Pharmaceutics and Drug Design Commons^™

Lipid Nanoparticle-Mediated Drug Delivery To Cns Targets, Purva Khare

Electronic Theses and Dissertations

Lipid nanoparticles (LNPs) have revolutionized drug delivery, particularly in the delivery of gene silencing siRNA to the liver (Onpattro) and COVID-19 mRNA vaccines (Pfizer-BioNTech, Moderna). It is no exaggeration to state that the LNP delivery technology has protected billions of vaccinated people against a severe COVID-19 infection and subsequent mortality. Despite extensive research on LNPs for hepatic and muscle delivery, their potential for brain drug delivery remains underexplored. Many neurological disorders lack effective treatments, making LNP-based approaches promising for crossing or targeting drug delivery to the blood-brain barrier (BBB). Brain endothelial cells (BECs), a key component of the BBB, play …

Advancing Continuous Manufacturing: The Role Of Process Analytical Technology In Process Development, Samuel R. Henson

Electronic Theses and Dissertations

The pharmaceutical industry is actively pursuing technologies which improve manufacturing processes with the goal of producing high-quality pharmaceutical products for patients, manifesting in an industry-wide investment in continuous manufacturing (CM). Process analytical technology (PAT) has been recognized for its successful monitoring of critical quality attributes during routine production and is often cited alongside CM due to its ability to make timely, in-line measurements of intermediate materials. Various PAT tools are valuable in process development, particularly as continuous wet granulation processes are developed for use within pharmaceutical manufacturing. This work applied PAT and chemometric modeling during CM process development to enhance …

Efficient Development Of Density-Insensitive Near-Infrared Methods For In-Line Drug Content Monitoring In Continuous Powder Streams, Natasha L. Velez-Silva

Electronic Theses and Dissertations

A well-defined action plan to respond effectively to sudden changes in product demand is critical for preventing drug shortages within the pharmaceutical industry. An effective way to increase the output of a continuous manufacturing (CM) process is through flow rate adjustments. However, robust analytical methods must be in place to ensure consistent analytical performance across varying flow rates. Existing approaches for mitigating the physical effects of flow rate on Near-Infrared (NIR) measurements are often burdensome. Thus, efficient robust modeling strategies that reduce the current calibration burden and ensure model insensitivity to the physical variations in CM systems are needed. In …

Uptake Of Extracellular Vesicles Into Brain Endothelial Cells And Development Of Motor Neuron-Derived Extracellular Vesicles For Amyotrophic Lateral Sclerosis, Jhanvi Rajan Jhaveri

Electronic Theses and Dissertations

Extracellular vehicles (EVs) are an emerging class of drug carriers and are primarily reported to be internalized into recipient cells via a combination of endocytic routes such as clathrin-mediated, caveolae-mediated and macropinocytosis pathways. In part one of this thesis, (1) we investigated potential effects of homotypic vs. heterotypic interactions by studying the cellular uptake of homologous EVs (EV donor cells and recipient cells of the same type) vs. heterologous EVs (EV donor cells and recipient cells of different types) and (2) determined the route of EV internalization into low pinocytic/hard-to-deliver cell models such as brain endothelial cells ( …

Delivery Of Mitochondria-Containing Engineered Extracellular Vesicles To The Blood-Brain Barrier For Ischemic Stroke Therapy, Kandarp Dave

Electronic Theses and Dissertations

Ischemic stroke is the second leading cause of death worldwide, and the lack of effective treatment options is an unmet clinical need for stroke survivors. Ischemic stroke-induced oxygen-glucose deprivation (OGD) in the affected brain tissue leads to mitochondrial dysfunction and adenosine triphosphate (ATP) depletion in the brain endothelial cells (BECs) lining the blood-brain barrier (BBB). ATP deprivation in the BECs dysregulates actin cytoskeleton dynamics, resulting in BBB breakdown. Restoration of blood flow (i.e., reperfusion) upon the first-line stroke treatment further leads to BBB breakdown and widens the paracellular spaces between BECs. …

