Pulmonary drug delivery
Pulmonary drug delivery is the inhalation of drug formulation through mouth and the further deposition of inhaled pharmacological agent to the site of action in the lungs for topically acting drugs, or the site of absorption for systemically acting drugs.
The respiratory tract includes the nasal mucosa, hypopharynx, and large and small airway structures (trachea, bronchi, bronchioles, and alveoli). This tract provides a large mucosal surface for drug absorption.
Lung epithelium is highly permeable and has low metabolic activity compared with the liver and intestine. With a large surface area and highly permeable membrane, alveolar epithelium permits rapid absorption. This route of administration is useful for treating pulmonary conditions and for drug delivery to other organs via the circulatory systems.
Since the lung has a large surface area and a highly permeable membrane, the lung is an ideal site for absorption of macromolecules, such as proteins, peptides, oligonucleotides, and genes. For example, DNase alpha (Pulmozyme®, Genentech), an enzyme used to reduce the viscosity of mucus in the airways of patients with cystic fibrosis, is most effective when inhaled.
This protein is thus delivered directly to its site of action by nebulization. The recent approval of inhaled human insulin by the FDA for use in diabetes mellitus stands as a major advancement in the field of pulmonary delivery of macromolecules and systemically acting drugs.
Advantages of pulmonary drug delivery
Lung epithelium is highly permeable and has low enzymatic/metabolic activity compared to the liver and intestine. With a large surface area (~100 m2) and a highly permeable membrane (~0.2–0.7 mm thickness), alveolar epithelium permits rapid drug absorption into the systemic circulation. There are 200–600 million alveoli in a normal human lung. This route of administration is useful for treating pulmonary conditions and for drug delivery to other organs via the circulatory systems.
In general, lipid-soluble molecules are absorbed rapidly from the respiratory tract, and thus, an increasing number of drugs are being administered by this route, including bronchodilators (e.g., beclomethasone dipropionate), corticosteroids, antibiotics, antifungal agents, antiviral agents, and vasoactive drugs.
Lung alveoli can also permit systemic absorption of macromolecules, such as proteins, peptides, oligonucleotides, and genes. For example, DNase alpha (Pulmozyme®, Genentech), an enzyme used to reduce the mucus viscosity in the airways of cystic fibrosis patients, is most effective when administered by inhalation. This protein is delivered directly to its site of action by nebulization. The recent approval of inhaled human insulin by the FDA for use in diabetes mellitus stands as a major advancement in the field of pulmonary delivery of macromolecules and systemically acting drugs.
Barriers to pulmonary drug delivery
The lung has evolved to maintain sterility of its pathways and to avoid undesired airborne pathogens and particles through mechanisms such as (a) airway geometry, (b) localized high humidity, (c) mucociliary clearance, and (d) the presence of alveolar macrophages. These mechanisms also present themselves as barriers to pulmonary drug delivery.
Devices for pulmonary drug delivery
- Metered dose inhaler: Pressurized spray is a metered dose inhaler (MDI) that incorporates propellant(s), surfactant(s), and the drug in either dissolved or suspended state in its formulation. Pressurized metered dose inhalers provide constant pressure on the liquid formulation and consistent quantity of drug release on actuation of the valve. The propellants used in these formulations include chlorofluorocarbons (CFCs) and hydrofluoroalkanes (HFAs).
Effective use of an MDI requires patient coordination of breathing and actuation to provide maximum amount and flow velocity of air going into the lungs. Drug solubility, vapor pressure, surface tension, solubility of oxygen/hygroscopicity, and density affect the effectiveness of drug delivery through the MDIs. MDIs are commonly used for the delivery of drugs for asthma and chronic obstructive pulmonary diseases (COPD).
- Nebulizer: The nebulizer uses an air compressor as a power source instead of a liquid propellant. Compressed air is brought in contact with an aqueous solution of the drug in a device. Liquid shearing leads to the formation of drug droplets that get inhaled by the patient. Droplet size is a key factor in effective pulmonary delivery of the drug through this route. The droplet size is typically controlled through the orifice diameter of the baffle, pressure of the gas, and the density, concentration, viscosity, surface tension, and flow rate of the drug solution. Nebulizers are frequently used in applications where patient’s strong inhalation is not required for effective drug delivery such as in pediatric or hospitalized patients.
3. Dry powder inhaler: The dry powder inhaler (DPI) allows the drug to be formulated in dry state, in which it may be more stable, does not require the use of a liquid propellant, and also does not require patient coordination between breathing and actuation. DPIs consist of a suspension of fine particulate drug formulation, which is dispersed by mechanical, pneumatic, or electrical energy, or by the strength of the vacuum generated by the patient’s breathing. DPIs have been used to treat diseases such as asthma, bronchitis, emphysema, and COPD.