Journey to the Center of the Lung

Pfizer's (New York) "Exubera" is only a recent example of a biological drug that was succesfully formulated for respiratory administration. In 1993, the USFood and Drug Administration approved Genentech's (South San Francisco, CA) "Pulmozyme"(inhalable dornase alfa), a biological drug for the treatment of cystic fibrosis.

What characteristics make a drug suitable for respiratory delivery? First, a drug must be stable in aqueous or powder formulations to be aerosolized. In addition, powders should be free-flowing so they do not aggregate and prevent consistent delivery, observes Robert E. Sievers, professor of chemistry at the University of Colorado and CEO of Aktiv-Dry (Boulder, CO).

Proteins, peptides, and monoclonal antibodies are good choices for inhaled delivery, according to Stephen M. Simes, president and CEO of specialty drug company BioSante Pharmaceuticals (Lincolnshire, IL). Currently these active ingredients can only be delivered through subcutaneous or intravenous routes. The high permeability of the alveolar epithelium makes pulmonary delivery of large molecules more beneficial than administration via injection, Simes says.

Claims that high molecular weight proteins would be hard to deliver to the lungs make Sievers skeptical. "Maybe, and maybe not," he says, adding that various strategies for the respiratory delivery of large proteins are under investigation. "In gene therapy," he explains, "they use tricks to get things into humans that the human system is normally arranged to defend itself against."

"Clearly, antibody-sized drugs can be delivered through the airways," notes John Patton, chief scientific officer and cofounder of Nektar Therapeutics (San Carlos, CA). He observes that Syntonix Pharmaceuticals (Waltham, MA) used an approach similar to PEGylation to deliver large molecules to the lungs. The company attached cytokines to their drug to transport it across the pulmonary epithelium. The technique resulted in good absorption and prolonged activity, Patton says.

Formulators must pay attention to particle size, Sievers argues, because that determines whether a drug is deposited in the nasal passages, the throat, or the lungs. Manufacturers must aim for a different target, depending upon the formulation. Drugs that can be formulated as 1–4-μm particles, for example, generally are good candidates for pulmonary delivery.

Low molecular weight hydrophobic molecules are also appropriate. These molecules are absorbed more rapidly and have better bioavailability than hydrophilic molecules. Molecules that are too hydrophobic, however, have low solubility and delayed action. Charge-masking can help formulators deliver charged, low-molecular weight molecules.

Bioavailability isn't a crucial concern for inhaled drugs providing systemic delivery unless the drugs are expensive, according to Igor Gonda, CEO of Aradigm (Hayward, CA). Dose size and therapeutic index are, however. Reproducibility of delivery is important for efficacy and safety if the drug has a relatively narrow therapeutic index.

Richard Dalby, professor of pharmaceutical sciences at the University of Maryland, agrees. "A small effective dose, wide therapeutic index, and evidence for complete absorption following respiratory delivery make a candidate scientifically promising," he says.

For more about respiratory delivery of biological drugs, see "Inhalable Drugs on the Launch Pad:Will They Take Off?"