Drug delivery
A major challenge facing researchers is overcoming poor bioavailability in oral protein and peptide delivery.
attracted by the fact that it can make peptides more cheaply than before,” says Brayden. “Rybelsus’ oral bioavailability is only 1%. If 1% of that oral format actually makes it to the blood, they’re losing 99% of that material. They must be able to make semaglutide more cheaply than they could maybe four or five years ago, as otherwise it wouldn’t be commercially viable.”
“A lot of researchers believe that nanotechnology or permeation enhancers are only going to give an incremental increase in the bioavailability of peptides and proteins.”
Special deliveries
There was great hope for nanoparticles in the not-too-distant past, however enthusiasm for them waned until recently due to, among other things, the difficulty of scaling and standardising their production. Brayden, who worked on nanoparticles as far back as the 1990s, says one of the issues he faced was the inability to make consistent batches of them. “We couldn’t scale them because we couldn’t put targeting agents on reproducibly; we’d do a rat study and it would work one week, we’d do it again and it wouldn’t work the next,” he says. “I think there is a credibility issue around a lot of the published research into nano[particles].” As understanding has evolved, Brayden says the situation has grown more positive. “Things have come around a bit,” he says, “because we now know a lot more about how nanos work in the GI tract, and we’ve got ways of getting them to cross the mucus by adding water-soluble coatings so that they can slip through where previously most of them were getting stuck. Now, we understand a lot more about how particles are taken up by the gut wall, or not.”
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This enhanced knowledge is fast becoming evident in the latest academic research, and some companies are working on oral insulin nanoparticles using silica, calcium phosphate or liposomes. There are also other delivery systems proving to be effective, particularly in type 2 diabetes, such as insulin inhalers for use at mealtimes. Cyclisation, N-methylation, stapling and scaffold grafting are all areas of interest for pharma and academia. But while researchers struggle to make breakthroughs by changing formulations or integrating nanoparticles, an approach that integrates medical devices into oral pharmaceuticals is showing the most promise. One company, Rani Therapeutics, claims it is “revolutionising healthcare” for millions of patients with chronic conditions with its RaniPill. Swallowed by the patient, the capsule travels through the GI tract wearing a protective coating so it can reach the intestine intact. It then triggers a balloon inside to inflate, prompting needles made of bioabsorbable materials, such as sugar, to inject their payload into the intestinal wall – a process the company claims has the same bioavailability as subcutaneous delivery. Brayden cautiously welcomes the concept, saying that a recent phase I study did well to demonstrate safety and proof of principle, despite a lot of variability in peptide levels in the blood of participants. Similarly, researchers at MIT and Novo Nordisk are investigating devices that orient themselves within the stomach, so that no matter how they land after being swallowed, they can inject drugs across the wall. Two developments are being pursued right now to meet this objective – Soma (self-orienting millimetre scale applicator) technology, and LUMI (luminal unfolding microneedle injector). Despite the excitement, though, Brayden says the promise for such devices must address snags, such as the potential damage they might cause to the GI tract’s internal structure, as well as blockages or a failure to activate.
“A lot of researchers believe that nanotechnology or permeation enhancers are only going to give an incremental increase in the bioavailability of peptides and proteins; you have to do something a lot more radical,” he concludes. “This is where the device field has really burgeoned in the last four or five years. That would range from using ultrasound, ballistics or microneedle patches to try and get drugs across the wall.”
Whether nanotechnology can make more of an impact in peptide and protein delivery will depend on how much researchers can increase the bioavailability. But if combining traditional pharmaceutical formulation with drug delivery mechanisms can match the benefits seen already in parenteral delivery, the tiny particles are going to need a big breakthrough to catch up. ●
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
White bear studior/
www.shutterstock.com
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