INTRODUCTION:

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 aflibercept¹. 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.

Diabetics are more likely to develop diabetes retinopathy (DR), the most significant microvascular complication. Diabetic retinopathy (DR) is a condition that causes blindness in people aged 20 to 65. After 10 years of diabetes, nearly all type 1 diabetes patients and more than 60% of type 2 diabetes patients are at risk of developing diabetic retinopathy (DR). Diabetic retinopathy (DR) is a kind of diabetes that results in vision loss and lowers patient quality of life. This study looks at the biochemical and anatomic anomalies that arise in DR in order to better understand and manage the development of new therapy alternatives⁴⁶.

Diabetes mellitus (DM) is a global disease that has already afflicted 382 million people and will afflict 559 million by 2035. Managing diabetes mellitus-related complications in addition to the basic disease is the major issue for researchers and health-care providers. Diabetes retinopathy, the most serious microvascular consequence, is more likely to occur in diabetic people. Diabetic retinopathy (DR) causes blindness in persons aged 20 to 65 years. Nearly all type 1 diabetes patients and more than 60% of type 2 diabetes patients are at risk of developing diabetic retinopathy after ten years of diabetes⁴⁷.

Retinopathy of Prematurity is a significant cause of preventable blindness in preterm babies across both the developed and developing countries. Recent advancements in neonatal care have led to an increase in the survival of preterm and low birth weight infants, resulting in a rise of ROP incidence. Globally, ROP is estimated to affect more than 50,000 infants annually⁴⁸.

Retina's Anatomy:^{49, 50, 51}

The retina is a single layer of tissue that contains nerve cells that transmit images to the optic nerve. The retina consists of the following components:

· Macula: A little area near the very centre of the retina. The macula is ideal for seeing little details on things right in front of you, such as the text in a book.

· Fovea: A little depression in the centre of the macula. The fovea (sometimes called fovea centralis) is the eye's sharpest focus point.

· Photoreceptor cells: Photoreceptor cells are nerve cells that allow the eye to detect light and colour.

· Cones: A cone is a type of photoreceptor cell that detects and processes red, blue, and green colours, allowing for full-colour vision. In the retina, there are around 6 million cones.

· Rods: A type of photoreceptor cell that senses light levels while also providing peripheral vision. There are around 120 million people in the world.

· Peripheral retina: The peripheral retina is the retinal tissue that extends beyond the macula. Nerves in the peripheral retina process peripheral vision.

Though the retina is located in the peripheral location, but it is also a part of the central nervous system, which represents the neural portion of the eye. The biological changes in the retinal physical structure has a very great diagnostic value as they possess important information used to detect and diagnosis a variety of retinal diseases such as Diabetic Retinopathy (DR), glaucoma, hypertension, Age-related Macular Degeneration (AMD) ⁵².

Retinopathy of Prematurity (RoP). The major disease that can disturb overall health condition of a person in general is the diabetes. The most common cause for the vision loss during working age is diabetic retinopathy.

Optic disk usually has highest intensity and circular in nature. Line operator, is used to capture circular brightness and orientation of line segment helps to detect optic disk ⁵³. Optic disk detection guided by deformable model with regional statistics is used by in⁵⁴. Grid based method followed by pre-processing is used to detect optic disk. Pixel intensity combined with vessel convergence is used for the optic disk detection in⁵⁵.

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 ⁵⁶.

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 ^[3]. 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 outcomes⁴.

A variety of natural and synthetic polymers undergo in-situ gel formation and may be used in the oral, ocular, transdermal, buccal, intraperitoneal, parenteral, injection, rectal, and vaginal routes⁵. Recent advances in in-situ gels have made it possible to take advantage of changes in physiological uniqueness and in different areas of the gastrointestinal tract to improve drug absorption and improve patient convenience and compliance⁶. Pectin, gellan gum, chitosan, alginic acid, guar gum, carbopol, xyloglucan, xanthan gum, HPMC, poloxamer, etc. are some of the natural polymers used in the in-situ gelling systems. This review focuses primarily on the introduction of in-situ gels, different approaches, the evaluation of the various polymers used, and their applications⁷.

Mechanisms of In-Situ Gel Formation:

In-situ gelation is primarily triggered by physiological stimuli, leading to the transformation of the formulation from a sol to a gel state. The main mechanisms include:

· Temperature-Sensitive Systems: Utilize polymers like Poloxamers (e.g., Pluronic F127) that gel upon reaching body temperature.

· pH-Sensitive Systems: Employ polymers such as Carbopol that gel in response to pH changes, particularly useful for ocular and oral delivery.

· Ion-Sensitive Systems: Involve polymers like gellan gum and alginate that gel in the presence of specific ions (e.g., Ca²⁺) found in bodily fluids.

