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Recent Submissions

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    Combination Approach of Salt Formation and Amorphous Solid Dispersions for Enhancing Aqueous Solubility and Dissolution Profile of BCS Class II Drugs
    (Creighton University, 2024) Pansare, Siddhesh, Mohan
    Purpose: Numerous pharmaceutically active drug molecules have recently been discovered owing to molecular modeling and high-throughput screening. However, their formulation and commercialization have been a major challenge due to their poor aqueous solubility and low bioavailability. Combining salt formation and amorphous solid dispersions (ASDs) is an emerging strategy that utilizes the benefits of crystal lattice energy depletion (by the amorphous form) and enhanced solvation energy and pH buffering effect (by salt formation), leading to improved aqueous solubility and dissolution rate. This project aims to optimize this dual approach for Biopharmaceutical Classification System (BCS) Class II weakly acidic drugs and potentially create formulations with enhanced aqueous solubility and dissolution profile.Methods: Three model BCS Class II drugs- indomethacin, gliclazide, and celecoxib were combined with four basic counterions to form salts by crystallization and solvent evaporation process. The prepared salts were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Infrared spectroscopy (IR). Equilibrium solubility studies were performed on the formed salts in deionized water following the WHO protocol. The drug-counterion pair with the highest solubility was further selected for ASD preparation using hot melt extrusion (HME). Intrinsic dissolution studies were performed using a modified Wood's apparatus on prepared salt solid dispersions (SSDs), their corresponding salts and compared. Results: Elevation in melting point using DSC combined with IR peaks confirmed salt formation for all drug-counterion pairs. All the prepared salts had more aqueous solubility as compared to pure drugs, with indomethacin arginine, gliclazide sodium, and celecoxib sodium showing maximum enhancement of 3666, 189, and 372 times the pure free drug, respectively. These three counterions were further used to prepare SSDs. Intrinsic dissolution rate (IDR) was calculated for pure drugs and compared to individual approaches (Salt and ASD) and the combined approach (SSD). The SSDs of model drugs showed significant improvement in IDR compared to individual approaches. Conclusion: The dual approach of salt formation and amorphous solid dispersions resulted in higher solubility and intrinsic dissolution rate than the individual approaches alone, suggesting that the combination approach was successful.
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    Development of Aerosolizable mRNA Incorporated Chitosan Nanoparticles for Efficient Lung Delivery
    (Creighton University, 2024) Kota, Sri Sai Nikitha
    Recently, the potential of messenger RNA (mRNA) as a promising therapeutic approach is beingunwrapped in the pulmonary medicine stream more than anywhere else. The unique function of directing the cells in protein synthesis “in vivo” has raised the mRNA as an effective alternative for a non-viral, inhalation delivery system. By leveraging the extensive surface area and vascularization of the lungs, inhalation delivery presents a non-invasive method to achieve localized treatment effects directly within the respiratory tract. The use of nanoparticles for mRNA delivery to the lungs opens a promising way for treating a wide variety of pulmonary disorders, including genetic and infectious diseases. Chitosan-tripolyphosphate (CS-TPP) nanoparticles present promising opportunities due to their biocompatibility and ability to encapsulate negatively charged nucleic acids. This research focuses on the intricacies of formulating CS-TPP nanoparticles that can encapsulate mRNA and be effectively aerosolized for targeted lung delivery, aiming to achieve localized therapeutic effects with high transfection efficiency. The research developed an in-house, cost-effective mRNA extraction method followed by its quantification and even purification if required. The mRNA-incorporated CS-TPP nanoparticles were produced through the Ionotropic gelation method using two different formulation approaches, with one approach containing Incremental concentrations of chitosan and the other in which chitosan and mRNA are mixed as per their weight ratios. The nanoparticles were then characterized for their particle size, zeta potential, polydispersity index, and encapsulation efficiencies. The blank and mRNA-incorporated nanoparticles had an average particle size of 150nm and 212nm with 1.5 and 16.38 mv of zeta potential, followed by a poly dispersity index of 0.1 and 0.3. The results indicated that the first formulation approach with increasing concentrations of chitosan produced better encapsulation efficiencies and was used for further studies. The aerodynamic characterization of these formulations was assessed using a vibrating mesh nebulizer, and particle size separation was performed using a Next-generation impactor (NGI). The aerodynamic characterization revealed that formulations had an optimal aerodynamic diameter between 1-5μm. Other properties like fine particle fraction and geometric standard deviation could be improved by optimizing the nebulization parameters further. The transfection efficiency of formulations pre and post-nebulization was studied on A549 (lung adenocarcinoma) and BEAS-2b (lung epithelial) cell lines. Cellular uptake and protein expression were observed using Confocal imaging on the BEAS-2b cell line. Immunogenicity studies on transfected cells revealed a dosedependent release of Inflammatory cytokines concerning the amount of Chitosan used in the formulations. In conclusion, the study developed and characterized mRNA-incorporated chitosan-tri polyphosphate nanoparticles, demonstrating their potential as a stable delivery vehicle for the inhalation delivery of mRNA.
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    Evaluating the Ocular Hypotensive and Neuroprotective Potential of Hydrogen Sulfide-Producing Compounds in Glaucoma, and Developing Its Delivery System Using Quality-by-Design Approaches
    (Creighton University, 2024) Rai, Anjali
    Glaucoma is an ocular neurodegenerative condition that leads to progressive irreversible blindness due to loss of retinal ganglion cells (RGCs) and optic nerve head (ONH) damage. Currently, glaucoma affects 80 million people globally and the burden of this disease is expected to increase to over 100 million people by 2040. Primary Open Angle Glaucoma (POAG) is the most prevalent type of glaucoma, and its pathophysiology is multifactorial. The main modifiable risk factor in POAG is elevated intraocular pressure (IOP). Most FDA-approved drugs for POAG target this IOP elevation to provide symptomatic relief. There is a growing recognition of the need for neuroprotective strategies to preserve vision in glaucoma patients. The lack of neuroprotective agents can be potentially fulfilled by the use of hydrogen sulfide (H2S)-producing compounds. H2S, is the third endogenous gaseous transmitter with physiological and pharmacological implications in mammalian cells. Multiple studies have reported its cytoprotective, anti-inflammatory, anti-apoptotic, and vasodilatory effects. In the context of glaucoma, studies have revealed its antioxidant effects can potentially preserve RGCs and the ONH from injury in glaucoma. Furthermore, H2S-producing compounds have been reported to lower to IOP by modulating aqueous humor (AH) dynamics in different animal models of glaucoma. These promising findings need to be fully harnessed by addressing the challenges associated with the development of H2S-producing compounds as therapeutic agents for glaucoma. Issues such as limited bioavailability and stability of H2S present hurdles in developing effective treatment strategies. Optimal dosing regimens and delivery systems must be refined to ensure sustained release of the gas while minimizing adverse reactions. This study aims to address these challenges because they will be instrumental in advancing H2S-based therapies as a viable strategy for lowering IOP and preserving vision in glaucoma patients. First, we assessed the hypotensive effects of H2S-producing compounds, DATTS and GYY4137 in female normotensive rabbits. Furthermore, we tested the ocular hypotensive effects of these H2S-producing compounds in an in vivo glaucoma model that we developed in male and female New Zealand albino rabbits by administering a bilateral intracameral injection of carbomer (100 µL; 0.3 w./v %) into eyes of these animals. Injection of carbomer resulted in ocular hypertension (OHT) in the rabbits and increased IOP by over 100% for up to 30 days in both male and female rabbits. This glaucoma model was also used to assess the neuroprotective effects of DATTS and GYY4137 using H&E and TUNEL assays, in vivo. Finally, a microparticle formulation of H2S-producing compound (Na2S) was formulated and optimized using Quality by design (QbD). Main Effects screening (MES) and a Response Surface design (RSD)-based design of experiments (DOE) were used to optimize Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) associated with microparticle formulation. In conclusion, pharmacological data from our studies affirm both an IOP-lowering and neuroprotective action of H2S-producing compounds in an animal model of glaucoma. Our formulation data supports the development of a microparticle formulation of a H2S-producing compound that may have utility in the treatment of glaucoma.
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    Leader Experiences of Limited Employment Terms at U.S. Army Garrisons Overseas
    (Creighton University, 2023) Morelock, Anna
    Many U.S. Army civilian employees who work for Installation Management Command Europe fall under a policy which limits their employment to five years overseas unless they have approval from higher headquarters. The policy, implementation of which varies across Army commands and other organizations impacted by the rule, creates challenges for the organization in regard to continuity, staff productivity, customer service, host nation relations, and employee well-being. For an organization that proclaims to put people first and encourages professional development, this policy creates a disconnect for leaders striving to create high-performing teams. Leaders within the Army show characteristics of the Army and Servant Leader Models, which when combined with challenges presented by the five-year rule can create an opportunity to use a leadership model provided in this Dissertation in Practice. Insights from leaders interviewed for this phenomenological study also provide valuable insight into the impacts of the rule on them and their staff.
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    Best Practices in Cardiology Healthcare Clearance: A Qualitative Case Study
    (Creighton University, 2023) Haswell, Kelsey
    Cardiovascular disease continues to be the number one cause of death worldwide and within the United States. The cost of cardiovascular care continues to be the highest cost of care for any disease process and is projected to rise. Cardiovascular healthcare clearance has become increasingly complex, resulting in greater time spent away from the patient for providers, delay in care for patients, and increased prior authorization professionals being hired to perform healthcare clearance. Given this significant problem and limited best practices to guide leaders and providers in making positive changes to address this problem, a qualitative case study was performed to determine best practices for cardiovascular healthcare clearance for imaging, procedures, and surgeries. The qualitative case study allowed for new insights to be appreciated in the field of cardiovascular healthcare clearance, a field where research is limited for leaders to make wise practice changes impacting their staff, providers, and cardiovascular patients. The study uncovered multiple themes validating the challenges of cardiovascular healthcare clearance articulated in past studies, outlining key best practices for healthcare leaders and cardiovascular providers specific to cardiovascular healthcare clearance, and articulated issues persisting in the healthcare insurance industry. The proposed solutions outlined are in the form of toolkits for healthcare leaders and cardiovascular.