Delivering aerosols to the lung
Pharmaceutical companies would not continue their inhaled-insulin programs unless respiratory delivery provided a tangible
benefit for patients and made economic sense. But before inhalable insulin formulations were developed, aerosols were used
to treat respiratory diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Drugs for these
diseases remain the dominant segment of the respiratory-delivery market.
Patton says that respiratory delivery is a good option for treating chronic respiratory conditions. He notes that at least
40 inhalation drugs have been approved, Genentech's (South San Francisco, CA) "Pulmozyme" among them, and they are considered
relatively safe. "Pulmozyme has proven to be a quite safe protein with chronic use-in sick lungs-over a decade," Patton remarks
Genentech developed the Pulmozyme biological as an inhalation solution to manage cystic fibrosis. The US Food and Drug Administration
approved the drug product in 1993.
Companies are seeking new inhalation treatments for cystic fibrosis. For example, BioSante is examining the possibility of
using its CaP system for respiratory delivery of α1 -antitrypsin. This medicine for cystic fibrosis could also be used to treat emphysema and venous thromboembolism, according
to the company.
Scientists have investigated respiratory-delivery methods for drugs that manage pulmonary hypertension (PH), including iloprost.
In Dec. 2004, FDA approved Actelion Pharmaceuticals's (Allschwil, Switzerland) "Ventavis" iloprost inhalation solution. In
Nov. 2007, United Therapeutics (Silver Spring, MD) announced positive results of its Phase III trial of "Viveta," an inhaled
formulation of treprostinil that treats PH.
Drugs that treat tuberculosis (TB) cannot be given at high doses because high systemic exposure causes toxic side effects.
But one can deliver these drugs directly to the lungs at much lower doses using an inhaler. This technique would have a better
therapeutic effect than a pill or syringe would. It would also result in fewer toxic side effects. "Pulmonary delivery is
a much better alternative than injection to treat local conditions," Simes says.
Researchers are developing inhalable vaccines against TB, remarks Dalby. In 2007, the Harvard University Gazette reported that a Harvard research team developed a spray-drying method to preserve and deliver the Bacillus Calmette-Guérin
(BCG) TB vaccine. This spray-drying technique could lead to aerosol delivery of BCG.
Sievers observes that some therapies such as small interfering RNA (siRNA) drugs are only effective if they can be delivered
into cells at the site of infection. Recent evidence suggests that "the administration of siRNAs in aerosol form works for
certain applications where injections were less effective," he says. Pharmaceutical companies "are bound to be looking at
siRNAs because they're such a wonderful strategy." siRNAs could be used to treat respiratory syncytial virus (RSV) infection
and diseases such as cancer.
Alnylam (Cambridge, MA) is developing ALN-RSV01, a siRNA, for the treatment of RSV. In Jan. 2008, the company announced study
results showing that ALN-RSV01 was safe, well tolerated, and demonstrated statistically significant antiviral activity. Alnylam
will use its "Direct RNAi" approach to deliver the drug directly to the lungs to neutralize the virus.
Formulating drugs for pulmonary administration presents challenges, however. Although scientists know the lung absorbs biologic
drugs that have a wide range of molecular weights, lipophilicities, and polarities, "our ability to predict the mechanism,
rate, and extent of absorption is at an early stage," Dalby cautions.
Delivering inhaled formulations to the lung may cause local toxic effects such as edema, cell injury, or altered tissue defenses.
Propellents, preservatives, or carriers such as sulfites may also harm the body.
Patton acknowledges that safety is always a concern for any new form of drug delivery, but he argues that it can be managed.
"The lung has a great capacity for handling foreign material," he says. Delivering grams of drug would be unwise, Patton admits,
but "for most biologicals and other drugs, that's usually not a problem" because they would be given in microgram to low milligram