Journey to the Center of the Lung - Pharmaceutical Technology

Latest Issue

Latest Issue
PharmTech Europe

Journey to the Center of the Lung
What makes a drug ripe for respiratory delivery?

Pharmaceutical Technology

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?"


blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
| Weekly

What role should the US government play in the current Ebola outbreak?
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Jim Miller Outsourcing Outlook Jim MillerOutside Looking In
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerAdvances in Large-Scale Heterocyclic Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler New Era for Generic Drugs
Sean Milmo European Regulatory WatchSean MilmoTackling Drug Shortages
New Congress to Tackle Health Reform, Biomedical Innovation, Tax Policy
Combination Products Challenge Biopharma Manufacturers
Seven Steps to Solving Tabletting and Tooling ProblemsStep 1: Clean
Legislators Urge Added Incentives for Ebola Drug Development
FDA Reorganization to Promote Drug Quality
Source: Pharmaceutical Technology,
Click here