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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/11391 |
| Date | 06 March 2012 |
| Creators | Khan, Zaheeda |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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