From Liquid to Gel: Multifunctional Stimuli-responsive Polymers for Targeted Oral Drug Delivery

Oral drug delivery is the delivery method of choice, as it is non-invasive and patients will comply with the delivery method, but many contemporary therapeutics, such as poorly soluble, permeable, and unstable drugs, fail because of rapid gastrointestinal absorption, enzyme degradation, and non-targetability. The in-situ gelling systems are now considered paradigms that no longer exist as liquids; instead, they form a depot in the gastrointestinal tract and transform into a gel in response to physiological signals such as pH, ions, or enzymes. This review will discuss how these so-called smart polymers have developed over the years, starting as simple gel-forming systems and evolving into the multifunctional platforms that are also designed to have a pointed and sustained action. Next generation in situ gels combine bioadhesion, permeation enhancement, and active targeting ligands to overcome sequential barriers to delivery transit, permeability, stability, and cellular uptake. We critically assess the chemistry, mechanisms, formulation strategies, and therapeutic use of these systems, including gastro-retention and localized therapy, as well as oral delivery of biologics. Despite encouraging preclinical results, we touch on translational issues of scalability, manufacturing, and regulatory pathways. Multifunctional stimuli-responsive polymers, which actively traverse the gastrointestinal environment, are the future of oral drug delivery because they provide precision, bioavailability, and improved patient outcomes.