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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/12533 |
| Date | 18 March 2013 |
| Creators | Shaikh, Rubina Perveen |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf, application/pdf |
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