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Title:	Pre-clinical safety evaluation, scaling up and human clinical safety and efficacy of co-loaded hydrocortisone-hydroxytyrosol chitosan nanoparticles for the treatment of atopic dermatitis.
Authors:	Muhammad Irfan Siddique (P74208)
Supervisor:	Haliza Katas, Assoc. Prof. Dr.
Keywords:	Atopic Dermatitis Hydrocortisone Dissertations, Academic -- Malaysia
Issue Date:	21-Jul-2016
Description:	Hydrocortisone (HC) is a class of topical glucocorticoids (TGs) and is used for the treatment of atopic dermatitis (AD). However, local and systemic side effects of HC have hampered its use clinically. In an attempt to minimise local and systemic adverse effects of HC, it was incorporated into chitosan nanoparticles (CSNPs) and co-loaded with hydroxytyrosol (HT), a polyphenol with strong antimicrobial, antioxidant and anti-inflammatory activities to obtain synergistic effects with HC. The objective of this study was to evaluate the safety of HC-HT CSNPs through a series of toxicological studies. HC-HT CSNPs with spherical morphology and an average diameter of <300 nm and zeta potential +39.2 ± 1.6 mV were successfully prepared using ionic gelation method. HC-HT CSNPs were later incorporated into aqueous cream (vehicle) and investigated for acute dermal toxicity, dermal irritation, and repeated dose toxicity of different HC-HT concentrations in albino Wistar rats. Local permeation and targeted delivery were investigated by in-vivo dermal pharmacokinetics (DPks) and its repeated dermal application was compared to commercial formulation. Nanoparticles formulation was also scaled up, characterised and stabilised prior to its safety and efficacy study on human. Stability of formulations was evaluated at 4, 25 and 40°C for a period of one year. HC-HT CSNPs exhibited LD50 > 125 mg/body surface area (BSA) of HC, which is 100-fold higher than the normal human dose of HC. In comparison to the commercial formulation, 0.5 g of HC-HT CSNPs did not cause skin irritation, as measured by Tewameter®, Mexameter®, and through visual observation. Moreover, no observed adverse effect was noted with respect to body weight, organ weight, feed consumption, blood hematological and biochemical, urinanalysis and histopathological parameters at the dose of 1000 mg/BSA/day for 28 days. DPks revealed that CSNPs penetrated 2.46-fold higher than the commercial formulation and had greater affinity at the skin target site. In repeated dermal application, HC-HT CSNPs showed no evidence of toxicity when compared to the commercial formulation. HC-HT CSNPs had higher antibacterial activity against gram-positive than gram-negative bacteria. Storage condition at 25°C was recommended for the nanoparticle formulation as minimal changes in terms of rheology, pH and morphology were observed. On healthy human skin, any signs of local and systemic adverse effects were not seen. Moreover, a clinical efficacy study proved that HC-HT CSNPs were safe and effective in treating AD. Thus, it can be concluded that positively charged CSNPs have a great potential to be utilised for topical delivery of TGs due to significantly reduced side effects and effective treatment against AD.,Doctor of Philosophy
Pages:	284
Call Number:	QV20.5.M952p 2016 9
Publisher:	UKM, Kuala Lumpur
Appears in Collections:	Faculty of Pharmacy / Fakulti Farmasi

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