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A novel controlled release intravaginal bioadhesive polymeric device

PhD Faculty of Health Sciences, University of the Witwatersrand, 2009. / HIV/AIDS was discovered almost a quarter of a century ago and has so far claimed the lives of
more than 25 million people worldwide. Developing countries remain disproportionately affected,
with sub-Saharan Africa contributing more than two-thirds of infections globally. Sexual
transmission is the primary route of HIV/AIDS acquisition, and women bear the greatest burden of
this pandemic. We are now at a stage where biotechnological advances are needed that can either
cure HIV/AIDS, stimulate the immune system to produce anti-HIV-antibodies by vaccination, or
prevent HIV infections. One of these advances has been the development of various microbicides.
However, a lack of effective drug delivery systems for these agents has remained as a rate-limiting
step towards successful HIV prevention. In an attempt to overcome this problem, this study aimed
at designing and developing a novel intravaginal bioadhesive polymeric device (IBPD) as a
delivery system to effectively deliver a microbicide {polystyrene sulfonate (PSS)} and antiretroviral
(ARV) {3'-azido-3'-deoxythymidine (AZT)} combination to the vagina. The development of a
successful intravaginal microbicidal drug delivery system requires the design of a formulation to
deliver the microbicide-ARV combination in a safe, effective, and consistent manner. The first step
therefore was to undertake extensive preliminary screening studies on various polymeric materials
using a one variable at a time (OVAT) approach to find suitable polymers for developing an IBPD.
Initially 18 biodegradable and biocompatible polymers were employed to produce 62 formulations
that were further screened through the OVAT approach to result in 15 lead formulations.
Two major concerns of this study were the attainment of satisfactory residence time of the IBPD in
the vagina as well as the ability of the IBPD to contain and release the microbicide-ARV in a
controlled manner. Therefore, optimization of the IBPD was based on these two requirements for
which proper matrix integrity was a pre-requisite. Artificial neural networks (ANNs), a computational
technique that is able to simulate the neurological processing ability of the human brain through
mathematical modeling, was employed for optimization. The ANN approach confirmed that 5 of the
18 studied polymers could be suitable for the development of an optimized IBPD. To finally attain
good vaginal retention for the developed delivery system, extensive bioadhesivity testing was
undertaken on the optimized device. Thorough in vitro and ex vivo bioadhesivity analysis was
conducted using physicomechanics and computational structural modeling. Allyl penta erythritolcrosslinked
poly acrylic acid (APE-PAA) appeared to contribute most to the bioadhesivity. Apart
from being employed as a matrix component, PAA was further used as a coating agent to achieve
extended bioadhesivity within the posterior fornix of the vagina. Since prolonged release and
suitable permeation of the microbicide-ARV across the vaginal tissue was a critical requirement of
this study, the device was designed to provide a controlled and prolonged drug release. Prolonged
release for up to 72 days was achieved. Furthermore, the design was constructed to ensure that
the released drug could permeate into the vaginal tissue and be retained substantially. This was
determined by measuring drug flux through ex-vivo permeation studies using freshly excised pig
vaginal tissue in a Franz Diffusion Cell (FDC) apparatus.
The ultimate aim of the study was to have the IBPD well accommodated in the vagina for
successful prevention of STIs and HIV infection. Achievement of this aim was ensured by
undertaking extensive in vivo studies in Large White pig model. The IBPDs were inserted under
anaesthesia into the posterior fornix of the vagina, using a novel applicator. To detect the retention
of the IBPDs and determine their sequential biodegradation pattern in the vagina, X-ray imaging
was employed, using radio-opaque Barium Sulphate (BaSO4). To demonstrate that the developed
drug delivery system acted locally and was only minimally absorbed systemically, blood samples
were taken from the jugular vein of each pig at pre-determined time intervals and subjected to
UPLC analysis. The drug content in the vaginal tissue at the end of the study was also determined.
Histopathological evaluation was carried out on vaginal epithelium to access the potential for
toxicity of the IBPDs. The drug content analysis revealed that greater amounts of AZT and PSS
were retained in the vaginal tissue with relatively small quantities (AZT:17%; PSS:13%) crossing
into the systemic circulation. The results from the toxicity studies showed that the IBPDs were safe
for use. This suggests that the developed drug delivery system (the IBPD) may be suitable for
application in the prevention of STIs and HIV infections.
Date28 June 2010
CreatorsNdesendo, , Valence Mathias Kessy
Source SetsSouth African National ETD Portal
Detected LanguageEnglish

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