Person:

Langer, Robert

Devices resident in the stomach -- which are used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric retentive dosage forms for prolonged drug delivery -- typically incorporate elastic polymers to compress the devices during delivery through the esophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric retentive devices.

For nearly four decades cancer-derived cell line monolayers have served as the recognized standard for the modeling of gastrointestinal (GI) absorption and have been widely used as a tool for oral drug development. However, they show limited in vivo predictability. We have developed approaches to cultivate porcine GI tissue and enable it to function ex vivo for prolonged periods. We then created an interface design that can achieve fully automated high-throughput interrogation of whole segments of the GI tract. This GI Tract-Tissue Robotic Interface System (GI-TRIS) demonstrated high predictive capacity of human oral drug absorption (Spearman correlation coefficient of 0.906 vs 0.302 for Caco-2 cell based systems) while allowing a sample throughput of several thousand samples per day in a fully automated robotic facility. To examine the capacity of the GI-TRIS, we analyzed the intestinal absorption of 2930 formulations with the peptide drug oxytocin resulting in the discovery of a novel enhancer that resulted in an 11.3-fold increase in oral bioavailability of oxytocin in vivo in a large animal model while no disruption of the intestinal tissue was observed. In sum, the GI-TRIS system has the potential to transform oral drug formulation development and introduces the ORIS concept as a pre-clinical strategy for a wide range of applications.

Insulin and other injectable biologic drugs transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3–5. Compared to subcutaneously administered drugs, oral formulations create less patient discomfort4, demonstrate greater chemical stability at high temperatures6, and don’t generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the Luminal Unfolding Microneedle Injector (LUMI), which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug we showed that, when actuated, the LUMI provided a faster pharmacokinetic uptake profile and a systemic uptake greater than 10% compared to a subcutaneous injection over a 4 hour sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.

A hydrogel binds to inflamed tissues, delivering therapeutics locally and reducing systemic drug exposure in mouse models of inflammatory bowel disease.

Nanoformulations of therapeutic drugs are transforming our ability to effectively deliver and treat a myriad of conditions. Often, however, they are complex to produce and exhibit low drug loading, except for nanoparticles formed via co-assembly of drugs and small molecular dyes, which display drug loading capacities of up to 95%. There is currently no understanding of which of the millions of small molecule combinations can result in the formation of these nanoparticles. Here, we report the integration of machine learning with high-throughput experimentation to enable the rapid and large-scale identification of such nanoformulations. We identified 100 self-assembling drug nanoparticles from 2.1 million pairings, each including one of 788 candidate drugs and one of 2686 approved excipients. We further characterized two nanoparticles, sorafenib-glycyrrhizin and terbinafine-taurocholic acid, both ex vivo and in vivo. We anticipate that our platform can accelerate the development of safer and more efficacious nanoformulations with high drug loading capacities for a wide range of therapeutics.

Inadvertent battery ingestion in children and the associated morbidity and mortality results in thousands of emergency room visits every year. Given the risk for serious electrochemical burns within hours of ingestion, the current standard of care for the treatment of batteries in the esophagus is emergent endoscopic removal. Safety standards now regulate locked battery compartments in toys, which have resulted in a modest reduction in inadvertent battery ingestion; specifically, 3,461 ingestions were reported in 2009, and 3,366 in 2013. Aside from legislation, minimal technological development has taken place at the level of the battery to limit injury. We have constructed a waterproof, pressure-sensitive coating, harnessing a commercially available quantum tunneling composite. Quantum tunneling composite coated (QTCC) batteries are nonconductive in the low-pressure gastrointestinal environment yet conduct within the higher pressure of standard battery housings. Importantly, this coating technology enables most battery-operated equipment to be powered without modification. If these new batteries are swallowed, they limit the external electrolytic currents responsible for tissue injury. We demonstrate in a large-animal model a significant decrease in tissue injury with QTCC batteries compared with uncoated control batteries. In summary, here we describe a facile approach to increasing the safety of batteries by minimizing the risk for electrochemical burn if the batteries are inadvertently ingested, without the need for modification of most battery-powered devices.