Bi-weekly drug dosing using a slow release device – applications in tropical disease elimination

On 16th November, Drs. Andrew Bellinger, Mousa Jafari and Tyler Grant (MIT, Harvard Medical School and Lyndra Inc.) and colleagues published a paper on their new, ultra-long-lasting drug delivery platform. The platform is intended to deliver a therapeutic dose of a small molecule medicine over at least one week, as a solution to poor adherence and having to deliver multiple doses under difficult circumstances, such as in remote populations.

The central challenge in long-lasting delivery is to prevent passage of the ingested device through the intestine with gastric emptying. To safely overcome this while delivering sustained release of the drug, the device needs to adopt a number of properties: Having a shape and size that precludes immediate gastric emptying; being able to adopt a new conformation once ingested; being able to carry large quantities of the delivery drug and ensure controlled release over days or weeks without the risk of sudden release; being able to maintain stability of the delivery drug in the gastric low pH environment; and have appropriate safety mechanisms to allow eventual degrading and exiting from the stomach without damaging the intestine.

To comply with these properties, the device developed by the authors consists of a combination of rigid and flexible recoil elements, held together with degradable/dissolvable linker elements. The flexible recoil elements allow the device to be folded into a gelatine capsule and spontaneously unfold in the stomach, while the rigid polymer acts as a drug delivery matrix. To test whether their device satisfied the required properties in vivo, the authors undertook experiments with 35-50kg Yorkshire pigs, which are considered good models for human gastric anatomy.

delivery-device

Using X-ray imaging and endoscopy, the authors confirmed the device was present in the stomach of the pigs for up to 10 days without causing damage to the stomach lining or preventing passage of food or liquids. In contrast, the broken down components were eliminated within approx. 3 days. Next, the stability and release of Ivermectin was studied over time. Ivermectin is an antiparasitic medicine, famously donated by Merck and widely used to treat onchocerciasis (river blindness). Ivermectin also kills Anopheles mosquitoes, which carry malaria. In the present study, the authors loaded their delivery polymer with 15-20% (w/w) Ivermectin and tested the in vivo serum levels in pigs. Serum Ivermectin varied according to the formulation used, but the authors confirmed therapeutic serum levels of 8-40 ng/mL at 10 days.

In summary, this paper describes a polymer-based flexible drug delivery device able to deliver therapeutic doses of Ivermectin over at least 10 days. Eventually, the device breaks down in the gastric cavity and is passed through the duodenum, without causing any apparent harm in vivo to pigs receiving the device. The device has applications in hard to reach populations, where multiple dosing can be difficult to achieve. It may also have applications in therapies where adherence is a significant barrier, such as tuberculosis.

For more information, see Bellinger et al, “Oral, ultra–long-lasting drug delivery: Application toward malaria elimination goals“, Science Translational Medicine (2016)

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