Activation-modulated stimuli-responsive systems: an intelligent platform for site-specific gastroretentive delivery of diverse therapeutic agents.

Activation modulated stimuli-responsive systems (AMS), commonly known as raft-forming systems (RFS), are an innovative platform within gastroretentive drug delivery technologies. These pH-triggered systems transform orally administered liquids from sol to a low-density, viscous floating gel or "raft" by ionotropic gelation upon contact with gastric-ions. Typically, composed of smart hydrophilic polymers, effervescent, and cross-linking agents, AMS stay buoyant in stomach and release drugs instantly in response to physiological stimuli to meet urgent clinical needs. These systems are especially valuable for drugs targeting local gastric action, reducing systemic exposure. AMS can be custom-designed to release therapeutic agents that exhibit high solubility or good stability in response to acidic conditions in stomach to maximize bioavailability. Owing to the strategic location, proximal to absorption window and ability to control release in stomach, AMS has the proven potential to improve the absorption of several therapeutics. AMS can be tailored to modulate microenvironment pH and thereby enhance delivery of drugs that exhibit solubility or stability challenges in an acidic milieu. This review is an attempt to offer an entirely new dimension to the composition, formulation strategies, evaluation techniques, and applications of AMS. Recent advances include development of systems comprising smart polymers that respond to specific physiological stimuli, multi-responsive systems, nanotechnology-integrated, and 3D printed systems. Despite challenges in formulation stability, scale-up, and reproducibility, these systems have generated considerable regulatory and commercial interest globally. Thus, AMS have emerged as a unique and innovative platform with high translational potential to leverage immense clinical benefits of diverse therapeutic agents.