PhD, University of Cincinnati, 2018, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics

Controlled release oral dosage form offers great advantages over conventional dosage form by providing steady drug plasma concentration, decreasing the frequency of administration, and providing enhanced patient compliance. However, orally ingested tablet is exposed to varying pH conditions and fluctuating mechanical agitations during its travel through the gastrointestinal tract (GIT). Selection of materials that provide controlled release mechanism to the oral dosage form is important as they can a) minimize drug release rate fluctuations for ionizable drugs during its travel along the changing pH environment of the GIT and b) maintain the release rate mechanism even when subjected to the physiological mechanical agitation forces. To examine these two important requirements, matrix tablets prepared using low glass transition temperature (Tg) silicone pressure sensitive adhesive (PSA) were evaluated and compared with matrix tablets prepared using high Tg ethyl cellulose (EC). Specifically, the effect of dissolution medium pH on drug release from binary tablets consisting of the polymer and ionizable model drugs verapamil hydrochloride and diclofenac sodium was studied using USP dissolution apparatus (without mechanical stress). The effect of simulated physiological mechanical stress agitation on drug release was studied using dissolution stress test apparatus for non-ionizable model drug acetaminophen. Mechanical properties, physical structures, electrical resistance, water uptake, and contact angle of pure polymer films and of matrix tablets were studied to understand the relationships of these factors to drug release. Our study indicated that increasing polymer amount decreased drug release rate from both silicone PSA and EC tablets using USP dissolution apparatus. However, silicone PSA tablets showed lower friability compared to EC tablets. The application of physiological simulated mechanical stress affected drug release from high Tg EC tablets that resulte (open full item for complete abstract)

Committee: Kevin Li Ph.D. (Committee Chair); Pankaj Desai Ph.D. (Committee Member); Sergey Grinshpun Ph.D. (Committee Member); Gerald Kasting Ph.D. (Committee Member); Gary Kelm Ph.D. (Committee Member); R. Randall Wickett Ph.D. (Committee Member) Subjects: Pharmaceuticals

PhD, University of Cincinnati, 2017, Engineering and Applied Science: Chemical Engineering

Cancer is still a major threat to public health worldwide. Thanks to the extensive studies in cancer biology and growing understanding in cancer, many novel and effective therapeutic agents and drug combinations have been discovered and designed. However, many of them are challenged in reaching their targeted site. Nano-scaled drug carriers that target and deliver therapeutic agents to the sites of diseases have shown great promises in cancer treatment. As a starting point, we designed a human epidermal growth factor receptor 2 (HER-2) targeting pH sensitive nanoparticle combining the advantages of polyhistidine (PHis) and Herceptin. This nanoparticle contains a pH sensitive hydrophobic core in which chemotherapeutic drug is loaded and hydrophilic layer which stabilizes the whole nanoparticle while providing active targeting to HER-2. This nanoparticle shows a pH triggered drug release (i.e. fast drug release at acidic condition and sustained release at physiological condition), a capability of endosomal escape which allows delivery of cargo to cytoplasm, and HER-2 targeting which enhances cellular uptake of the nanoparticle. This work is described in detail in chapter 2. In addition, there are growing needs in delivery of micro RNA inhibitor (miRi) for RNA interferences (RNAi). In chapter 3, a novel lipid coated calcium phosphate miRi complex was made to address poor encapsulation of hydrophilic RNA molecules in hydrophobic polymeric core for co-delivery of molecules with different physicochemical properties. This novel complex was co-encapsulated with paclitaxel in nanoparticle to achieve co-delivery. The co-delivery nanoparticle was found effective in regulating gene expression in vitro. The synergistic effects of co-delivery of miRi and paclitaxel were confirmed in culture cells. In the last part of the study, chapter 4-5 were focused on developing drug delivery systems address the unmet needs for systematic sequential delivery of combination th (open full item for complete abstract)

Committee: Joo Youp Lee Ph.D. (Committee Chair); Chia Chi Ho Ph.D. (Committee Member); Yoonjee Park Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member) Subjects: Chemical Engineering