· Multi-Responsive Systems: Combine multiple stimuli-responsive mechanisms to achieve precise control over gelation and drug release profiles.

Polymers Utilized in In-Situ Gel Formulations:

Both natural and synthetic polymers are employed to formulate in-situ gels:

· Natural Polymers: Pectin, gellan gum, alginic acid, chitosan, and xyloglucan are favored for their biocompatibility and biodegradability.

· Synthetic Polymers: Poloxamers, poly (DL-lactic acid), poly (DL-lactide-co-glycolide), and polycaprolactone offer tunable mechanical properties and controlled degradation rates.

The selection of polymers is crucial, as it influences the gelation mechanism, mechanical strength, and drug release kinetics of the final formulation.

Formulation Strategies:

Developing an effective in-situ gel involves careful consideration of several formulation parameters:

· Polymer Concentration: Determines the viscosity and gel strength; optimal concentrations ensure ease of administration and adequate gel formation.

· Solvent System: Common solvents include water, dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP), selected based on polymer solubility and biocompatibility.

· Additives: Incorporation of mucoadhesive agents (e.g., Carbopol 934P, chitosan) enhances residence time at the administration site, improving drug absorption.

· Drug Incorporation: The drug is uniformly dispersed within the polymer solution, ensuring consistent dosing upon gelation.

Evaluation Parameters:

Comprehensive evaluation of in-situ gels is essential to ensure their efficacy and stability:

· Gelation Temperature and Time: Critical for thermosensitive systems; the gel should form promptly at physiological temperatures.

· pH and Viscosity: Should be compatible with the administration site to prevent irritation and ensure patient comfort.

· Drug Release Profile: In vitro studies assess the sustained release characteristics, aiming for a controlled and prolonged therapeutic effect.

· Mechanical Strength: Ensures the gel maintains its integrity during the intended duration of action.

Applications of In-Situ Gels:

In-situ gels have been explored for various routes of administration:

· Ocular Delivery: Enhance precorneal residence time, improving drug bioavailability for conditions like glaucoma and conjunctivitis.

· Oral Delivery: Provide sustained release in the gastrointestinal tract, beneficial for drugs with narrow absorption windows.

· Parenteral Delivery: Allow for localized and prolonged drug release, reducing systemic side effects.

· Periodontal Therapy: Deliver antimicrobial agents directly to periodontal pockets, improving treatment outcomes.

Challenges and Future Perspectives:

Despite the advantages, several challenges persist in the development of in-situ gels:

· Reproducibility: Ensuring consistent gelation behavior across batches is critical for clinical success.

· Stability: Long-term stability of the formulation under various storage conditions must be established.

· Regulatory Approval: Comprehensive characterization and clinical studies are required to meet regulatory standards.

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 characteristics⁸.

In-situ formation Based on Physical Mechanism:

Diffusion: Diffusion is the type of physical approach used in in-situ gel formulations. This method involves the release/ diffusion of solvent from a polymer solution to surrounding tissue resulting in Precipitation or Coagulation of polymer matrix⁹.

Swelling: In-situ formation can also occur when a material absorbs water from the surrounding environment and expand to occur desired space. In this method, the polymer absorbs surrounding fluids that are present in the exterior environment and swell to release the drug slowly¹⁰.

In-situ formation based on physiological stimuli:

Thermally trigged system: Temperature-sensitive hydrogels are probably the foremost commonly studied class of environment-sensitive polymer systems in drug formulation development¹¹. The use of polymers, where the transition from sol-gel is caused by increased temperature, is an attractive way to approach in-situ formation¹². The ideal critical temperature range for such systems is ambient and physiological temperatures, facilitating clinical manipulation and requiring no external heat source other than the body to gel the trigger ¹³. The useful system must be adjustable to account for small differences in local temperature that may be encountered on the surface of the skin or the appendages in the oral cavity¹⁴.

pH triggered systems: In these systems solution to gel transition is triggered by pH change. All pH-sensitive polymers contain additional acidic or basic groups that accept or release protons in response to changes in environmental pH¹⁵. Polymers with many ionizable groups are known as polymer electrolytes. The polyelectrolytes are present in the formulation causes an increase in external pH that leads to swelling of hydrogel that forms in-situ gel¹⁶.

In-situ formation based on chemical reactions:

Chemical reactions that result in in-situ gelation may include enzymatic processes, precipitation of inorganic solids from supersaturated ionic solutions, and photo-initiation processes¹⁷.

Ionic crosslinking:

Polymers can undergo a phase transition in the presence of various ions like Na+, K +, Ca+, and Mg+. Some of the polysaccharides fall into the ion-sensitive class²¹.

Enzymatic cross-linking:

In this method, a gel is made by cross-linking with the enzymes which are present in body fluids. In-situ formation catalyzed by natural enzymes has not been extensively studied but appears to possess several advantages over chemical and photochemical approaches²².

