Exploring the buccal delivery potential of an antiretroviral drug.
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Abstract
Whilst antiretroviral drugs (ARVs) have significantly improved treatment of Human
Immunodeficiency Virus infection and Acquired Immune Deficiency Syndrome (HIV and AIDS),
several limitations exist with their oral route of administration. Several orally administered ARVs
such as, didanosine, saquinavir, tenofovir and zidovudine are associated with low and erratic
bioavailability due to extensive first pass effect (FPE) as well as gastrointestinal (GI) acids and
enzymatic degradation. Moreover, the half-life for several ARV drugs is short, which requires
frequent administration of doses leading to systemic side effects and decreased patient
compliance. Alternative routes of administration, such as buccal, rectal and vaginal, are widely
investigated in the literature. Buccal delivery of drugs may therefore overcome the above
limitations by bypassing FPE and GI degradation, thus improving bioavailability. Furthermore,
drug absorption following buccal administration is not influenced by the potential variations in
the gastric emptying rate or the presence of food. However, drug absorption can be limited by
low buccal permeability due to the epithelial lining the mucosa. Identifying optimal novel
enhancers is paramount to designing and developing drugs as buccal delivery systems. In an
attempt to explore the potential of the buccal mucosal route for the delivery of an ARV drug
using didanosine (ddI) as a model drug, the aims of this study were to: 1] investigate the
permeability properties of ddI across the buccal mucosa route in order to determine its
suitability for development as a buccal delivery system, 2] determine the effects of novel
permeation enhancers, i.e. aloe vera gel (AVgel), oleic acid (OA) and its novel synthesized
oleodendrimer derivatives, on the buccal permeability of ddI, and 3] to find out (through histomorphological
evaluation) whether ddI and the novel enhancers, i.e. AV gel and novel OA
derivatives have any toxic effects on the buccal mucosa.
The buccal mucosa was harvested from pigs, and all the excess connective tissue was
surgically removed. In vitro buccal permeation experiments were undertaken using modified
vertical Franz diffusion cells, with phosphate buffered saline pH 7.4 (PBS) at 37 °C. ddI was
quantified at 250 nm using a validated UV spectrophotometric method. The histomorphological
evaluations were undertaken using light microscopy (LM) and transmission electron
microscopy (TEM).
ddI permeated through the buccal mucosa and its permeability was concentration-dependent.
A linear relationship (R² = 0.9557) between the concentrations and flux indicated passive
diffusion as the mechanism of drug transport. AVgel, at concentrations of 0.25 to 2 %w/v,
significantly enhanced ddI flux (p<0.05), with permeability enhancement ratios from 5.09 (0.25
%w/v) to 11.78 (2 %w/v), but decreased permeability at 4 and 6 %w/v. OA and its derivatives,
i.e. ester (OA1E), the dicarboxylic acid (OA1A), the bicephalous dianionic surfactant (OA1ANa)
and their parent compound, OA, all enhanced the buccal permeability of ddI. OA, OA1E, OA1A
and OA1ANa at 1 %w/w all showed potential, with enhancement ratios (ER) of 1.29, 1.33, 1.01
and 1.72 respectively. OA1ANa at 1 %w/w demonstrated the highest flux (80.30 ± 10.37 μg
cm ˉ².hr), permeability coefficient (4.01 ± 0.57 x 10 ˉ³ cm hrˉ¹) and enhancement ratio (1.72).
The highest flux for ddI (144.00 ± 53.54 μg cm ˉ².hr) was reported with OA1ANa at 2 %w/w,
which displayed an ER of 3.09 more than that with ddI alone (p=0.0014). At equivalent
concentrations, OA1ANa (ER=3.09) had a significantly higher permeation enhancing effect
than its parent OA (ER=1.54).
Histomorphological studies showed that ddI did not have any adverse effects on the buccal
mucosae. Ultrastructural analysis of the buccal mucosae treated with phosphate buffer saline
pH 7.4 (PBS), ddI/PBS and ddI/PBS/AVgel 0.5 %w/v showed cells with normal plasmalemma,
well-developed cristae and nuclei with regular nuclear envelopes. However, cells from 1, 2 and
6 %w/v AVgel-treated mucosae showed irregular nuclear outlines, increased intercellular
spacing and plasmalemma crenulations. AVgel enhanced the buccal permeation of ddI and
0.05 %w/v was identified as a potentially safe and effective concentration for developing and
optimizing buccal delivery systems. OA1ANa at all concentrations, except 6.0 %w/w had no
adverse effects on the mucosae. OA1ANa at 2 %w/w was identified as a potentially safe
concentration, and the optimal novel OA derivative that can widen the pool of fatty acid
derivatives as chemical permeation enhancers for buccal drug delivery. The cellular changes,
such as vacuoles formation and increased intercellular spaces, were attributed to the buccal
permeation enhancing effects of AVgel and OA1ANa.
The results in this study confirmed the potential of buccal delivery of ddI, identified permeability
parameters of ddI across the buccal mucosa and its permeability enhancement by both AVgel
and OA derivatives as novel permeation enhancers. The study showed that both OA1ANa at
2 %w/w and AVgel at 0.5 %w/v, or lower concentrations, can be used as buccal permeation
enhancers to develop and optimize novel buccal delivery systems for ddI to improve ARV
therapy. The novel enhancers are recommended for selection as buccal permeation
enhancers, to design and optimize ddI buccal delivery systems, and application to other ARV
drugs for improved therapy.
Description
Ph. D. University of KwaZulu-Natal, Durban 2014.
Keywords
Antiretroviral agents., Drug delivery systems., HIV (Viruses)--Treatment., AIDS (Disease)--Treatment., Theses--Pharmacy and pharmocology., Buccal delivery.