الفهرس 
Preparation and characterization of alpha-arbutin loaded-chitosan nanoparticlesOnly 14 pages are availabe for public view
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Abstract
An excess of melanin level in skin leads to an aesthetically undesirable skin disorder known as melasma, resulting in a wide search for effective treatments. Nevertheless, the aggressiveness of physical treatments, such as cryotherapy, chemical peels and laser therapy have shed thelights on the importance of topical treatments, in which the skin whitening agents have been considered. In fact, a multi-therapy approach is needed in most cases of hyperpigmentation. However, the poor chemical stability of the majority of whitening agents and the need to enhance their skin bioavailability have been the major concern of several studies focusing on nanocarrier systems as potential protectors. Recent research has demonstrated that using whitening agents in nanocarrier systems as a therapeutic approach is very promising for treatment of melasma.
Arbutin is a naturally occurring Beta-D-glucopyranoside derivative of hydroquinone, existing in the dried leaves of bearberry. Arbutin is widely used as a skin whitening or depigmenting agent as it acts by inhibiting melanosomal tyrosinase, which is the main cause for skin hyperpigmentation disorder. There are two isomeric forms for arbutin, alpha and beta isomers. Studies have shown that alpha-arbutin possesses an even stronger inhibitory effect on human tyrosinase activity as well as better stability compared to the beta isomer.
The purpose of the first chapter was to formulate chitosan nanoparticles (CSNPs) for enhanced topical delivery of α-arbutin for treatment of melasma. Ionic gelation method was used to prepare α-arbutin-CSNPs. A 24 full factorial design study was utilized to study the effect of the formulation independent variables on the product characteristics as dependent ones. All possible combinations were studied. Two functional additives namely; hyaluronic acid (HA) and/or collagen were added to potentialize the clinical efficacy of the prepared system. The prepared formulations were characterized for particle size (P.S), zeta (ξ) potential and entrapment efficiency (EE%) and stability. In vitro release experiments as well as morphology and ex-vivo deposition throughout rat skin were conducted on the selected formulae based on a desirability study. Differential scanning calorimetry (DSC) and Fourier Transform Infrared spectroscopy (FT-IR) were carried out in order to study the possible interaction of α-arbutin with the excipients used in the selected formulae.
CSNPs showed P.S in the nanometer range, positively charged ξ potential, high EE% of α-arbutin and good stability properties. The selected formulae showed sustained release of α-arbutin for 24 hours. Exvivo deposition of CSNPs proved their superiority in accumulating the drug in deep skin layers with no transdermal delivery. The DSC thermogram showed the disappearance of α-arbutin melting endothermic peak in the selected CSNPs formula, suggesting that the entire drug was completely entrapped inside the polymeric matrix of the prepared nanoparticles. The FT-IR data of the selected CSNPs confirmed the interaction of α-arbutin with the polymeric matrix that might account for the reasonable encapsulation of α-arbutin in these nanoparticles. The best formulae from this chapter were prepared using 0.15% (w/v) chitosan, 0.1% (w/v) TPP with or without the two functional additives (HA and Collagen, 0.1% w/v).
Additionally, in the second chapter, liposomes were formulated using the reversed phase evaporation technique. A 23 full factorial design study was utilized to study the effect of the formulation independent variables on the product characteristics as dependent ones. All possible combinations were studied. Liposomes were prepared using two different amounts of phospholipids in presence of α-arbutin, HA and/or collagen. The optimized liposomal formula was utilized for the preparation of PEVs containing two penetration enhancers (labrasol or transcutol; 5 or 10%) and invasomes containing penetration enhancers (cineole or limonene; 1.5 or 3% and 3% ethanol). All α-arbutin vesicular formulae were characterized as previously described with CSNPs.
The three vesicular systems showed P.S in the nanometer scale, negatively charge values, high EE%, good stability properties and high-sustained release properties. Ex-vivo deposition of such vesicles proved their superiority in accumulating the drug in different skin layers with transdermal delivery. The DSC thermograms revealed the disappearance of α-arbutin melting endothermic peak in the selected vesicular systems, suggesting that the entire drug was completely encapsulated inside the vesicles. The FT-IR data of the selected vesicles revealed the interaction of the drug with the lipid matrix which reflected the successful interaction of α-arbutin in these vesicles. Two formulae were selected from this chapter, one of which was prepared with 100 mg phospholipid, HA and Collagen (0.1% w/v, each) and the other was prepared with 100 mg phospholipid, 5 % transcutol, HA and Collagen (0.1% w/v, each).
Finally, in the third chapter, the selected formulae were tested for their clinical efficacy on patients suffering from melasma in comparison with the α-arbutin hydrogel. The encapsulation of α-arbutin in vesicular systems as liposomes and PEVs as well as polymeric based nanocarriers (CSNPs) allowed for maximization of its therapeutic potential in melasma, as could be deduced from the patients’ assessment criteria through clinical and histopathologic evaluation.
Therefore, it can be concluded that the proposed approach adopted in this thesis of using polymeric nanoparticles such as CSNPs as well as different types of vesicular systems containing a skin whitening agent as a drug, HA and collagen as functional additives for treatment of melasma has shown very promising results, and if well implemented, it is expected to overcome the drawbacks of conventional routes of administration.