The current study aimed to develop pH-responsive hydrogel beads based on sodium alginate (SA) and acrylic acid (Aa), crosslinked in the presence of calcium chloride, for the controlled delivery of ketorolac tromethamine. The hydrogel beads were fabricated using the ionic gelation technique and subsequently characterized for their structural properties, surface morphology, and thermal stability. Additional investigations, including sol-gel analysis, drug loading efficiency, and drug quantification, were conducted to evaluate the physicochemical attributes of the prepared beads. Furthermore, Monte Carlo simulations using the adsorption locator module in Materials Studio were conducted to investigate the adsorption behavior of ketorolac on the SA/Aa hydrogel beads. The negative adsorption energy obtained from the simulations suggested that the interaction between the drug and polymer was both spontaneous and exothermic, indicating a thermodynamically favorable binding mechanism. The pH responsiveness of the beads was evaluated through swelling and drug release studies under different pH conditions (pH 1.2 and 7.4). The results indicated markedly significant swelling and drug release at pH 7.4 as compared to 1.2, thereby confirming the pH-responsive behavior of the formulated beads. The toxicity of the hydrogel beads was evaluated using the Hen's Egg Test on Chorioallantoic Membrane (HET-CAM), which revealed no signs of irritation or toxicity. An in vivo pharmacokinetic study in rabbits further demonstrated that the drug-loaded hydrogel beads achieved higher plasma concentrations of ketorolac tromethamine compared to the drug solution, supporting their potential for improved bioavailability. Hence, the developed SA/Aa-based hydrogel beads exhibited favorable physicochemical, biocompatibility, and pharmacokinetic profiles, making them promising candidates for controlled drug delivery systems.

Arthritis conditions are widely treated with oral nonsteroidal anti-inflammatory drugs, yet long-term therapy is often limited by gastrointestinal toxicity and variable systemic exposure. To overcome these issues, an injectable thermosensitive chitosan/β-cyclodextrin-graft-poly(N-isopropylacrylamide) hydrogel was developed as a subcutaneous depot for sustained diclofenac sodium delivery. The hydrogel was synthesized via free-radical polymerization using glutaraldehyde as a crosslinker. FTIR and ¹H NMR confirmed network formation and drug incorporation, while DSC, TGA, and DTG analyses demonstrated enhanced thermal stability. SEM revealed a porous, interconnected structure, and EDX mapping verified uniform drug distribution. Rheological and swelling studies indicated shear-thinning behavior, good injectability at room temperature, rapid sol-gel transition at 37 °C, and reversible temperature-responsive swelling. In vitro release, with profiles best fitted by the Korsmeyer-Peppas model, indicating a non-Fickian diffusion-relaxation mechanism. Enzymatic degradation confirmed sufficient structural stability to support drug release for more than 10 days. HET-CAM and hemolysis assays demonstrated good biocompatibility. In vivo studies showed reduced peak plasma concentration, prolonged T_max, mean residence time, and half-life, with an approximately three-fold increase in relative bioavailability compared with the control, supporting depot-like sustained release. Overall, this thermosensitive hydrogel represents a promising platform for controlled and sustained subcutaneous drug delivery.

Injectable thermosensitive hydrogels have emerged as a promising class of biomaterials for the sustained delivery of drug. These smart systems undergo a sol-gel phase transition in response to physiological temperature, enabling minimally invasive injection and the formation of an in situ drug depot capable of controlled and sustained drug release. In recent years, thermosensitive hydrogels have drawn increasing attention in type 2 diabetes mellitus (T2DM) therapy, offering enhanced patient adherence, stable glycemic control, and reduced injection frequency compared with conventional formulations. Importantly, beyond glucose lowering, several hydrogel-based incretin therapies-particularly GLP-1 receptor agonists and dual GIP/GLP-1 agonists-have demonstrated clinically significant body-weight reduction and improved metabolic outcomes, addressing both hyperglycemia and obesity, two core components of T2DM pathophysiology. This review summarizes the classification, polymer composition, and drug release mechanisms of thermosensitive hydrogels. Special emphasis is placed on their use in the sustained delivery of insulin, GLP-1 receptor agonists and dual GIP/GLP-1 agonists. These hydrogel-based depots have demonstrated prolonged pharmacological efficacy, while preserving drug bioactivity, minimizing burst release, and achieving superior improvements in glycemic control and providing superior body-weight management with GLP-1 receptor agonists-loaded thermosensitive hydrogels, as compared with conventional injectable regimens. Finally, the challenges and future prospects of thermosensitive hydrogel systems are discussed, including the need for improved formulation stability, scalable manufacturing, and regulatory translation. With continued interdisciplinary advancements, injectable thermosensitive hydrogels hold strong potential as next-generation, long-acting, and patient-friendly delivery platforms for comprehensive diabetes management, encompassing both glycemic control and body-weight reduction in T2DM patients.