Photo-polymerization:

Photo-polymerization method of in-situ gel formation involves the use of electromagnetic radiation. A solution of monomer or reactive macromer and initiator can be injected into the tissue site and electromagnetic radiation can be applied to form a gel²³.

Evaluation Parameters:

Evaluation of in-situ gel formulations encompasses various parameters, including rheological properties, gelation kinetics, in vitro drug release profiles, ocular tolerance, and pharmacokinetics²⁴. 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 cavity²⁵. 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 irritation²⁶.

Physical evaluation:

Compatibility studies:

Compatibility studies carried out for a physical mixture of interaction between drug and excipients by a suitable method such as Fourier Transform Infra-Red Spectroscopy (FTIR) or Differential Scanning Calorimetry (DSC)²⁷.

Appearance:

Preferably, the gels should be transparent. The formulations were observed for a general appearance by the naked eye, such as color, odor, and the presence of suspended particulate matter²⁸.

Clarity test:

The clarity of the product checked using a black and white background²⁹.

Ph:

The pH was checked by using a calibrated digital pH meter immediately after preparation. In the case of ocular preparations, the pH preferably near to ocular pH to avoid eye irritation and enhance patient compatibility and tolerance³⁰.

Homogeneity:

By placing the preparation between two glasses, then observe particle roughness under the light³¹.

Isotonicity:

The formulation is mixed with few drops of blood, observe under a microscope, and compare with standard ophthalmic preparations. For all ophthalmic preparations, maintenance of isotonicity must need to prevent tissue damage and irritation to the eye³².

Sol-gel transition temperature:

The temperature of the phase transition of ‘sol’ meniscus was noted first and then heated at a specified rate. ‘Gel’ formation is indicated by a lack of movement of the meniscus on tilting the tube and note down the temperature^33,34.

Gelling time:

Gelling time is the time required for the first detection of gelation, as defined in sol-gel transition temperature^35,36.

Texture analysis:

The cohesiveness, consistency, firmness of in situ gels assessed using a texture profile analyzer, which mainly indicates the syringe ability of ‘sol’ so the formulation can be quickly administration via in vivo³⁷.

Spreading coefficient:

The device consists of a ground glass slide fixed on the wooden block. Each formulation weighing about 2 grams was placed and studied on this ground slide. Gel preparation was then sandwich between this slide and second slide having some dimension as that of the fixed glass slide. The second slide was provided with a hook. Weight of 1gram placed on top of the two slides for 5 min. to expel air and provide a uniform film of gel between two slides. Measured weight is placed on a pan attached to the pulley with the help of a hook. The time required by the top slide to separate from a ground slide was noted. A shorter interval indicates a better spreading coefficient (S)^38,39.

Gelling strength:

The rheometer determined the gelling strength, and it depends on the mechanism of the gelling agent, a specified amount of ‘gel’ prepared in a beaker, from the ‘sol’ form. This ‘gel’ containing beaker to be raised at a specific rate, so pushing a probe slowly through the ‘gel’ and the load on the probe is measured by the depth of the immersion of the ‘gel’ surface⁴⁰.

Viscosity and rheology:

At room (i.e., 25°C) and body temperatures (i.e., 37±0.5 °C), observe the viscosity using Brookfield viscometer. Rheology was observed due to the thixotropic behavior of the gel. In situ gel preparations should show pseudo-plastic and Newtonian flow before and after the gelation process. Before and after gelling, it should be 5-1000 m Pas (‘sol’) and after 50-50,000 m Pas (‘gel’), respectively. The gel formulation in situ should be well-formulated, so administration to the patient is proper, especially in ocular administration. However, these agents have the disadvantage of making blurred vision and leaving residue on the eyelids; due to high viscosity can cause difficulties in screening^41,42.

Drug Release Studies:

In vitro drug Release:

In vitro release study of in situ gelling systems can be carried out by using Franz diffusion cell to check the duration^43,44.

In vivo drug release:

Evaluation of drug preparation is one drug release in the body (in vivo). By knowing the time devastated and the polymer components used, we can design the drug as per the needs of pharmacotherapy⁴⁵.

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 ^[18]. 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 effects¹⁹.

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.

ACKNOWLEDGEMENT:

I Ms. Shivangi Das confirms sole responsibility for the following: study conception and design, data collection, analysis and interpretation of results, and manuscript preparation. I would also like to thank my guide Geetanjali Sahu for her continuous guidance and my colleague Ms. Suruchi Prasad for her consistent support throughout completion of this article.

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Received on 24.01.2025 Revised on 27.03.2025

Accepted on 03.05.2025 Published on 18.10.2025

Available online from November 03, 2025

Res. J. Pharma. Dosage Forms and Tech.2025; 17(4):286-292.

DOI: 10.52711/0975-4377.2025.00040

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