Pharmaceutical nanoparticles have failed to leverage their unique aerosol drug delivery potential for the treatment of local and systemic diseases due to poor pulmonary deposition efficiency. Because of their submicrometer size, aerosolized nanoparticles can potentially overcome many of the problems associated with traditional inhalation therapy if their lung deposition can be significantly increased. In order to make many next- generation inhaled medications a viable drug delivery alternative, utilizing the full potential of nanoparticles for increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The goal of this project is to address the challenges facing inhaled nanoparticle delivery by developing aerosol formulations that can ensure efficient targeted nanoparticle lung deposition. This concept consists of engineering dry powder nanoparticle aerosols containing a model drug and a hygroscopic excipient. The engineered nanoparticles will be delivered in the size range of 100 - 900 nm in order to minimize mouth- throat deposition and maximize drug payload. After bypassing the upper airways, the natural humidity in the lungs will cause the hygroscopic excipient to accumulate water, increasing the size and weight of the nanoparticles. The increased aerodynamic diameter of the particles will then ensure increased lung deposition rather than exhalation of the aerosol and can potentially be used to target the site of deposition. To achieve this goal, the following specific aims are proposed:
Specific Aim 1 : Generate and characterize engineered pharmaceutical nanoparticles consisting of drug and a hygroscopic excipient to be used in the excipient enhanced growth (EEG) studies.
Specific Aim 2 : Evaluate nanoparticle growth in conjunction with upper and lower lung deposition of the engineered aerosol using concurrent CFD modeling and in vitro testing.
Specific Aim 3 : Evaluate and optimize a dry powder inhaler (DPI) design for nanoparticle dispersion and delivery using a quantitative analysis and design approach. By delivering nanoparticles past the mouth-throat and then increasing their aerosol size through excipient enhanced hygroscopic growth, significant reductions in upper airway deposition are expected. As a result of using this concept, reduced variability in dose can be achieved together with near full lung retention, which are necessary for the effective use of many next-generation pharmaceutical aerosols.

Public Health Relevance

The inhalation of pharmaceutical nanoparticles may offer many unique advantages compared to conventional delivery methods for the treatment of respiratory diseases, systemic conditions and to unlock the potential use of the lungs to deliver vaccines and gene therapy. However, the current methods used to administer these next-generation nanoparticle pharmaceuticals to the lungs are often inefficient, which can significantly reduce drug effectiveness, increase unwanted side effects, and make dosing difficult to control. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled nanoparticles that minimizes deposition in the mouth and throat while maximizing deposition in the lungs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL104319-01
Application #
7976385
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Banks-Schlegel, Susan P
Project Start
2010-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$183,905
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Behara, Srinivas R B; Longest, P Worth; Farkas, Dale R et al. (2014) Development and comparison of new high-efficiency dry powder inhalers for carrier-free formulations. J Pharm Sci 103:465-77
Son, Yoen-Ju; Worth Longest, P; Hindle, Michael (2013) Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: effect of spray drying process conditions on aerosol performance. Int J Pharm 443:137-45
Son, Yoen-Ju; Longest, P Worth; Tian, Geng et al. (2013) Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. Eur J Pharm Sci 49:390-9
Longest, P Worth; Son, Yoen-Ju; Holbrook, Landon et al. (2013) Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols. Pharm Res 30:1608-27
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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
Longest, P Worth; Hindle, Michael (2012) Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: comparison of CFD predictions with experimental results. Pharm Res 29:707-21
Hindle, Michael; Longest, P Worth (2012) Condensational growth of combination drug-excipient submicrometer particles for targeted high-efficiency pulmonary delivery: evaluation of formulation and delivery device. J Pharm Pharmacol 64:1254-63
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

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