Complex medication regimens have major implications on patient therapy. When we consider that
these regimen therapies can also be further convoluted by co-morbidity, it is then seen as an essential
opportunity to research possible solutions to alleviate such complications. Globally identified
conditions such as the Human Immuno-deficiency Virus (HIV) and Tuberculosis (TB) are known to
have such complications within their respective regimens. In many cases, the regimental therapies
themselves are overbearing with high pill burdens having to be taken in segregated manners
throughout the day. Within a standard TB regimen, isoniazid and rifampicin are seen to have a
deleterious drug-drug interaction in which the bioavailability is compromised through formation of an
insoluble complex. Despite this interaction, the 2 active drugs must be taken concurrently for
successful TB therapy. No true solution exists as fixed dose combinations of isoniazid and rifampicin
(Rifinah®) are still in production despite the detrimental interaction that impedes successful
bioavailability. The once daily multi-unit drug delivery system (ODMUS) has the benefits of
superseding the described problems and aiding in therapeutic outcomes.
Preliminary studies utilized preliminary testing to ascertain the science surrounding the 2 components
of the ODMUS, the memblet and the multiparticulate components. pH-sensitive polymers (Eudragit®
L100-55 and E 100) were of critical importance to the success of the system and were individually
manipulated for each component to produce a novel memblet and multiparticulate system through a
unique salting out approach.
Primary studies focused on drug release testing and drug entrapment for the multiparticulate
component. Testing of the memblet system addressed dissolution and thermal analysis. Utilizing this
data, a series of process variables were used to achieve an optimized formulation through a Box-
Behnken statistical design.
Optimized formulations used response testing to establish the optimal characteristics of both
components. Multiparticulates achieved controlled release for 12 hours with an enhanced 71% drug
entrapment efficiency. Memblet release profiles were confirmed over 2 hours with a maximal Tg of
56°C. Molecular modeling corroborated release understanding for both components. Surface area and
porosity analysis, surface morphology, fourier transform infrared spectroscopy as well as thermal,
rheological and mechanical analysis were additional tests undertaken on the optimized formulations.
In vivo analysis was the final testing to verify validity of the ODMUS components and utilized a pig
model for the investigation. UPLC blood analysis revealed increase blood levels of INH (CmaxINH=
0.0138ng/mL) and RIF (CmaxRIF= 0.052ng/mL) in relation to conventional dosage forms validating
segregated site-specific release and increased bioavailability.
Ideally, a segregated means of drug delivery throughout the gastrointestinal tract was achieved such
that an enhanced bioavailability, a more controlled release and a simplified medication regimen was
produced. This study aimed to achieve said goals through novel technique analysis, innovation and
globally approved science to critically assess the success of the ODMUS as a potential means to
reduce the complexities of medication regimen therapy.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/10584 |
| Date | 19 October 2011 |
| Creators | Cooppan, Shivaan |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | M.Pharm., Faculty of Health Sciences, University of the Witwatersrand, 2011 |
| Format | application/pdf |
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