1. Field of the Invention
This invention generally relates to the field of drug delivery. More particularly, this invention is directed to inhaled medications (for example medications delivered through pressurized metered dose inhalers (“pMDIs”) or other inhalers) and the delivery of medications to conducting airways and alveoli in a respiratory system.
2. Background of the Invention
Inhaled medications are commonly used to target drugs to the lungs in the treatment and prevention of various medical conditions. A. Steimer, E. Haltner, & C. M. Lehr, Cell Culture Models of the Respiratory Tract Relevant to Pulmonary Drug Delivery, 18 J. Aerosol Med. 137 (2005); R. Dalby & J. Suman, Inhalation Therapy: Technological Milestones in Asthma, 55 Adv. Drug. Del. Rev. 779 (2003). Drugs administered through the pulmonary route either act locally in the lungs or enter the systemic circulation following dissolution and absorption. Numerous particle and device engineering approaches have been attempted to incorporate drugs into small particles or make small pure drug particles for delivery to the most desirable lung locations. Such approaches include modifications to nebulizers, pressurized metered dose inhalers (pMDIs), active or passive dry powder inhalers (DPIs), or changes to the nature of the particles themselves. The ultimate objectives of particle and device engineering are to generate small slow moving particles with favorable aerodynamic properties. S. J. Farr, S. J. Warren, P. Lloyd, J. K. Okikawa, J. A. Schuster, A. M. Rowe, R. M. Rubsamen & G. Taylor, Comparison of in Vitro and in Vivo Efficiencies of a Novel Unit-Dose Liquid Aerosol Generator and a Pressurized Metered Dose Inhaler, 198 Int. J. Pharm. 63 (2000); VIII R. W. Niven, Respiratory Drug Delivery, Powders and Processing: Deagglomerating of a Dose of Patents and Publications 257-266 (R. N. Dalby, P. Byron, J. Peart, & S. Farr eds., DHI, Rayleigh 2002); K. R. Chapman, L. Love, & H. Brubaker, A Comparison of Breath-Actuated and Conventional Metered-Dose Inhaler Inhalation Techniques in Elderly Subjects, 104 Chest. 1332 (1993).
The fraction of drug delivered to the bronchial tree may be cleared by mucociliary transport and absorption through the airway epithelium into the systemic circulation. Thus, after initial deposition, drug particles do not migrate deeper into the lung. The opposite occurs: once particles encounter the fluid lining of the lung; they are either absorbed or transported to the larger airways of the lung by lung clearance mechanisms. Drug reaching the target region (which may be conducting airways or alveoli) of the lung following pulmonary inhalation (expressed as bioavailability or a deposition fraction) is often estimated at less than 10%. VIII M. Sakagami, Respiratory Drug Delivery, Pulmonary Insulin: a Critical Review of Its Biopharmaceutics 69-78 (R. N. Dalby, P. Byron, J. Peart, & S. Farr eds., DHI, Rayleigh 2002).
Following premature births, structurally immature and surfactant-deficient lungs containing reduced levels of pulmonary phospholipids are sometimes treated with natural and synthetic exogenous surfactants (treatment of Respiratory Distress Syndrome RDS). G. K. Suresh & R. F. Soll, Lung Surfactants for Neonatal Respiratory Syndrome: Animal Derived or Synthetic Agents, 4 Pediatr. Drugs. 485 (2002). These exogenous surfactants are complex colloidal dispersions composed primarily of phospholipids. They may contain additional components such as fatty acids, triglycerides and spreading agents. The dose of surfactant is relatively high and is administered to premature infants affected with RDS via endotracheal or intratracheal instillation wherein the surfactant is dripped directly into the bronchioles.
After instillation, the surfactant is distributed throughout the airways and the bolus advances distally while coating the airway walls with a thin layer of surfactant. F. F. Espinosa & R. D. Kamm, Bolus Dispersal Through Lungs in Surfactant Replacement Therapy, 86 J. Appl. Physiol. 391 (1999). The thickness of the coat of surfactant is dependent on surfactant concentration, viscosity and surface tension. In addition, a “reservoir” of surfactant remains in the larger airways as the surfactant expands into the lungs. Surface tension gradients draw exogenous surfactant distally to high surface tension locations thereby allowing surfactant to reach the alveoli.
FDA approval and continuous commercial availability of exogenous surfactants and their use in critically ill neonatal patients confirms the safety of phospholipid administration to the human respiratory tract. Their mode of administration (tracheal instillation) and site of action (alveolar spaces) confirms that the active components of these surfactant mixtures successfully spread from the trachea to the alveoli to exert their beneficial effect. R. J. Rodriguez, Management of Respiratory Distress Syndrome: An Update, 48 Respir. Care. 279 (2003).