Master of Science in Engineering, Youngstown State University, 2022, Department of Civil/Environmental and Chemical Engineering

Precise control over the release of drugs from wearable bioelectronic devices on wound sites, such as quantity and timing, is highly desirable in order to optimize wound treatment. The aim of this study is to obtain and characterize an electro-responsive ferrocene-chitosan/alginate polyelectrolyte complex (PEC) hydrogel that can be used as a smart wound dressing. First, chitosan/alginate PEC hydrogel was obtained as a control and characterized in terms of chemical properties and drug release kinetics. Natural chitosan (CHI) was chemically conjugated with ferrocene (Fc) moieties to create Fc-CHI. The Fc-CHI was interacted with alginate (ALG) to form Fc-CHI/ALG PEC through electrostatic interaction. The turbidity test was performed to find the optimum ratio between the Fc-CHI and ALG, thus the stoichiometric PEC hydrogel. The PEC hydrogel was characterized by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectrometer (EDS), in addition to the swelling behavior and gel content tests. Comparative analysis of the ATR-FTIR spectra of CHI, Fc-CHI, ALG, and their mixtures indicated the formation of a polyelectrolyte complex. The SEM images showed the porosity of the PEC. The EDS analysis proved the incorporation of the Fc into the CHI by the appearance of the Fc peaks in the analysis. The PEC hydrogel showed a comparative swelling percentage to be 4400% and also showed excellent stability, proved by almost 100% gel content after incubation in phosphate buffer saline (PBS) solution. To demonstrate the drug delivery potential of the developed PEC-based wound dressing, fluorescence (FITC) and FITC-Dextran were used as model drugs. First, the drug loading and release kinetics of the PEC were studied in solution. In three days, about 83% and 61% were released of the FITC, and FITC-Dextran, respectively in PBS solution. Secondly, the drug release properties on the phantom skin surface (a (open full item for complete abstract)

Committee: Byung-Wook Park PhD (Advisor); Pedro Cortes PhD (Committee Member); Holly Martin PhD (Committee Member) Subjects: Biomedical Engineering; Chemical Engineering; Materials Science

Master of Science, University of Akron, 2019, Polymer Science

Adequate post-operative pain management has been proven to enhance the healing and recovery of patients following most major procedures.1 However, it remains significantly under managed and is a serious unmet need in the medical field. The mainstay of post-operative pain management is the prescription of oral opioids, which, although effective, have many pitfalls. Most notably, opioids prescriptions are currently based on a “one-size-fits-all” model, providing an imbalance of doses given to patients and leaving the medication at the risk for misuse and abuse. Opioids are still in practice today ultimately due to a lack of a better solution. Herein, we propose a drug-loaded polymer film to control post-operative pain. Poly(ester urea)s were used to load drugs into solvent cast blade-coated films and tested for drug release of non-opioids agents. Specifically, etoricoxib, a selective cyclooxygenase isoform 2 (COX-2) was used to monitor the efficacy of delivery from these films both in vitro and in a rat model. To obtain different release profiles, film thickness, drug-load, and polymer composition was analyzed in order to get desired profile for analgesic release. The polymer analogs that were implemented for this study are copolymers, 10%, 20% and 30% 1-PHE-6 P(1-VAL-8), and homopolymers, P(1-VAL-8), P(1-VAL-10), and P(1-VAL-12). Moreover, a multi-modal analgesia model with bupivacaine (a local anesthetic) has been sought out to show the versatility of this device. The goal of this study was to study a controlled release system that will produce little to no inflammation while providing pain relief for 3-5 days following a surgical procedure. Ultimately, this device's intended purpose is to replace or minimize the need for prescription opioids. We hypothesize that by tuning the multiple factors available with PEUs that a variety of drug release profiles can be obtained to fit a number of different applications (i.e. acute to chronic pain).

