Thesis (Ph. D.)--University of Texas at Austin, 2002. / Supervisor: JAmes W. McGinity. Vita. Includes bibliographical references.

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Thesis (Ph. D.)--Ohio State University, 2004. / Document formatted into pages; contains 181 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Nov. 24.

Thesis (Ph. D.)--University of Oregon, 2002. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 184-193). Also available for download via the World Wide Web; free to University of Oregon users. Address: http://wwwlib.umi.com/cr/uoregon/fullcit?p3045088.

Thesis (Ph. D.)--Ohio State University, 2005. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 Apr 27.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xxiii, 163 p.; also includes graphics. Includes bibliographical references (p. 118-123). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--Dept. of Chemistry and School of Computing and Engineering. University of Missouri--Kansas City, 2004. / "A dissertation in chemistry and software architecture." Advisor: Yan-Ching Jean. Typescript. Vita. Description based on contents viewed Feb. 27, 2006; title from "catalog record" of the print edition. Includes bibliographical references (leaves 205-218). Online version of the print edition.

M. Pharm., Dept. of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, 2011 / Chronotherapy is a form of therapy where treatment is administered according to a schedule that corresponds to an individual’s biological clock. Research demonstrates that the body’s natural processes follow a 24-hour pattern, or circadian rhythm. In addition, symptoms of disease fluctuate according to this 24-hour pattern. These diseases, termed chronotherapeutic disorders may include amongst other disorders, hypertension, cardiovascular disease and asthma. Common therapy for these disorders involves the use of controlled zero-order release formulations. Here, the same quantity of drug is released over a period of time. Although beneficial, these formulations are not ideal in the treatment of chronotherapeutic disorders. Treatment of these disorders aims to release drug at specific periods, only when it is required, such that therapy coincides with the body’s natural rhythm. Ideally, drug should be released in pulses with two or more pulses released from the dosage form. In this manner, the patient is exposed to drug only when required, reducing the number of dosages, reducing side-effects and ultimately increasing patient compliance. Therefore, the aim of this research was to develop a Multi-Layered Multi-Disk Tablet (MLMDT) that incorporates two drug-loaded disks enveloped by three polymeric layers. The proposed system, to be used in the treatment of chronotherapeutic disorders, is designed to provide a lag phase and then two pulses of drug release separated by a ‖switch-off‖ phase. During the ―switch-off‖ phase no drug is released from the system. Initially, preliminary screening studies were performed on various polymeric materials to assess their effectiveness to generate the desired drug release profile. Of the numerous polymer combination and ratios, only a few were relevant and were subsequently tested further. From the preliminary studies it was ascertained that the composition of disk 2 was critical in generating the ―switch-off‖ phase separating the two pulses. Artificial Neural Networks (ANN); a computational technique that simulates the thinking process of the human brain was employed for optimization. Results from this technique outlined the polymer combination suitable for the optimized MLMDT. The optimized formulations were subjected to friability, hardness and uniformity of mass analysis as well as swelling, erosion and magnetic resonance imaging techniques to observe and confirm the performance of the MLMDT during dissolution. In addition, textural analysis, computational modeling and temperature modulated differential scanning calorimetry techniques were used to elucidate any incompatibilities or complexes formed. In vitro drug release analysis revealed that the MLMDT generated a lag phase followed by two pulses of drug release over the 24 hour period. The two pulses were separated by a ―switch-off‖ phase. To confirm data obtained during preclinical in vitro testing, animal studies were undertaken using the Large White Pig model. Pigs were dosed with conventional products and the optimized MLMDT. Blood samples collected over a 24 hour period were analyzed using Ultra Performance Liquid Chromatography to determine the drug concentration in blood. Drug concentration analysis from conventional products revealed increasing plasma concentrations up to 2 hours followed by a steady decline in concentration while the developed MLMDT displayed two pulse drug release separated by a ―switch-off‖ phase.