Injectable Formulations For Localized Delivery Of Immunomodulators, Ketki Velankar

Electronic Theses and Dissertations

Dysregulation of immune homeostasis is fundamental to the development of autoimmune disorders. Fibroblastic reticular cells (FRCs) within lymph nodes play crucial roles in forming a microenvironment conducive to immune cell interactions and regulating autoreactive T cells driving autoimmune diseases. Studies have shown the potential of FRCs as a form of personalized cell therapy to correct dysregulated immune responses. Successful translational efforts, however, require the cells to be formulated as injectable suspensions while retaining their native architecture, which is essential for their regulatory functions. The main challenge resides in retaining the native reticular organization of FRCs lost in conventional monolayer cultures …

The Implications Of The Halogen Atom On The Physical Stability Of Amorphous Solid Dispersions, Mustafa Bookwala

Electronic Theses and Dissertations

Amorphous solid dispersions (ASD), although a promising formulation strategy for poorly water-soluble drugs, are susceptible to rapid, spontaneous recrystallization owing to their metastable nature. Non-covalent interactions (NCI) between the drug and polymer are known to help prevent ASD physical destabilization. Conventionally, hydrogen-bonding (H-bonding) is considered important for ASD formation and persistence. However, carbon-bound halogen atoms, which are frequently present on drug molecules and can form specific halogen-bonds (X-bond) with the polymer, remain relatively unexplored with respect to their ability to stabilize ASDs. It was, therefore, hypothesized that the presence of a peripheral Br on bromopropamide, and Cl on chlorpropamide will …

Systematic Product And Process Design Of Versatile Perfluorocarbon Nanoemulsions For Elimination Of Hypoxia And Reactive Oxygen Species, Eric Lambert

Electronic Theses and Dissertations

According to a 2022 report, organs destined for transplantation are discarded 15% of the time for various reasons (Israni et al. 2022). This highlights a critical need in transplant practices. Transplant donor tissues are in need of essential nutrients, including molecular oxygen, to maintain integrity during preservation. A current trend in preservation is to perfuse the ex vivo tissue graft with nutrient-rich aqueous perfusate on a closed circuit. This practice, known as machine perfusion (MP) is limited by the absence of an oxygen-carrying component in the perfusate. Additionally, injuries to the recipient are sustained on reperfusion of the transplanted …

Quality By Design Based Optimization Of Anti-Inflammatory Nanoemulgels For Local Treatment Of Burn Wounds, Leah Dickey

Electronic Theses and Dissertations

Burns are some of the most traumatizing and damaging skin injuries, with the potential of causing extensive internal damage that increases the risk of chronic wound development. Oral and topical analgesics in combination with antibiotics can provide temporary relief and improve wound healing progress for both mild and severe burns. However, recurrent systemic exposure to pain relievers and antibiotics has been associated with adverse side effects including nausea, drowsiness, abdominal pain, etc., and increased risk of new infections or even ulcers. Local and targeted drug delivery systems, such as nanomedicine, have gained attention as potentially more effective alternatives to improve …

Development Of Anti-Inflammatory Theranostic Nanocolloids Using Quality By Design Approaches, Michele Herneisey

Electronic Theses and Dissertations

Nanocolloids are attractive delivery vehicles for drugs with poor aqueous solubility. Despite this, relatively few nanocolloid products exist on the market. Currently, there is a lack of standardization in the pre-clinical, academic setting regarding nanocolloid development and quality control testing. Adaptation of quality by design (QbD) methods used in the pharmaceutical industry to nanocolloid development is a desirable approach that can improve nanocolloid product and process understanding, resulting in an increased number of marketable products.

The central hypothesis of this work is that QbD approaches can be utilized to optimize theranostic (therapeutic and diagnostic) nanocolloid stability, drug loading, and imaging …

Development Of A Combined Feedforward-Feedback Quality Control System For Extended-Release Granules Using A Quality By Design Approach, Yuxiang Zhao

Electronic Theses and Dissertations

Objectives

For a fluid bed film coating process to consistently deliver quality products, its control system needs to be robust against the variability of input materials and environmental disturbances. Presently, limited studies have been reported to understand the effects and interactions of the material attributes, environmental variables, and process parameters on the product in vitro drug dissolution. A control system can be developed with a proper understanding of the coating process, by adjusting the process parameters in feedback and feedforward manners to compensate for the undesired effect caused by disturbances, and ensure consistent product quality.

