Malaria is an infectious disease caused by various forms of the Plasmodium parasite. It is
responsible for thousands of deaths yearly with 90 % of those deaths being in sub-Saharan
Africa, thus making it a disease of global importance. The global burden of malaria is
worsened by resistance to current treatment, a lack in funding and limited research outputs.
More alternative ways of treatment must be explored and may include the co-formulation of
antimalarial drug substances as well as alternative ways of drug delivery.
Antifolates are drugs which interfere with an organism’s folate metabolism by inhibiting
dihydropteroate synthase (DHPS) or dihydrofolate reductase (DHFR). Dapsone is a synthetic
sulfone which has a mechanism of action that is very similar to that of sulphonamides. The
mechanism of action is characterised by the inhibition of folic acid synthesis through the
inhibition of dihydropteroate synthase (DHPS). Another antifolate drug, proguanil, is the
prodrug of cycloguanil. Its mechanism involves the inhibition of dihydrofolate reductase
(DHFR), thus inhibiting the malaria parasite to metabolise folates and therefore stunting its
growth. Unfortunately, dapsone has a serious side-effect in people with a deficiency of the
enzyme glucose-6-phosphate dehydrogenase (G6PD) causing oxidative stress on the red
blood cells leading to the rupturing of these cells.
The main objective of this study was to formulate and characterise TMC-TPP microparticles
loaded with the effective but toxic drug combination of dapsone and proguanil and to
determine if these drug-containing microparticles had in vivo efficacy against malaria.
N-trimethyl chitosan chloride (TMC), a partially quaternised chitosan derivative, shows good
water solubility across a wide pH range thus having mucoadhesive properties and excellent
absorption enhancing effects even at neutral pH. A faster, more efficient microwave
irradiation method was developed as an alternative to the conventional synthesising method
of TMC. TMC with the same degree of quaternisation (DQ), ± 60 %, was obtained in a quarter
of the reaction time (30 min) by using the newly developed method. The TMC synthesised
with the microwave irradiation method also exhibited less degradation of the polymer
structure, thus limiting the chance for the formation of any unwanted by-products (Omethylation,
N,N-dimethylation and N-monomethylation).
The formation of complexes by ionotropic gelation between TMC and oppositely charged
macromolecules, such as tripolyphosphate (TPP), has been utilised to prepare microparticles
which are a suitable drug delivery system for the dapsone-proguanil combination. Both these
drugs were successfully entrapped. These particles were characterised and the in vivo
efficacy against the malaria parasites was determined. The microparticles with both the
drugs, separately and in combination, displayed similar or better in vivo efficacy when
compared to the drugs without the TMC microparticles.
An in vitro dissolution study was also performed by subjecting the dapsone and proguanil
TMC formulations to 0.1N HCl dissolution medium. Samples were withdrawn after
predetermined time points and the drug concentration was determined with HPLC. It was
found that the TMC microparticles resulted in a sustained release profile since only 73.00 ±
1.70 % (dapsone) and 55.00 ± 1.90 % (proguanil) was released after 150 minutes. The in vivo
bioavailability of the dapsone and proguanil TMC formulations was evaluated in mice by
collecting blood samples at predetermined time points and analysing the samples with a
sensitive and accurate LC-MS/MS method. The in vivo bioavailability of the dapsone TMC
formulation relative to the normal dapsone formulation was found to be 244 % and 123 % for
the proguanil TMC formulation relative to the normal proguanil formulation.
These TMC-TPP microparticles formulations showed better in vivo efficacy and bioavailability
when compared to the normal formulation. Together with the sustained release, these
formulations may be a promising cheaper and more effective treatment against malaria. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nwu/oai:dspace.nwu.ac.za:10394/15694 |
| Date | January 2014 |
| Creators | Van Heerden, Jacobus |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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