Drug delivery
This, alongside the fact that one in every three clinical trials now involves peptides or proteins, drives home just how much the field has evolved.
The oral barrier
This success has primarily related to injectable versions of peptides, proteins and antibodies, with around eight in ten therapies delivered subcutaneously and the remainder via IV. But neither of these methods is ideal when it comes to patient comfort, which is why the major challenge faced by researchers has been, and continues to be, overcoming poor bioavailability in oral protein and peptide delivery.
One benefit that could result from translating the advancements made with parenteral methods to oral delivery is medication adherence. According to a review published in the Annals of Internal Medicine, one in five patients don’t even f–ill their prescriptions and half of all patients with chronic conditions fail to take treatments in line with guidance. If we look at this knowledge in the context of multiple other studies that have shown patients prefer to swallow pills over more invasive forms of delivery – which is hardly a surprise, it’s not difficult to imagine oral protein and peptide treatments reducing medication nonadherence. When it comes to the challenge of oral bioavailability, unfavourable physicochemical properties, such as enzymatic degradation, large molecular weights and poor membrane permeability, all contribute. These issues were largely overcome for parenteral administration, in some cases thanks to excipients that help to preserve the protein structure – but for oral delivery, the gastrointestinal (GI) tract remains a barrier.
“If you think about the epithelial membranes all around the body, in the gut and airways small molecules will cross because they are quite lipophilic,” says Brayden. “The big challenge for peptides and proteins is getting enough across to achieve the levels you would get with a parenteral.” That isn’t the only issue; permeation is just the start. “On these other surfaces, like in the stomach, you’ve got acid and all of these enzymes coming out of your pancreas into the small intestine, as well as mucus,” says Brayden. “All of these are going to interfere with a protein or peptide getting across the gut wall, so you have metabolic issues too.”
Small pills, big business
Among the solutions currently under investigation are enteric coatings for tablets and capsules, enzyme inhibitors, intestinal permeation enhancers, nanoparticles and intestinal microdevices. The likes of Novo Nordisk are investing heavily in peptide and protein formulations with the aim of increasing oral offerings in the coming years. In 2020, after 15
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net 21 Tortoise-inspired capsules and unfolding arms
MIT and Novo Nordisk have adopted an injection-based method similar to that of Rani Therapeutics, but their Soma technology, which stands for self-orienting millimetre scale applicator, was actually inspired by the leopard tortoise. Native to Africa, this reptile has a dome-shaped shell that’s higher than that of other species. This, combined with its low centre of gravity, mean that if it happens to end up on its back, flipping back over is no great feat. Novo Nordisk worked with MIT researchers on a pill designed based on the same features and came up with the Soma, which has the ability to reorient itself wherever it lands in the stomach. The device contains a needle with a tip made of nearly 100% compressed, freeze-dried insulin. This is attached to a compressed spring that is held in place by a disk made of sugar. Once the Soma is in position in the stomach, the sugar dissolves and the needle is injected into the stomach tissue – releasing the insulin into the blood. Reports on the promise shown by the device were plenty back in 2019, but although the company suggested animal studies were encouraging, they were quick to state that human studies were a matter of years away – and that’s evident from the relative silence about the technology since.
The other technology MIT and Novo Nordisk are looking at is LUMI (luminal unfolding microneedle injector). This method trades the single injection of Soma for multiple 1mm needles attached to four arms, which unfold from a drug capsule while it’s in the small intestine and deliver the payload. The process lasts about ten minutes, after which the needles dissolve, followed by the arms over the following 24 hours. Trials performed on pigs and lengths of human small intestine have been encouraging, but as of yet no human studies have taken place.
years of development, the company announced: “the world’s first and only oral glucagon-like peptide-1 (GLP-1)-RA treatment for type 2 diabetes”. Prior to this point, GLP-1 (product name Rybelsus) was delivered via disposable pen injection devices.
Having previously partnered with Emisphere
Technologies to make use of its Eligen SNAC drug delivery technology, which enables the transport of therapeutic molecules across biological membranes like those of the GI tract, Novo Nordisk acquired the company for more than $1.3bn at the end of 2020. This highlighted its expectation that such technologies would become considerably more commonplace as they evolve.
But Brayden believes the deal had more to do with cost than effectiveness. “I think the industry is
Parenteral delivery methods like
subcutaenous injection provide the highest levels of bioavailability.
PongsakY/
www.shutterstock.com
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