Parkinson’s Disease (PD) is a progressively debilitating neurodegenerative disease that affects
the central nervous system and leads to severe difficulties with body movements. PD occurs due
to the selective degeneration of neurons in the region of the brain known as the substantia nigra
pars compacta. To date PD remains an incurable disease. Currently prescribed drugs provide
only symptomatic relief to patients. Furthermore, they have considerable side effects and are
often ineffective in the later stages of the disease or need to be used in combination in order to be
effective. The role of neuroprotectants as a preventative measure in PD therapy is consequently
receiving a great deal of attention and is being subjected to extensive research. This study
sought to develop a novel prolonged-release drug delivery device for providing site-specific
administration of newly researched neuroprotective agents. Nicotine was employed as the model
neuroprotectant to incorporate in a novel reinforced crosslinked multiple-unit multi-polymeric
drug delivery device. The study was the first of its kind to develop and employ the alkaloid for
this purpose in a formulated delivery system. The device was intended to be one that provided
zero-order prolonged release of the drug over a period of 1-2 months. The device was formulated
such that its design was in keeping with the potential for implantation into the substantia nigra
pars compacta to provide site-specific drug delivery. In order to do so, polymers, with
biocompatible and bioerodable characteristics were selected to incorporate the drug within a
reinforced crosslinked matrix. The study elucidated the mechanism of crosslinking of
ionotropically crosslinked alginate spheres (gelispheres) with a variety of crosslinking agents
through an evaluation of physicomechanical properties of the crosslinked system. The presence
of barium in the crosslinked matrices generated densely networked gelispheres which retained
their robustness following exposure to hydrating media and displayed promising potential for
4
entrapping drug molecules and retarding their release. The system was reinforced employing
hydroxyethylcellulose (HEC) and polyacrylic acid (PAA). A Design of Experiments approach
employing a Plackett-Burman screening design enabled optimisation of the proposed device in
terms of reinforcing polymers (HEC and PAA) and crosslinking agents (barium and calcium). In
order to further attenuate drug release rate the optimised crosslinked gelispheres were exposed to
dilute hydrochloric acid (HCl) which significantly decreased gelisphere matrix swelling and
erosion following exposure to simulated cerebrospinal fluid (CSF). These gelispheres were
thereafter incorporated into a compressed release-rate modulating polymeric discs. Zero-order
drug release was observed for a period of 50 days in simulated CSF when the optimised
gelispheres were incorporated into compressed poly(lactic-co-glycolic) acid (PLGA) discs.
Alternative approaches to modify drug release kinetics were also evaluated including the use of
PLGA coatings on compressed hydroxypropylmethylcellulose-polyethylene oxide (HPMC-PEO)
discs incorporating gelispheres and the use of crosslinked alginate-pectinate gelispheres as
carrier systems to deliver PLGA-PLA (polylactic acid) microparticles incorporating drug. A
Box-Behnken statistical design was employed to formulate and optimise the drug carrying
PLGA-PLA microparticles. In both of the abovementioned cases we obtained sustained zeroorder
drug release.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/5470 |
| Date | 20 August 2008 |
| Creators | Singh, Neha |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 3290885 bytes, application/pdf, application/pdf |
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