Abstract
Not many topics in drug delivery science have exercised so many pharmaceutical, formulation, and bioengineering minds than the oral delivery of macromolecules, especially when insulin is the focus. The year 2021 marks a hundred years since the discovery of insulin by Banting and Best to treat Type 1 diabetes. Repeated efforts to deliver it orally since then have met with failure, with particular disappointment resulting from encouraging preclinical studies in the 1980s. Here, the barriers to synthesizing successful oral inulin formulations are discussed. It is apparent that this peptide has chemistry and pharmacology features that make its oral delivery one of the toughest challenges in delivery science. At this seminal point in its history, the question is whether oral delivery of insulin will ever be possible, or even if this quest is still desirable?
Highlights
After insulin was discovered, one of the very first studies indicated that insulin could not be delivered by the oral route using dilute alcohol as a solvent (Harrison, 1923)
A significant recent technical achievement for pain-free administration has allowed short-acting insulin to be delivered across the pulmonary epithelium for meal-time administration in inhaled formulations (Afrezza® Mannkind, NJ, United States; Exubera® (Pfizer, CT, United States), (Al-Tabakha, 2015)
Perhaps this is a disservice to current efforts, as several recent studies in rodents suggest that substantial oral bioavailability for oral insulin (based indirectly on Area Above the Curve (AAC) calculations from plasma glucose reductions) can be achieved with high-performing new enhancer- and nanoparticle-based systems
Summary
After insulin was discovered (reviewed in Vecchio et al, 2018), one of the very first studies indicated that insulin could not be delivered by the oral route using dilute alcohol as a solvent (Harrison, 1923). Despite what was a pilot study, serious attempts did not follow for decades as the received wisdom was that macromolecule delivery by the oral route was not possible To this day, basal- and short-acting insulins are administered either by subcutaneous (SC) injections for both Type 1 and 2 diabetics, or by implantable pumps for Type 1 diabetics. Patient take-up for Afrezza® remains elusive due to cost and reimbursement issues, a reluctance of endocrinologists to switch their patients from injections, and the lack of competition in insulin pricing in the United States (Knox, 2020) These important nonscience factors must be considered if an orally delivered insulin ever proves to be technically possible. Insulin may be considered a weak candidate for oral delivery because it has a low therapeutic index (Lamont et al, 2010) and because there will be very large variation in oral bioavailability from
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