Methods

The control system was …

Pharmacological Characterization Of Novel Serotonin Transporter Inhibitors Identified Through Computational Structure-Based Virtual Screening, Michael Wasko

Electronic Theses and Dissertations

Depression is a mental health disorder affecting greater than 350 million people worldwide with roughly 7% of the United States population diagnosed as of 2017. The selective serotonin reuptake inhibitors (SSRIs) have been the mainstay of pharmacotherapies for depression for the last 40 years. The SSRIs target the serotonin transporter (SERT), a monoamine transporter (MAT) responsible for terminating serotonergic neurotransmission. The SSRIs are not perfect therapeutics and suffer from delayed response times, inconsistent efficacy among patients, and often produce intolerable side effects. Therefore, a strong need exists to develop new antidepressants that are more efficacious and have fewer adverse effects. …

Gene Delivery To The Blood-Brain Barrier For Ischemic Stroke Therapy, Wanzhu Zhao

Electronic Theses and Dissertations

Stroke is a major cause of death in the United States. We aim to develop safe and efficient approaches for the treatment of stroke. Regenerative therapies have been identified as the major need for curing stroke [1]. We explored two different carriers (poly (ethylene glycol)_5k-poly (L-aspartate-diethylenetriamine)₄₈ (PEG-DET) / Pluronic P84 (P84) and exosomes (EXOs) / microvesicles (MVs)) to deliver brain-derived neurotrophic factor (BDNF) plasmid DNA (pDNA), a functional gene encoding a neurotrophin. In the first project, our data showed that DNA nanoparticles (NPs) with 0.03% P84 was a promising formulation to deliver Luciferase pDNA into immortalized human …

Pilot Study Exploring The Effect Of Targeted Cox-2 Inhibition In Macrophages Responding To Neuronal Injury; Promoting Enhanced Axonal Regeneration, Alyssa Brauckmann

Electronic Theses and Dissertations

Celecoxib nanoemulsion (CXB-NE) has been developed as a macrophage targeted analgesics by Dr. Janjic and her team at Duquesne University, (Janjic et al, 2018; Liu et al, 2020; Saleem et al, 2019b; Vasudeva et al, 2014). The CXB-NE nanoemulsion carrying a Nonsteroidal Anti-inflammatory (NSAID) inhibitor of COX-2 activity result in a reduction in PGE2 expression in macrophages. Using CXB-NE in rats that have peripheral nerve injury constricting the sciatic nerve relieves hypersensitivity, a pain-like behavior. The treatment also decreases inflammation associated with this chronic constriction injury (Janjic et al, 2018; Saleem et al, 2019b; Stevens et al, 2019). In this …

Design And Synthesis Of Pyrimidine Based Heterocycles As Potential Anti-Cancer Agents With Combination Chemotherapeutic Potential Or Targeted One Carbon Metabolism Inhibition And Anti-Opportunistic Agents, Arpit Doshi

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic, bicyclic and tricyclic pyrimidine-based heterocycles as a) single agents with combination chemotherapy potential having dual antiangiogenic effects and cytotoxic effects or b) one-carbon metabolism inhibitors for targeted tumor therapy; or c) selective Pneumocystis jirovecii (pj) dihydrofolate reductase (pjDHFR) inhibitors for pneumocystis pneumonia (PCP) infection.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization or thymidylate synthase as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), epidermal growth …

A Quantitative Study Of Drug Recrystallization In Drug-In-Adhesive Transdermal Patches Using Vibrational Spectroscopy, Yi Li

