Date of Award

2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering

Department

Chemical Engineering

First Advisor

Samantha Meenach

Abstract

Pulmonary drug delivery is a rapidly growing area of interest in the field of inhalable therapeutics and provides the possibility for specialized engineered inhalable drug-loaded particles capable of improving treatment efficacy. Pulmonary drug delivery provide several advantageous when compared to other routes of administrations, as therapeutics delivered to the lungs avoid the first-pass effect of the liver, which is a major hurdle for other routes of administration. The potential for drug degradation is also decreased as the lungs have low to no enzymatic activity. Furthermore, the lungs have a large surface and are highly vascular, resulting in rapid onset of actions and higher bioavailability. Direct delivery to the lungs can provide a high local drug concentration, which can be beneficial for treating pulmonary diseases and infections while decreasing off-site side effects. The alveolar region of the lungs only has a single cell layer, which is advantageous for nanoparticle transport through the epithelial layer and into the cardiovascular system. Importantly, the lungs are the only organ that the entire cardiovascular output passes through.

As a result, various approaches have been utilized to create inhalable pulmonary drug delivery formulations. Nanoparticles and microparticles have been extensively investigated for such drug delivery applications. These particle-based systems offer advantages in comparison to tradition delivery systems, such as increased surface area, improved stability, tunability, and the potential for surface functionalization. As a result, particle-based delivery systems can be tailored to treat and target specific disease states while increasing treatment efficacy. Limitations associated with poorly water-soluble or highly sensitive therapeutics can be overcome by encapsulating them in particles. Particle- based systems can be loaded with various therapeutics, including small drug molecules and biomolecules, allowing for a wide range of applications and treatment options. Such systems can also provide controlled and sustain release of these therapeutics. However, the lungs have several mechanisms to clear inhaled particles, such as mucosal entrapment, mucociliary clearance, and alveolar macrophage clearance. These mechanisms must be taken into consideration for effective application of inhalable dry powder therapeutics.

Acetalated dextran (Ac-Dex) is a biodegradable, pH-responsive polymer with a simple synthesis method. Ac-Dex is synthesized by converting hydroxyl groups in dextran to acyclic or cyclic acetal groups, which results in the dextran transitioning from being hydrophilic to the hydrophobic Ac-Dex. While many other polymers have been used in particle drug delivery systems, Ac-Dex provides the unique ability as its degradation rate can be easily tuned by adjusting the reaction time used during its synthesis. Ac-Dex also exhibits pH-responsive release, where at physiological pH, Ac-Dex has sustained release of therapeutics, whereas Ac-Dex experiences rapid release when exposed to lower pH due to its acid-catalyzed degradation mechanism. As a result of these characteristics, Ac-Dex is an attractive polymer for the development of particle-based drug delivery systems.

For particle-based delivery systems to be effectively implemented for pulmonary delivery, they must have the appropriate aerosol dispersion characteristics. Without this, particles will not be effectively deposited in the lungs. This is especially relevant for nanoparticles, which are too small to deposit in the lungs on their own and will be exhaled. Other the other hand, particles that are too large will be restricted to the oropharyngeal region and never reach the lungs. It is important, therefore, to have a method to produce formulations possessing the appropriate aerosol characteristics. Spray drying, a one-step scalable process, is a technique used to created inhalable dry powders capable of effective pulmonary deposition. Spray drying uses a dispersion gas to atomize a liquid feed into a drying chamber, allowing micron-sized particles to form and be collected as a dry powder. Nanoparticles can be formulated into nanocomposite microparticles (nCmP) via spray drying, which allows nanoparticles to be effectively delivered to the deep lung, overcoming the pulmonary deposition issues associated with nanoparticles while still taking advantage of the benefits of microparticles.

The aim of this dissertation was to (1) develop and characterize inhalable rifampicin-loaded nanocomposite microparticles to overcome the limitations of current treatments for tuberculosis infection, providing a targeted and controlled release in the alveolar region of the lungs, (2) develop and characterize inhalable microparticles capable of enhancing alveolar macrophage phagocytosis, and (3) optimize nanocomposite microparticle spray drying properties via design of experiment to allow pulmonary delivery of therapeutics from a dry powder inhaler.

Rifampicin-loaded biodegradable nanoparticles were formulated using Ac-Dex, where rifampicin is a first line drug extensively used for the treatment of tuberculosis. The nanoparticles were formulated into nanocomposite microparticles via spray drying to allow pulmonary delivery of an inhalable dry powder formulation. In addition to rifampicin-loaded nanoparticles, rifampicin-cyclodextrin inclusion complexes were used during the spray drying process as an additional delivery mechanism and as a bulk material to form rifampicin-cyclodextrin nanocomposite microparticles (RIF-CD nCmP). The resulting nCmP exhibited excellent in vitro aerosol dispersion properties displaying their ability to be deposited in the deep lung, which is the site of tuberculosis infection. In vitro cytotoxicity analysis showed that the RIF-CD nCmP did not adversely affect pulmonary epithelial cell viability. Furthermore, RIF-CD nCmP were capable of delivering an initial high dose of rifampicin from the rifampicin-cyclodextrin complexes, while the rifampicin-loaded nanoparticles provided controlled, sustained release.

Alveolar macrophages are critical to the innate immune system and for clearing debris from the lungs. However, many diseases take advantage of this, and as a result macrophages become reservoirs for infections such as that related to tuberculosis. Treatment efficacy for many of these macrophage-associated diseases can be improved by targeting macrophages directly as opposed to utilizing systemic delivery. Not only will this reduce off-site side effects, but it also provides a high concentration of therapeutics directly to the site of infection. Therefore, phosphatidylserine-loaded microparticles (DPPS MP) were synthesized using a simple one-step spray drying process. Curcumin, a hydrophobic and fluorescent molecule, was used as a model therapeutic loaded into the microparticles. The spray dried formulations displayed favorable in vitro aerosol dispersion characteristic capable of delivery to the alveolar regions of the lungs, which is the location of alveolar macrophages, which can serve as reservoirs for infection. Importantly, DPPS MP exhibited significant increase in macrophage uptake during in vitro studies, while there was no increase in DPPS MP uptake when evaluated using A549 lung epithelial cells. This shows that DPPS-mediated uptake is macrophage specific and can be used to effectively target macrophages for the treatment of diseases such as tuberculosis.

Inhalable particles present a unique way to treat pulmonary and systemic diseases. In particular, acetalated dextran-based inhalable dry powder formulations demonstrate promise as a tunable and effective drug delivery platform for pulmonary delivery of therapeutics. The parameters used during spray drying such as feed concentration, pump rate, and nanoparticle percentage can influence the characteristics of nanocomposite microparticles. To elucidate the impact these parameters have on the characteristics of the spray-dried nanocomposite microparticles, design of experiments was implemented and analyzed. The resulting data showed that the three aforementioned spray drying parameters impacted a variety of nanocomposite microparticles, in particular the drug loading, aerodynamic dispersion properties, morphology, and yield.

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