Stabilization of Self-Pressurized Gelatin Capsules for Oral Delivery of Biologics.

Oral delivery of biologics offers advantages for patient access and adherence compared to injection, but suffers from low bioavailability due to mucosal barriers and drug degradation in the gastrointestinal tract. We previously developed an oral self-pressurized aerosol (OSPRAE) capsule that uses effervescent excipients to generate CO gas, building internal pressure to eject powdered drug at high velocity across intestinal mucosa. Here, we developed two key design improvements: (i) an enteric covering to protect the capsule delivery orifice in gastric fluids and (ii) reduced humidity content of capsules to extend shelf-life. Enteric-covered capsules prevented drug release in simulated gastric fluid and then enabled rapid release upon transfer to simulated intestinal fluid. Burst pressure for enteric-covered capsules was ~3-4 times higher than non-covered capsules. After storage for up to three days, the capsules' effervescent excipients pre-reacted, making them unable to achieve high pressure during subsequent use. To address this limitation, we prepared capsules under reduced humidity conditions, which inhibited pre-reaction of effervescent excipients during storage, and a polyurethane coating to improve water uptake into the capsule to drive the effervescence reaction in intestinal fluid. These design improvements enable improved functionality of OSPRAE capsules for continued translation in pre-clinical and future clinical development.