Electronic Theses and Dissertations

Drug-in-adhesive (DIA) transdermal patches are an important type of transdermal drug delivery system (TDDS). The drugs used in the DIA system are frequently present in metastable forms, such as amorphous solids or supercooled liquids. These drug states are thermodynamically unstable and tend to undergo recrystallization. Recrystallization of the active pharmaceutical ingredient can adversely affect the efficacy of transdermal products. This dissertation demonstrates a systematic approach to quantify the crystalline content of the API in DIA systems. This approach uses a novel method of preparing calibration standards and a spectroscopic method to reliably predict crystalline content in DIA patches. Spectroscopic tools, …

The Development Of Hybrid Process Control Systems For Fluidized Bed Pellet Coating Processes, Hanzhou Feng

Electronic Theses and Dissertations

The conventional basic control for pharmaceutical batch processes has several drawbacks. The basic control often uses constant process settings discovered by trial and error. The rigid process operation provides limited process understanding and forgoes the opportunities of process optimization. Product quality attributes are measured by the low efficient off-line tests, therefore these cannot be used to monitor and inform the process to make appropriate adjustments. Frequent reprocessing and batch failures are possible consequences if the process is not under effective control. These issues raise serious concerns of the process capability of a pharmaceutical manufacturing process.

An alternative process control strategy …

Modeling And Prediction Of Amorphous Solid Dispersion Formation Using A Molecular Descriptor, Kevin Deboyace

Electronic Theses and Dissertations

Poor aqueous solubility of an active pharmaceutical ingredient (API) is a significant hurdle during drug development. Delivering a drug in its amorphous solid-state is a potential method to overcome this issue, since the amorphous form has increased apparent aqueous solubility. However, the amorphous state is only metastable, and is thermodynamically driven to recrystallize. As a result, pure amorphous drugs are seldom used in marketed products. Intimately mixing a drug in its amorphous form with a polymer, known as an amorphous solid dispersion (ASD), has the potential to significantly extend the physical stability of the amorphous form, while maintaining the benefit …

Self-Assembling Bioaffinity Hydrogels For Localized Antibody Delivery, Wen Liu

Electronic Theses and Dissertations

The scope of illnesses that are being treated using monoclonal antibodies (mAbs) has been expanding from cancers to autoimmune diseases due to their high specificity to their molecular target. Because many of the new mAbs are aimed to modulate the immune system, an emerging concern is that patients with chronic illnesses are subjected to immune-related Adverse Events (irAEs). Loss of immunological tolerance to self-antigens or increased susceptibility to infections have been documented in some mAb treatments. Localized sustained release of mAb at disease sites might mitigate the risk of such toxicities. Antibody drugs are formulated typically for parenteral delivery because …

Designing A Calibration Set In Spectral Space For Efficient Development Of An Nir Method For Tablet Analysis, Md Anik Alam

Electronic Theses and Dissertations

Designing a calibration set is the first step in developing a spectroscopic calibration method for quantitative analysis of pharmaceutical tablets. This step is critical because successful model development depends on the suitability of the calibration data. For spectroscopic-based methods, traditional concentration based techniques for designing calibration sets are prone to have redundant information while simultaneously lacking necessary information for a successful calibration model. The traditional method also follows the same design approach for different spectroscopic techniques and different formulations, thereby lacks the optimizing capability to be technique and formulation specific.

A method for designing a calibration set in the Near …

Synthesis Of 2,4,6-Substituted Pyrrolo[2,3-D]Pyrimidines As Potential Anticancer Agents, Si Yang

Electronic Theses and Dissertations

This thesis mainly focuses on the introduction of the background and work have been done in the areas of antifolates development, such as folate function, its three uptake mechanisms inside human cells, antifolates’ role in chemotherapy, et. al. In addition, the Structure-Activity-Relationship design rationale for the series of antifolates will also be discussed. Nevertheless, the details of synthesizing these pyrrolo[2,3-d]pyrimidines as potential antifolates have been described, including chemistry reviews on the pyrrolo[2,3-d]pyrimidine scaffold, and the challenges encountered and the solutions how to solve or improve in order to achieve better yield.