The oral delivery of biopharmaceuticals is highly desirable because it would provide ease of administration and improve patient compliance. But oral administration remains an elusive goal in biopharmaceutical drug delivery. To date, major obstacles have included problems of bioavailability caused by low absorption, poor cellular permeability, and protein instability and degradation. Several specialty pharmaceutical and other companies are applying various absorption-enhancing technologies to address the problem with some success. Nevertheless, challenges remain, including limitations on the size of the macromolecules that can be delivered.
In certain cases, permeation enhancers have enabled formulators to achieve 10% bioavailability in preclinical research studies. But the amount of permeation enhancers required in these studies raises concerns about toxicity. Various types of permeation enhancers entail various levels of risk, but even agents that are generally recognized as safe, such as ethanol and fatty acids, could pose toxicity problems because of the dosage amount and frequency. Formulators thus must conduct comprehensive toxicity studies, says Dai.
Another strategy to compensate for low bioavailability is to increase the dose of protein in a tablet. For example, if a tablet contained hundreds of milligrams of insulin—far more than is administered in an injection—and if 1–5% of it were absorbed into the bloodstream, it could be enough to achieve the desired therapeutic effect. But this approach has limitations. "You may be able to jack up the dose, but your absorption window may be so small that you just don't have enough time for the drug to be absorbed," says Carlos N. Velez, managing partner of LacertaBio, a biotechnology business-development consulting firm.
Aside from absorption issues, increasing the level of protein in an oral formulation may not be cost-effective in the absence of a superior clinical benefit. "My guess is there just aren't enough suppliers for some of these proteins to bring the cost down to the point where you've got a $5-per-day dose," says Velez. He cites one company that has an oral formulation of a modestly sized peptide, but cannot buy the active ingredient at a low price. "It'll be an enormous dollar-per-day dose, and that program is probably not going to get very far because of a supply-cost issue," says Velez.