A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, in
fulfilment of the requirements for the degree of Master of Pharmacy.
2016Genetic auto-inflammatory inflammatory skin disorders (GAISDs) are a group of inherited disorders which are characterized by seemingly unprovoked recurrent episodes of fever and severe localised inflammation. GAISDs are associated with abnormal activation of the innate immune system, leading to clinical inflammation and high levels of acute-phase reactants. The most common disorder is Familial Mediterranean Fever (FMF), followed by Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). TRAPS episodes generally last longer than FMF and FMF patients tend to respond well with colchicine while TRAPS management seems to be challenging. Hence this work is directed towards improving TRAPS diseases management. A definitive treatment for TRAPS has yet to be identified, and current corticosteroid treatment is mainly limited by the long-term side-effects due to high systemic drug exposure, and the poor availability of drugs at the site of action.
A number of measures were taken in order to overcome the limitations of corticosteroids.Herein a novel stimuli responsive nanocolloidal gel system was developed. A nanoliposomal gel was the stimuli responsive gel system of choice due to its advantages of skin penetration enhancement in transdermal drug delivery system. In this research, a phospholipid based system with Eudragit® E100 (EuE100) chemically modified into EuE100-cystamine derivative for dual pH/redox responsive delivery of [Copper-glycylglycine-prednisolone succinate] ([Cu(glygly)(PS)]) was developed. The rationale of using [Cu(glygly)(PS)] complex instead of the pure PS corticosteroid was supported by comparing the biological activities of these two compounds. Results indicated a high inflammatory/oxidant inhibitory activity of [Cu(glygly)(PS)] in comparison to the free PS drug. The [Cu(glygly)(PS)] complex exhibited a significant free radical-scavenging activity (60.1±1.2%) and lipoxygenase (LOX-5) inhibitory activity (36.6±1.3%) in comparison to PS which gave activity of 4.4±1.4% and inhibition of 6.1±2.6% respectively. The [Cu(glygly)(PS)] loaded NLs showed a low level of [Cu(glygly)(PS)] release of 22.9±5.4% in 6h at pH 7.4, in comparison to a significant accelerated release at pH 5 in a reducing environment of 75.9±3.7%in 6h. Thereafter optimized [Cu(glygly)(PS)]-loaded NLs were dispersed in hydroxypropyl methylcellulose (HPMC)/Polyvinyl alcohol(PVA) gel resulting in a [Cu(glygly)(PS)]-loaded nanoliposomal gel termed asdermal sludge.A dermal sludge is defined as a viscous gel suspended with solid particles ([Cu(glygly)(PS)]-loaded nanoliposomes). The sludge was characterized using ex vivo permeation, in vitro release, cytotoxicity and in vivo studies, and compared to the conventional PS formulations. The results indicated that the novel dual redox/pH responsive nanoliposomal dermal sludge holds great potential for targeted bioactive delivery in TRAPS through the transdermal route, hence improving the therapeutic outcome.MT201