Oral drug delivery is perceived by many as the ideal method of drug delivery due to its versatility, ease and convenience. However, the bioavailability of drugs delivered via the oral route remains questionable. Typically, conventional marketed drug delivery systems release drugs in variable and erratic fashions, causing sub-therapeutic or even toxic doses. As a result, patient compliance is threatened, ultimately affecting the success of the therapeutic intervention. Furthermore, the harsh gastric environment further compromises oral bioavailability due to the presence of a highly acidic environment and proteolytic enzymes. A multi-component, membranous drug delivery system (MMDDS) was thus designed, formulated and evaluated for the site-specific delivery of two (or more) drugs in a prolonged release manner, ultimately easing complicated treatment regimens, and improving patient compliance. The MMDDS essentially comprises of a gastric-targeted and an intestinal-targeted component, each containing a protective coat, a drug-loaded layer incorporating the respective drugs, and a pH-responsive mucoadhesive layer for site-specific mucoadhesion. The MMDDS employs a combination of controlled and targeted drug release mechanisms, in addition to gastro-retentive or intestinal retentive mechanisms. Furthermore, the system physically protects the drug delivery system from acidic or proteolytic degradation within the human gastro-intestinal tract. The present study employed the use of pH-dependant mucoadhesion for site-specific, segregated and gastroretentive drug delivery while crosslinking was employed for rate-modulated drug delivery. Rifampicin and isoniazid were selected as the model drugs in this study as they are known for interacting when administered simultaneously (detrimentally affecting the bioavailability of rifampicin). Notwithstanding this interaction, rifampicin and isoniazid must be taken concurrently for successful TB therapy. Therefore these drugs would benefit from the site-specific drug delivery offered by the MMDDS. The primary aim of the pH-responsive mucoadhesive layer was to ensure prolonged adhesion of the MMDDS at a specific site within the human gastro-intestinal tract. The pH-responsive mucoadhesive layer was the fundamental aspect that promoted site-specific and segregated drug delivery. Preliminary in vitro investigations led to the identification of a combination of polymers best suited to develop the respective pHresponsive mucoadhesive layers. A central composite design was employed to determine the optimal ratios of the polymers selected which would impart the largest degree of mucoadhesion within the respective pH ranges. Each mucoadhesive layer was thereafter optimized and subject to various in vitro investigations to determine the effects of the GIT on the properties of the mucoadhesive layer, as well as determine the behaviour of the mucoadhesive layer when subject to simulated gastrointestinal conditions. Electrospinning, a versatile technique employed in the fabrication of fibres in the nanometre size range, was employed to develop the drug loaded layer. Poly(vinyl alcohol) (PVA) nanofibres were thereafter crosslinked employing glutaraldehyde vapours to ensure controlled release of the incorporated drugs. The drug-loaded layer demonstrated good versatility in incorporating vastly different drugs, with only minor adjustments to the fabrication procedure. Furthermore, PVA demonstrated good loading of rifampicin and isoniazid, and near zero-order drug release was achieved after the crosslinking procedure. Prolongation of drug release fundamentally decreases the numbers of doses required to be taken daily, and as such, patient compliance is improved. Furthermore, in vitro analysis revealed that the developed MMDDS behaved superiorly in terms of controlling drug delivery in a site-specific and prolonged fashion in comparison to a marketed gold standard formulation, Rifinah®. These findings were further substantiated by in vivo analysis, which was conducted in a swine model. Results indicated that minimal release of isoniazid was observed in the stomach, based on the plasma concentrations of the drug. Release of isoniazid was initiated only when the intestinal-targeted component entered the intestine of the pig, corresponding to higher plasma concentrations of isoniazid. In this manner, the delivery of isoniazid and rifampicin was segregated, thus improving the oral bioavailability of rifampicin. To summarize, the MMDDS was able to overcome the many challenges associated with oral drug delivery, by easing complicated treatment regimens, and improving the bioavailability of drugs delivered orally. The benefits associated with oral drug delivery have clearly been exploited by the present study, producing a versatile drug delivery “tool” which can successfully be adapted to incorporate any number of drugs (including an entire treatment regimen in one dosage form!) for targeted delivery within the human gastro-intestinal tract in a prolonged manner.