Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science in Chemical Engineering (MSChE)

Department

Chemical Engineering

First Advisor

Samantha A. Meenach

Abstract

Pulmonary arterial hypertension (PAH) is an incurable cardiovascular disease characterized by high blood pressure in the arteries leading from the heart to the lungs. Over 2 million people in the United States are diagnosed with PAH annually and the typical survival rate is only 3 years after diagnosis (Archer, Weir et al. 2010). Current treatments are insufficient because of limited bioavailability, toxicity, and cost associated with approved therapeutics. Aerosol delivery of drugs is an attractive approach to treat respiratory diseases because it increases localized drug concentration while reducing systemic side effects. Dry powder inhalers (DPIs) allow for increased physicochemical stability of drugs and increased patient compliance. Dry powder aerosols can be easily designed to meet certain specifications including size, morphology, and crystallinity via spray drying (Meenach, Vogt et al. 2013). Tacrolimus (TAC) is a drug that has recently been found to be useful in treating PAH (Spiekerkoetter, Tian et al. 2013). TAC interacts with bone morphogenic protein receptor type II (BMPR2), which is often mutated or underexpressed in patients with PAH (Humbert, Morrell et al. 2004). The expression of BMPR2 inhibits vascular remodeling, thereby reducing blood pressure. Unfortunately, TAC is poorly watersoluble and toxic when delivered systemically over a long period of time, this driving the need for improved formulations and delivery of the compound. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) are phospholipids naturally present in the lungs that act as a biodegradable surfactant when used in a 3:1 ratio as an excipient in dry powder microparticles. DPPC and DPPG can improve particle migration in the lungs and increase lung residence time (Hadinoto, Phanapavudhikul et al. 2007). I hypothesize that targeting the delivery of tacrolimus to the lungs using phospholipid-based dry powder aerosol microparticles will result in increased localized drug concentrations, improving the treatment of pulmonary arterial hypertension and decreasing the severity of side effects experienced by patients.

In this study, phospholipid-based aerosol microparticles were developed via spray drying. These particles were shown to be smooth and spherical in size, ranging from 1-3 μm in diameter. The microparticles exhibited thermal stability and were found to be amorphous after spray drying. Water content in the microparticles was under 10%, which will allow successful aerosol dispersion and long-term storage stability. In vitro aerosol dispersion showed that the microparticles could successfully deposit in the deep lung, as they exhibited favorable aerodynamic diameters and high fine particle fractions. In vitro dose-response analysis showed that TAC is nontoxic in the low concentrations that would be delivered to the lungs. Overall, this work shows that tacrolimus-loaded phospholipid based microparticles can be successfully created with optimal physicochemical characteristics.

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