Exploring Antibubbles for Oral Drug Delivery

Abstract

The design of effective drug delivery systems is central to pharmaceutical research, aiming to ensure that therapeutic agents reach their intended sites of action with stability, bioavailability, and controlled release. Conventional carriers such as liposomes, nanoparticles, microparticles, dendrimers, hydrogels, and solid lipid nanoparticles often face limitations, including low encapsulation efficiency, premature burst release, and inadequate site-specific targeting. These shortcomings highlight the need for new encapsulation strategies with improved stability, drug loading, and release control. Antibubbles are proposed as promising alternatives. They possess a water-in-air-in-water (W/A/W) structure, in which aqueous drug cores are surrounded by an air film stabilized by colloidal particles. This unique shell prevents premature leakage and enables stimulus-responsive release. Particle stabilization offers enhanced stability by irreversibly adsorbing colloids at interfaces to form rigid shells. The fabrication process involves preparing a water-in-oil (W/O) emulsion stabilized by hydrophobic nanoparticles, dispersing it in an aqueous phase to form a W/O/W Pickering emulsion, and freeze-drying to remove the volatile oil. Upon rehydration, stable antibubbles are formed with intact air films. This versatile structure allows loading of hydrophilic and lipophilic drugs and enables tailored release under gastrointestinal conditions. Chapter 2 provides an overview of antibubble formation, mechanisms of collapse, factors influencing stability, and potential applications in drug delivery, while identifying research gaps and future directions. Chapter 3 introduces acid-responsive antibubbles stabilized with calcium carbonate particles pre-coated with stearic acid or prepared in situ with sodium stearoyl lactylate, demonstrating their responsiveness to acidic conditions. Chapter 4 describes daunorubicin-loaded silica nanoparticle-stabilized antibubbles engineered for intestinal delivery. These antibubbles remained stable under gastric conditions but released their contents in response to bile salts, confirming protection of daunorubicin against degradation and targeted intestinal release. Chapter 5 presents a novel triple-emulsion-based antibubble system enabling co-encapsulation of hydrophilic and hydrophobic drugs, thereby expanding the scope of multidrug formulations. Chapter 6 investigates premix membrane emulsification (PME) as a gentler fabrication technique. PME produced smaller antibubbles while maintaining high entrapment efficiency and was especially suitable for shear- and heat-sensitive compounds. Chapter 7 introduces antibubbles stabilized by prednisolone-loaded Eudragit® RS100 nanoparticles with mesalamine encapsulated in the cores. This system demonstrated prolonged release across gastric, intestinal, and colonic environments for up to 32 hours, with tunability achieved through nanoparticle type and concentration. Finally, Chapter 8 summarizes the research findings, discussing the mechanisms of drug release, opportunities for loading hydrophilic and hydrophobic actives, and the broader implications of antibubbles in oral drug delivery. Future perspectives highlight strategies for enhancing performance, scalability, and clinical translation. In conclusion, this thesis demonstrates that particle-stabilized antibubbles are versatile and effective oral drug delivery systems. Their ability to protect drugs, enable site-specific release, and allow multidrug encapsulation makes them strong alternatives to conventional carriers, opening new directions for controlled drug delivery technologies.