An ingestible self-orienting system for oral delivery of macromolecules

Abstract

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise's ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator's safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration.

Fig. 1.. Mechanical API localization and injection for oral gastric delivery.

(A) The SOMA localizes to the stomach lining, orients its injection mechanism toward the tissue wall, and injects a drug payload through the mucosa. The drug dissolves and the rest of the device passes out of the body. (B) A fabricated SOMA. (C) A comparison between the shape of the leopard tortoise (S. pardalis) and that of the SOMA. The SOMA quickly orients and remains stable in the stomach environment after reaching its preferred orientation. [Photo: M. M. Karim/ Wikimedia Commons, CC-BY-SA 2.5] (D) The SOMA uses a compressed spring fixed in caramelized sucrose (brown) to provide a force for drug-loaded millipost (blue) insertion. After actuation, the spring remains encapsulated within the device.

Fig. 2.. The SOMA self-orients quickly from any position and remains stable once oriented.

(A) Imaging at 1000 frames per second reveals that the SOMA, made from a mixture of PCL and stainless steel, self-orients. (B) Simulation-predicted and (C) experimentally measured (n = 15) orientation times from a given initial angle, θ₁, of ellipsoids, spheres, and SOMAs made from the same mass of PCL and stainless steel. The SOMA self-orients most quickly in the shaded regions between 0° and 45° and between 100° and 180°. The corner on the SOMA lengthens orientation times in the region of 45° to 100°, but (D) the corner also stabilizes the preferred orientation. The experimentally determined maximum tilting angle, θ₂, when exposed to a rocking motion of 15° at 0.5 rad/s (n = 10), is effectively 0° for the SOMA. This prevents the drug from misfiring into the lumen rather than the tissue. (E) Experimentally measured orientation times in fluids with varying viscosities from a 90° starting angle (n = 6). (F) SOMAs with weighted metal bottoms self-orient in vivo, whereas (G) PCL-only SOMAs fail to orient appropriately. Error bars indicate SD. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Fig. 3.. Millipost fabrication and insertion-force characterization.

(A) (I) Millipost stainless steel mold. (II) API mixture screen-printed into tip section. (III) Vibrations ensure powder fills cavity. (IV) Top section filled with biodegradable polymer. (V) Material compressed at 550 MPa. (B) 7-mm-long insulin millipost. (C) In vivo insertion force profile of insulin milliposts propelled at 0.2 mm/s in swine stomach (n = 2 stomachs, n = 8 insertions). Error bars indicate SD. (D) Micro-CT imaging of SOMA delivering a barium sulfate millipost into swine stomach tissue. Bottom is larger to ensure millipost stability during imaging. (E) Swine stomach hematoxylin and eosin-stained histology of dye injected by Carr-Locke needle in vivo to demonstrate penetration depth, (F) insulin millipost injected via a 5-N spring in the SOMA in situ, and (G) steel millipost inserted with a 9-N spring ex vivo. (H and I) Immunohistochemistry histology stained against α-smooth muscle actin of events in (F) and (G). M, mucosa; MM, muscularis mucosa; SM, submucosa; OM, outer muscularis.

Fig. 4.. In vivo API millipost delivery and device evaluation.

(A and B) Blood plasma levels for human insulin (H.I.) recorded in swine after manual subcutaneous millipost injection (S.C.) (n = 5), intragastric (I.G.) surgical millipost placement (n = 5), or I.G. millipost placement via a SOMA (n = 3). These swine are compared with animals dosed with SOMAs designed to localize the millipost to the tissue wall without injection (I.G. no inj.) (n = 5). 300 μg of human insulin was submerged underneath the tissue for each injection trial. Manually placed milliposts contain 80% human insulin and 20% PEO 200k. (C and D) All swine administered with an insulin injection demonstrated hypoglycemia, and many were rescued with dextrose. The SOMA datasets only include swine with successful fasting without residual food or measurable gastric fluid. Error bars indicate SD. N.D., no statistically significant difference.