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.
The challenges
ILLUSTRATION: MELISSA MCEVOY. IMAGES: JEAN-PAUL NACIVET/GETTY IMAGES; TOM NULENS
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Formulation concerns.
Achieving sufficient absorption of proteins is the most crucial challenge in formulation development, according to Wei-Guo
Dai, a research fellow in drug delivery and device development at Johnson & Johnson Pharmaceutical R&D. Delivering an adequate
amount of protein into circulation by oral delivery is difficult because enzymes in the body degrade the protein, the gastrointestinal
membrane is poorly permeable, and large molecules cannot easily enter into the bloodstream intact. Past efforts involving
particulate delivery systems (e.g., nanoparticles or liposomes, multifunctional polymers, and enzyme inhibitors) have achieved
low rates of absorption that were not adequate to achieve therapeutic efficacy, says Dai.
Permeation enhancers are one strategy to improve oral absorption. These agents include surfactants, fatty acids, and bile
salts. They can be added to the formulation as excipients, or incorporated into the delivery systems using proprietary technologies.
Permeation enhancers function by disrupting the intestine's epithelial membrane or by loosening the tight junctions (i.e.,
intracellular barriers) between epithelial cells.
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.
