal gold–labeled second antibodies. Relative levels in retinal pigment epithelium cell cytoplasm and lysosomes were determined of five enzymes believed to protect cells from oxidative stress, as well as levels of the retinal pigment epithelium marker cytoplasmic retinaldehyde-binding protein, for comparison with the enzymes. Copper, zinc superoxide dismutase immune reactivity increased and catalase immune reactivity decreased with age in cytoplasm and lysosomes from macular retinal pigment epithelium cells of normal eyes and eyes with age-related macular degeneration. Cytoplasmic retinaldehyde-binding protein immunoreactivity showed no significant relationship to age or the presence of neovascular age-related macular degeneration. Glutathione peroxidase immunoreactivity was absent from human retinal pigment epithelium cells. Both heme oxygenase-1 and heme oxygenase-2 had highly significantly greater immunoreactivity in retinal pigment epithelium cell lysosomes than in cytoplasm, differing from the much greater cytoplasmic immunoreactivity of the other proteins studied¹⁵.

Cataract:

Oxidative stress is an important factor in age-related processes in the body including senile cataract. Production of ROS and reduction of endogenous antioxidants both contribute to cataract formation. UV-induced oxidation damage seems to play a major role in specific pathological conditions of cataract and retinal degeneration. The eye lens is also subjected to oxidative stress from radiation and others sources and this can damage the crystalline proteins, lipids, polysaccharides and nucleic acids^19,20,21

Glaucoma:

The perturbation of the oxidants versus antioxidant balance can lead to increased oxidative damage, especially when the first line of antioxidant defense weakens with age. In glaucoma oxidative stress can cause chronic changes in the aqueous and vitreous humor, which may induce alterations in the trabecular meshwork and the optic nerve head²².

Autoimmune Uveitis:

Autoimmune and inflammatory uveitis are a group of potentially blinding diseases that arise without a known infectious trigger and are often associated with immunological responses to unique retinal proteins²³.

Pseudoexfoliation Syndrome:

Pseudoexfoliation syndrome (PEX) is a common age-related fibrillopathy of unknown cause, recognized by chronic deposition of abnormal pseudoexfoliation material on the anterior segment structures of the eye. Oxidative stress has been implicated in the development of this condition²⁴

Macular Degeneration

Macular degeneration involves gradual loss in middle acuity and the presence of drusen (bumps) in the macula in the eye. The macula is located in the middle portion of the retina which is responsible for acute vision. The middle portion of the macula, in the innermost layers of the retina are displaced to one side allowing light to pass directly to the retina and offer high visual acuity, along with increased risk of radiation damage to the retina. The main cause of generation of reactive oxygen species is when UV and visible light radiation passes from retina to the photoreceptor (rod and cones) and pigmented epithelial cell (PE). The transformation of light into the nerve impulse through the photoreceptors develops free radicals. These free radicals include reactive oxygen species like hydrogen peroxide, superoxide and hydroxyl radicals²⁵.

In-situ gel formulations have emerged as a promising strategy for the sustained delivery of therapeutic agents to the posterior segment of the eye, offering several advantages over conventional dosage forms. These thermoresponsive gels undergo sol-to-gel transition in response to physiological conditions, such as temperature or pH, thereby facilitating easy administration and prolonged drug release at the target site. Moreover, in-situ gels can minimize systemic exposure and adverse effects associated with frequent injections, potentially improving patient adherence and treatment outcomes³.

Table 1; Basic clinical classification 11

S.No	Stages	Abnormalities
1	No ageing changes	No drusen and no pigment abnormalities
2	Normal ageing changes	Only small drusen ≤63 µm and no pigment abnormalities
3	Early AMD	Medium drusen >63 µm and ≤125 µm, and no pigment abnormalities
4	Intermediate AMD	Large drusen >125 µm or any pigment abnormalities
5	Late AMD	Neovascular AMD or geographic atrophy

Figure 1; Classification of AMD ¹²

Table 2: Risk factors that lead to cause AMD ¹³

Risk factors	Strength and consistency of association
Older age	Strong and consistent
Older age
Previous cataract surgery
Family history of AMD
Higher body mass index	Moderate and consistent
History of cardiovascular disease
Hypertension
Higher plasma fibrinogen
Gender	Weak and consistent
Ethnicity
Diabetes
Iris color

Formulation Strategies:

The formulation of in-situ gels for wet AMD therapy involves careful selection of biocompatible polymers capable of forming a stable gel matrix under ocular conditions. Commonly used polymers include thermoresponsive copolymers such as Pluronic F127 and Pluronic F68, which exhibit a sol-gel transition at physiological temperatures. Other polymers, such as chitosan, hyaluronic acid, and alginate, have also been investigated for their mucoadhesive properties and sustained drug release characteristics⁴.

Evaluation Parameters:

Evaluation of in-situ gel formulations encompasses various parameters, including rheological properties, gelation kinetics, in vitro drug release profiles, ocular tolerance, and pharmacokinetics. Rheological studies assess the viscoelastic properties of the gel, such as gel strength, viscosity, and gelation temperature, which influence the ease of administration and retention within the ocular cavity. In vitro drug release studies are essential for determining the release kinetics and duration of therapeutic action, guiding the selection of optimal polymer compositions and drug loading concentrations. Ocular tolerance studies evaluate the biocompatibility and safety of the gel formulation following instillation into the eye, assessing parameters such as corneal integrity, tear film stability, and ocular irritation^6,7,8.

Recent Developments:

Recent advancements in polymer science and nanotechnology have led to the development of novel in-situ gel formulations with improved drug delivery and therapeutic efficacy. Nanostructured lipid carriers (NLCs) and polymeric nanoparticles have been incorporated into in-situ gels to enhance drug encapsulation efficiency and ocular retention. Furthermore, stimuli-responsive polymers, such as smart hydrogels and pH-sensitive nanoparticles, enable triggered drug release in response to specific ocular microenvironments, enhancing therapeutic precision and minimizing systemic side effects^9,10.

CONCLUSION:

In-situ gel formulations represent a promising approach for the treatment of wet AMD, offering sustained drug delivery and improved patient compliance compared to conventional therapies. However, several challenges remain, including optimizing gel properties, ensuring long-term stability, and conducting comprehensive preclinical and clinical studies to validate safety and efficacy. Future research efforts should focus on developing innovative formulations and delivery systems tailored to the unique pathophysiology of wet AMD, ultimately improving treatment outcomes and quality of life for affected individuals.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGEMENT:

We would like to thank Dr. Dheeraj Ahirwar for his kind support and guidance and also we would like to thanks our parents for their moral support throughout the work.

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Received on 07.04.2024 Revised on 10.12.2024

Accepted on 08.04.2025 Published on 23.04.2025

Available online from April 26, 2025

Asian J. Pharm. Tech. 2025; 15(2):173-176.

DOI: 10.52711/2231-5713.2025.00027

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.