Inhaled aerosol medications offer an opportunity to directly treat sites of disease within the lung. Current delivery techniques rely mostly on aerodynamic mechanisms to disperse and distribute these medications inside the lung after inhalation. The elements of obstruction common to lung diseases such as cystic fibrosis, bronchiectasis, or chronic obstructive pulmonary disease (COPD) can decrease ventilation in portions of the lung, preventing aerosol drugs from reaching these zones. The unusual aerodynamics associated with obstructive disease can also cause very non-uniform deposition patterns, further limiting penetration of active drug. Poor distribution of these medications ultimately limits their efficacy. For example, the inhaled antibiotics used to treat bacterial infections associated with cystic fibrosis lung disease often provide successful suppression of infection but rarely provide eradication. Drug resistance has also been associated with these therapies likely due to the consistent delivery of sub-therapeutic doses at sites of infection. Our goal here is to develop novel self-dispersing platforms for inhaled antibiotics that will provide improved drug distribution and improved performance in the treatment of bacterial infections associated with cystic fibrosis (CF) lung disease. We hypothesize that adding certain surfactants (amphiphilic molecules that adsorb to and spread over liquid surfaces) or low surface tension fluids to inhaled medications will promote the formation of self-dispersing medicated films in the lung. These films will spread medications throughout the airways improving dose uniformity and increasing the dose of medication delivered to regions of reduced ventilation. While surfactant replacement therapies for premature infants have been extensively studied, the use of surfactants as aerosol carriers to enhance drug transport in the lung, including the adult lung, has received much less attention. These studies will evolve a new generation of highly effective aerosol antibiotic medications which will allow for the eradication of infections in the lung and decrease the potential for antibiotic resistance. Airways-based bacterial infections are a major source of morbidity and mortality in CF. Reaching more sites of infection with therapeutic doses of drug would improve the efficacy of inhaled antibiotic therapies, providing immediate benefit to the 30,000 Americans afflicted with cystic fibrosis lung disease. Knowledge gained from these studies could also be applied to the other inhaled medications and ultimately benefit the nearly 35 million Americans suffering from obstructive lung diseases.

Public Health Relevance

Inhaled aerosol antibiotics are often used to treat pulmonary infections associated with cystic fibrosis (CF) lung disease;however, the airway obstructions associated with CF can make it difficult to reach all sites of infection with the aerosol. We propose to create special self-dispersing inhaled antibiotics that will spread medication throughout the lungs, like soap spreads over water, bringing more medication to sites of infection and improving the efficacy of these drugs. These medications could provide immediate benefit to the 30,000 CF patients in the U.S. and may ultimately be of benefit to the 35 million other Americans suffering from obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105470-02
Application #
8399077
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Banks-Schlegel, Susan P
Project Start
2011-12-15
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$379,475
Indirect Cost
$71,155
Name
Carnegie-Mellon University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Stetten, Amy Z; Moraca, Grace; Corcoran, Timothy E et al. (2016) Enabling Marangoni flow at air-liquid interfaces through deposition of aerosolized lipid dispersions. J Colloid Interface Sci 484:270-278
Sharma, Ramankur; Khanal, Amsul; Corcoran, Timothy E et al. (2015) Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 2: Low Deposition Flux Representative of Aerosol Delivery to Small Airways. J Aerosol Med Pulm Drug Deliv 28:394-405
Khanal, Amsul; Sharma, Ramankur; Corcoran, Timothy E et al. (2015) Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 1: High Deposition Flux Representative of Aerosol Delivery to Large Airways. J Aerosol Med Pulm Drug Deliv 28:382-93
Sharma, Ramankur; Corcoran, Timothy E; Garoff, Stephen et al. (2013) Quasi-immiscible spreading of aqueous surfactant solutions on entangled aqueous polymer solution subphases. ACS Appl Mater Interfaces 5:5542-9
Sharma, Ramankur; Kalita, Roomi; Swanson, Ellen R et al. (2012) Autophobing on liquid subphases driven by the interfacial transport of amphiphilic molecules. Langmuir 28:15212-21
Corcoran, Timothy E; Thomas, Kristina M; Garoff, Stephen et al. (2012) Imaging the postdeposition dispersion of an inhaled surfactant aerosol. J Aerosol Med Pulm Drug Deliv 25:290-6
Koch, Kevin; Dew, Beautia; Corcoran, Timothy E et al. (2011) Surface tension gradient driven spreading on aqueous mucin solutions: a possible route to enhanced pulmonary drug delivery. Mol Pharm 8:387-94