Inhaled pharmaceutical aerosols are often deposited in the lung at very low deposition efficiencies. Perhaps more significant than the quantity of drug deposited is the large inter- and intra-subject variability that is often observed with these medicinal aerosols and the associated dose delivered to the lung. In order to make many next-generation inhaled medications a viable drug delivery alternative, increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The objective of this study is to develop an approach for improved lung delivery and retention of nanoparticle and submicrometer aerosols using enhanced condensation growth. This concept consists of combining (1) a controlled inhalable water vapor humidity source with (2) a submicrometer aerosol generation and delivery device. The humidity source is used to create a controlled supersaturated relative humidity environment within general regions of the lung. This conditioning of the respiratory tract may be accomplished through an inhalation of supersaturated water vapor with pre-specified temperature and relative humidity (RH) conditions. The aerosol, in particle or droplet form, will be delivered either concurrently or following the controlled inhalation of the humidity source. The aerosol should have a size that can effectively penetrate the mouth-throat and upper tracheobronchial regions, e.g., approximately 1 ?m and below. Upon transport into the lung, the aerosol will increase in size due to enhanced condensation growth (water accumulation) in the controlled supersaturated environment, thereby increasing retention. To achieve this objective, the following specific aims are proposed:
Specific Aim 1 : Develop an in vitro system to evaluate the controlled enhanced condensation growth concept in the upper respiratory tract and assess the effects of RH under steady flow conditions.
Specific Aim 2 : Develop and validate a computational fluid dynamics (CFD) model of hygroscopic droplet growth in the upper tracheobronchial region and apply the model to evaluate aqueous wall boundary conditions and transport into distal bronchi.
Specific Aim 3 : Employ the developed in vitro and CFD models to test the effects of (1) transient flow, (2) aerosol concentration density, and (3) aerosol hygroscopic properties and physical form on the hygroscopic growth of 100 - 1000 nm aerosols. By delivering submicrometer aerosols past the mouth-throat and then increasing aerosol size through enhanced condensation growth, significant reductions in upper airway deposition and increased lung retention are expected. As a result, reduced variability in dose can be achieved, which is necessary for the effective use of many next-generation pharmaceutical aerosols. Public Health Relevance: A number of inhalable medications are in development for the treatment of respiratory diseases (such as lung cancer, respiratory infections, and cystic fibrosis) and systemic conditions (such as diabetes, chronic pain, and growth deficiency). However, the delivery of these next- generation inhaled pharmaceuticals to the lungs is often inefficient, which can significantly reduce drug effectiveness and increases unwanted side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled medicines that minimizes deposition in the mouth and throat and maximizes deposition in the lungs.

Public Health Relevance

A number of inhalable medications are in development for the treatment of respiratory diseases (such as lung cancer, respiratory infections, and cystic fibrosis) and systemic conditions (such as diabetes, chronic pain, and growth deficiency). However, the delivery of these next- generation inhaled pharmaceuticals to the lungs is often inefficient, which can significantly reduce drug effectiveness and increases unwanted side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled medicines that minimizes deposition in the mouth and throat and maximizes deposition in the lungs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL094991-02
Application #
7760144
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Noel, Patricia
Project Start
2009-01-10
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
2
Fiscal Year
2010
Total Cost
$182,421
Indirect Cost
Name
Virginia Commonwealth University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Longest, P Worth; Spence, Benjamin M; Holbrook, Landon T et al. (2012) Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery. J Aerosol Sci 51:66-80
Longest, P Worth; Tian, Geng; Li, Xiang et al. (2012) Performance of combination drug and hygroscopic excipient submicrometer particles from a softmist inhaler in a characteristic model of the airways. Ann Biomed Eng 40:2596-610
Longest, P Worth; Holbrook, Landon T (2012) In silico models of aerosol delivery to the respiratory tract - development and applications. Adv Drug Deliv Rev 64:296-311
Tian, Geng; Longest, Philip Worth; Su, Guoguang et al. (2011) Characterization of respiratory drug delivery with enhanced condensational growth using an individual path model of the entire tracheobronchial airways. Ann Biomed Eng 39:1136-53
Longest, P Worth; Tian, Geng; Hindle, Michael (2011) Improving the lung delivery of nasally administered aerosols during noninvasive ventilation-an application of enhanced condensational growth (ECG). J Aerosol Med Pulm Drug Deliv 24:103-18
Longest, P Worth; Hindle, Michael (2010) CFD simulations of enhanced condensational growth (ECG) applied to respiratory drug delivery with comparisons to in vitro data. J Aerosol Sci 41:805-820
Hindle, Michael; Longest, P Worth (2010) Evaluation of enhanced condensational growth (ECG) for controlled respiratory drug delivery in a mouth-throat and upper tracheobronchial model. Pharm Res 27:1800-11
Longest, P Worth; McLeskey Jr, James T; Hindle, Michael (2010) Characterization of Nanoaerosol Size Change During Enhanced Condensational Growth. Aerosol Sci Technol 44:473-483