Committee: Matthew Becker (Advisor); Andrey Dobrynin (Committee Member) Subjects: Biomedical Research; Polymers

Doctor of Philosophy, University of Akron, 2017, Chemical Engineering

This dissertation describes the design and development of several sustained delivery systems based on alginate for delivering small hydrophilic drugs. The release behaviors and specific release mechanisms were investigated to determine how each system prolongs the release of hydrophilic drugs from alginate. The first approach utilizes the coating of a hydrophobic organosilane, octadecyltrichlorosilane (OTS), to hydrophilic alginate microspheres (Alg-Ms), the hydrogel drug carrier, to sustain the release of sodium benzoate (NaB), a model hydrophilic drug. The hydrophobicity of Alg-Ms increased with the incorporated OTS concentration, prolonging the release duration of NaB from hours to days. The release mechanism of NaB from Alg-Ms switched from combined diffusion/polymer relaxation to diffusion as the amount of OTS incorporated increased. The results demonstrate the simplicity of improving hydrophobicity of hydrogel drug carriers using OTS to broaden the drug delivery applications of hydrogels in delivering small hydrophilic drugs. The second coating based method applies layer-by-layer (LbL) deposition of polyelectrolyte to alginate microgels. The polyelectrolyte shell acted as an effective diffusion barrier to extend the release of hydrophilic compounds of NaB and zosteric acid (ZA) from a few hours up to 3 days and 5 days, respectively, as the LbL deposited layer thickness increased. The deposition of polyelectrolyte onto Alg-Ms was confirmed by with microscopic imaging. The release of NaB and ZA was found to be proportional to the bilayers' number and followed the Fickan 2nd law of diffusion. The results indicate that LbL polyelectrolytes coated Alg-Ms have a potential as controlled drug-delivery devices for hydrophilic drugs. The third platform involves a modified double-emulsion technique to generate alginate based poly lactic-co-glycolic acid (PLGA) microparticles for controlling hydrophilic drug (e.g., NaB) delivery. The formulation parameters, such as (open full item for complete abstract)

Committee: Bi-min Zhang Newby Dr (Advisor); Gang Cheng Dr (Committee Member); Jie Zheng Dr (Committee Member); Leah Shriver Dr (Committee Member); Marnie Saunders Dr (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Chemical Engineering; Chemistry; Materials Science; Medicine; Pharmaceuticals; Polymer Chemistry; Polymers

PhD, University of Cincinnati, 2003, Pharmacy : Pharmaceutical Sciences

The objective of this project was to study the effect of modifications of endhydroxylated poly(dimethylsiloxane) (PDMS) formulations on tablet drug release. Emulsions of crosslinked endhydroxylated PDMS, a novel film-forming polymer, were characterized and investigated for their ability to be applied onto tablet cores in a spray-coating process for controlled drug release. Modifications of the crosslinking agent from the most commonly used tetraethylorthosilicate (TEOS) to the trifunctional 3-(2,3-epoxypropoxy)propyltrimethoxysilane (SIG) and a 1:1-mixture of the two crosslinker were undertaken. Addition of vermiculate clay, copolymeric substances and different channeling-agents were studied. Copolymers of methylpolysiloxane with polyoxyethylene (DC193 and DC5324) or dimethyl,methyl (polyoxyethylene) (DCQ2-5220) as well as poly (acrylamide-co-acrylic acid) were used. Lactose, microcrystalline cellulose (MCC) and polyethyleneglycol 8000 (PEG) were the channeling-agents applied. A change in molecular weight of the PDMS was analyzed. Effects on dispersion properties were characterized by particle size distribution, viscosity and visual observation of phase-separation. Mechanical properties of resulting cast and sprayed films were studied to determine applicability in a pan-coating process. Release of Hydrochlorothiazide (marker-drug) was studied from tablets coated in a lab-size conventional coating pan. Dispersions were found suitable for a spray-coating process. Only the formulation with acrylic-copolymer addition was unstable as phase separation occurred. Preparation of free films showed that methylpolysiloxane-copolymers negatively affected the mechanical properties so that coating onto tablet cores was not possible. Tablets coated with formulations crosslinked using the 1:1-mixture of SIG/TEOS and containing polyethyleneglycol were most suitable to control drug release, at 5% coating weight. Constant release rates were achieved for formulations with up to 25% (w/w (open full item for complete abstract)

