A once-a-month oral contraceptive.

Poor patient adherence to oral contraceptives is the predominant cause of failure of these therapies, leading to unplanned pregnancies that can negatively affect female health worldwide. To improve patient adherence, we developed an oral contraceptive that is administered once a month. Here, we describe the design and report in vivo characterization of a levonorgestrel-releasing gastric resident dosage form in pigs.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

3D-Printed Gastric Resident Electronics.

Long-term implantation of biomedical electronics into the human body enables advanced diagnostic and therapeutic functionalities. However, most long-term resident electronics devices require invasive procedures for implantation as well as a specialized receiver for communication. Here, a gastric resident electronic (GRE) system that leverages the anatomical space offered by the gastric environment to enable residence of an orally delivered platform of such devices within the human body is presented. The GRE is capable of directly interfacing with portable consumer personal electronics through Bluetooth, a widely adopted wireless protocol. In contrast to the passive day-long gastric residence achieved with prior ingestible electronics, advancement in multimaterial prototyping enables the GRE to reside in the hostile gastric environment for a maximum of 36 d and maintain ≈15 d of wireless electronics communications as evidenced by the studies in a porcine model. Indeed, the synergistic integration of reconfigurable gastric-residence structure, drug release modules, and wireless electronics could ultimately enable the next-generation remote diagnostic and automated therapeutic strategies.

Scalable Gastric Resident Systems for Veterinary Application.

Gastric resident dosage forms have been used successfully in farm animals for the delivery of a variety of drugs helping address the challenge of extended dosing. Despite these advances, there remains a significant challenge across the range of species with large variation in body size. To address this, we investigate a scalable gastric resident platform capable of prolonged retention. We investigate prototypes in dimensions consistent with administration and retention in the stomachs of two species (rabbit and pig). We investigate sustained gastric retention of our scalable dosage form platform, and in pigs show the capacity to modulate drug release kinetics of a model drug in veterinary practice, meloxicam, with our dosage form. The ability to achieve gastric residence and thereby enable sustained drug levels across different species may have a significant impact in the welfare of animals in both research, agricultural, zoological, and clinical practice settings.

Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy.

The efficacy of antiretroviral therapy is significantly compromised by medication non-adherence. Long-acting enteral systems that can ease the burden of daily adherence have not yet been developed. Here we describe an oral dosage form composed of distinct drug-polymer matrices which achieved week-long systemic drug levels of the antiretrovirals dolutegravir, rilpivirine and cabotegravir in a pig. Simulations of viral dynamics and patient adherence patterns indicate that such systems would significantly reduce therapeutic failures and epidemiological modelling suggests that using such an intervention prophylactically could avert hundreds of thousands of new HIV cases. In sum, weekly administration of long-acting antiretrovirals via a novel oral dosage form is a promising intervention to help control the HIV epidemic worldwide.

Defining optimal permeant characteristics for ultrasound-mediated gastrointestinal delivery.

Ultrasound-mediated drug delivery in the gastrointestinal (GI) tract is a bourgeoning area of study. Localized, low-frequency ultrasound has recently been shown to enable significant enhancement in delivery of a broad set of active pharmaceutical ingredients including small molecules, proteins, and nucleic acids without any formulation or encapsulation of the therapeutic. Traditional chemical formulations are typically required to protect, stabilize, and enable the successful delivery of a given therapeutic. The use of ultrasound, however, may make delivery insensitive to the chemical formulation. This might open the door to chemical formulations being developed to address other properties besides the deliverability of a therapeutic. Instead, chemical formulations could potentially be developed to achieve novel pharmacokinetics, without consideration of that particular formulation's ability to penetrate the mucus barrier passively. Here we investigated the effect of permeant size, charge, and the presence of chemical penetration enhancers on delivery to GI tissue using ultrasound. Short ultrasound treatments enabled delivery of large permeants, including microparticles, deep into colonic tissue ex vivo. Delivery was relatively independent of size and charge but did depend on conformation, with regular, spherical particles being delivered to a greater extent than long-chain polymers. The subsequent residence time of model permeants in tissue after ultrasound-mediated delivery was found to depend on size, with large microparticles demonstrating negligible clearance from the local tissue 24h after delivery ex vivo. The dependence of clearance time on permeant size was further confirmed in vivo in mice using fluorescently labeled 3kDa and 70kDa dextran. The use of low-frequency ultrasound in the GI tract represents a novel tool for the delivery of a wide-range of therapeutics independent of formulation, potentially allowing for the tailoring of formulations to impart novel pharmacokinetic profiles once delivered into tissue.

Wireless Power Transfer to Millimeter-Sized Gastrointestinal Electronics Validated in a Swine Model.

Electronic devices placed in the gastrointestinal (GI) tract for prolonged periods have the potential to transform clinical evaluation and treatment. One challenge to the deployment of such gastroresident electronics is the difficulty in powering millimeter-sized electronics devices without using batteries, which compromise biocompatibility and long-term residence. We examined the feasibility of leveraging mid-field wireless powering to transfer power from outside of the body to electronics at various locations along the GI tract. Using simulations and ex vivo measurements, we designed mid-field antennas capable of operating efficiently in tissue at 1.2 GHz. These antennas were then characterized in vivo in five anesthetized pigs, by placing one antenna outside the body, and the other antenna inside the body endoscopically, at the esophagus, stomach, and colon. Across the animals tested, mean transmission efficiencies of -41.2, -36.1, and -34.6 dB were achieved in vivo while coupling power from outside the body to the esophagus, stomach, and colon, respectively. This corresponds to power levels of 37.5 µW, 123 µW and 173 µW received by antennas in the respective locations, while keeping radiation exposure levels below safety thresholds. These power levels are sufficient to wirelessly power a range of medical devices from outside of the body.

Flexible piezoelectric devices for gastrointestinal motility sensing.

Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.

Oral, ultra-long-lasting drug delivery: Application toward malaria elimination goals.

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine large-animal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malaria-transmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malaria-transmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy.