The absorption enhancing ability of chitosan, a linear polysaccharide, is mediated
by protonated amino groups on the C-2 position of the molecules that induce
interaction with the anionic sites on the cell membranes to subsequently alter
tight junction integrity. In neutral and basic environments, such as those found in
the small and large intestines, most chitosan molecules will lose their charge and
precipitate from solution rendering it ineffective as an absorption enhancer. To
increase the solubility of this polymer, methylation of the amino groups on the C-
2 position was proposed.
A partially quaternised and water soluble derivative of chitosan, N-trimethyl
chitosan chloride (TMC), which exhibits superior solubility in a basic environment
compared with other chitosan salts was synthesised and included in a chitosan
microbead solid drug delivery system. Two TMC derivatives were synthesised
by reductive methylation from high and medium molecular weight Chitoclear™
chitosan respectively. The degree of quaternisation calculated from the 1H-NMR
spectra for the medium molecular weight TMC (TMC-M) and the high molecular
weight TMC (TMC-H) polymers were 74.7 % and 48.5 % respectively. The mean
molecular weights of the synthesised TMC-M and TMC-H polymers were 64 100
g/mole and 233 700 g/mole respectively. The effect of different concentrations
TMC-M and TMC-H on chitosan microbeads was studied with results obtained
from scanning electron microscopy (SEM), TMC loading capacity and microbead
swelling behaviour. After selection of the most suitable TMC concentration, the
effect of varying concentration (0.1, 0.2 and 0.5 %) additives on TMC and
ibuprofen release was studied. Commonly used modified cellulose gum (Ac-di-sol®(ADS)), sodium starch glycolate (Explotab®(EXP)) and ascorbic acid (AA)
were added as disintegrants to different microbead formulations to promote
release of both the ibuprofen as model drug and TMC from the beads. It was
noticed that the loading (% drug loading capacity) of TMC-M was much lower
than that obtained with TMC-H while the inclusion of different additives in varying
concentrations did not seem to have a profound influence on the loading of either
TMC-M or TMC-H. It was further noticed from the fit factors (f1 and f2) for
dissolution profiles of eighteen chitosan microbead variations that the formulation
containing TMC-H and 0.5% (w/v) ascorbic acid was the only formulation with a
significantly higher ibuprofen and TMC-H release profile compared to all other
formulations tested.
The chitosan microbead formulation containing 2%(w/v) TMC-H and 0.5 % (w/v)
ascorbic acid (H-AA-0.5) was used for in vitro absorption studies through rat
intestine in Sweetana-Grass diffusion chambers. Chitosan containing TMC-H
(no ascorbic acid) (CHIT-H) only and a plain chitosan microbead (CHIT)
formulation was used as control formulations during the in vitro studies. Although
the H-AA-0.5 formulation exhibited the highest transport rate for ibuprofen, the
mean rate of transport (P app) obtained from the two formulations containing TMCH
(CHIT-H and H-AA-0.5) showed no significant difference in the transport rate of
ibuprofen. Compared to the CHlT formulation as control, both formulations
containing TMC-H exhibited increased ibuprofen transport across in vitro rat
jejunum. However, a statistical significant increase in transport was obtained
only from the H-AA-0.5 formulation in comparison with the CHlT formulation.
It can be concluded that the combination of high molecular weight TMC with a
low degree of quaternisation and ascorbic acid (0.5% w/v) in a chitosan
microbead lead to a statistical significant increase in the in vitro transport rate of
ibuprofen through rat jejunum. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2006.
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/937 |
| Date | January 2005 |
| Creators | Venter, Johannes Petrus |
| Publisher | North-West University |
| Source Sets | North-West University |
| Detected Language | English |
| Type | Thesis |
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