Committee: DR. ADEL SAKR (Advisor) Subjects:

Doctor of Philosophy, The Ohio State University, 2010, Chemical and Biomolecular Engineering

The nanoporous PCL membranes were prepared via the combination of thermally- and nonsolvent-induced phase separations. For the phase separation process, nonsolvent has significant effect on pore formation and drug release rate. In nonsolvent-induced phase separation, a large amount of nonsolvent was added to casting solutions in order to improve pore connectivity within the membrane. The use of a Teflon plate for membrane casting can result in uniform nanoporous membranes and consistent lysozyme diffusion. Pore connectivity was improved significantly when coagulation bath temperature was lowered. By using a 5°C water coagulation bath in the wet-process precipitation, the average pore size reduced from 90 nm to 55 nm while increasing the casting solution concentration from 15 wt% to 25 wt% PCL. Thus, by varying the polymer concentration of the casting solution, the lysozyme release rate can be manipulated with precise control. The potential application of nanoporous PCL membranes to achieve the preferable zero-order release rate is demonstrated in this dissertation. Along with achieving the zero-order release rate, the nanoporous PCL membranes also provide immunoprotection for cell-based therapies/devices. Immunoisolation can be achieved by preventing Immunoglobulin G (IgG) from diffusing through the nanoporous PCL membranes. With appropriate pore size, the nanoporous PCL membranes can allow the diffusion of therapeutic agents (lysozyme) and block the diffusion of immune molecules (IgG). The application of the nanoporous PCL membranes to cell-based therapies/devices is also demonstrated in this dissertation. Extensive fibrosis induced by the healing process can be detrimental to the long-term performance of implantable applications. The prevention of fibroblast adhesion to the nanoporous PCL membrane surface is crucial for constant and well controlled drug release. This study shows a novel method to modify the nanoporous PCL membrane surface with poly(ethylene glyco (open full item for complete abstract)

Committee: W.S. Winston Ho (Advisor); Boyaka Prosper N. (Committee Member); Koelling Kurt W. (Committee Member); Lee L. James (Committee Member) Subjects: Biomedical Research; Chemical Engineering; Engineering; Polymers

Doctor of Philosophy, The Ohio State University, 2005, Electrical Engineering

Considerable advances have been made in the field of drug delivery technology over the last three decades, resulting in many breakthroughs in clinical medicine. However, important classes of drugs have yet to benefit from these technological successes. One of the major requirements for an implantable drug delivery device is controlled release of therapeutic agents, especially biological molecules, at a constant rate over an extended period of time (i.e. a zero order release kinetics). Another significant challenge in drug delivery is to engineer a delivery system that can deliver drug in a manipulated non-zero order fashion such as pulsatile, ramp or delivery on demand. The goal of this research is to deliver technological innovations to address these requirements. Silicon was chosen as a carrier vehicle and nanochannel delivery systems (nDS) of progressively increasing degrees of functionality were conceived. The fundamental embodiment of the first device, nDS1, employs high-precision nanoengineered clefts to yield the long-term zero-order release of therapeutic agents. This device was designed and fabricated targeting four nanochannel sizes. These were 20 nm, 40 nm, 60 nm and 100 nm. The achieved nanochannel heights measured by Atomic Force Microscope (AFM) were 18 nm, 43 nm, 70 nm, and 108 nm, respectively. Glucose diffusion through a nominal 100 nm channel for a period of 15 days, through a nominal 60 nm channel for a period of 5 days and interferon-alpha (IFN-alpha) release through a nominal 100 nm channel for a period of 7 days showed a zero order release profile through this device. Further, it was proved that IFN-alpha preserves its functional activity after being released through this device. Next, the top substrate of the nDS1 device was replaced with a glass substrate (nDS1g) for improved bonding and a visual observation of fluid flow through the nanochannels of the device. Another implantable drug delivery system (nDS2) that is capable of being integrate (open full item for complete abstract)

Committee: George Valco (Advisor) Subjects: