الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
Uveitis is defined as an inflammatory process of the middle layers of the eye, also called the uveal tract or uvea. The uvea is very important because its many veins and arteries transport blood to the parts of the eye that are critical for vision. Topical administration is usually preferred over systemic route to avoid systemic toxicity, rapid onset of action, thereby decreasing the required dose. For uveitis not caused by infection corticosteroids are the drugs of choice to reduce swelling and relieve pain. Recently, the US FDA approved difluprednate (DFP) for the treatment of post-operative ocular inflammation and pain.
Lipid nanocapsules (LNC) are one of the approaches developed to increase both the retention of the drug in the precorneal area and the penetration of the drug through the cornea.
DFP.loaded LNC were prepared according to a solvent-free phase inversion method that allows the preparation of very small nanocapsules by thermal manipulation of oil/water emulsified system.
Chapter I comprises the preparation and optimization of DFP loaded LNCs using a mixture design of experiments followed by their characterization via particle size (PS) and size distribution analysis, zeta potential (ZP), pH, viscosity, particle morphology using high resolution-transmission electron microscopy (HR-TEM) and in-vitro drug release.
All the developed LNC dispersions are considered convenient for ocular use as the sizes of the obtained nanocapsules are in the range of 18.56 ± 1.62 to 98.97 ± 1.94 nm with a PDI extending from 0.016 ± 0.002 to 0.163 ± 0.004. Their pH values were almost neutral with suitable viscosity measurements. Based on the statistical analysis of the design adopted, the data were well fitted on the suggested PS, ZP and viscosity models with R2 values of 0.9835, 0.7548, and 0.9652, respectively. The higher surfactant to oil ratio at specified salted water concentration was the key elements for smaller LNC sizes. The higher the ratio of the surfactant to salted water used, the smaller sizes of the LNC were also formed. The combined effects of all independent variables showed significant effects (p<0.01) on the viscosity of the prepared formulations. After storage for nine months, the mean PS results of all the prepared formulations showed significant changes (p<0.05) yet differences in PDI and ZP were minor. DFP-loaded LNCs were successfully sterilized by gamma radiation and retained their integrity.
In Chapter II, DFP Optimized formulae from Chapter I were successfully incorporated into a novel hybrid nano-colloidal system composed of both chitosan polymer and lipids forming chitosan-coated lipid nanocapsules (CLN). Two modified chitosan grades (low and high Mw) were employed. The prepared formulations were characterized in terms of PS, PDI, ZP, viscosity and pH measurements, particle morphology using HR-TEM, in vitro release of DFP-loaded CLN, in vitro mucoadhesion study. The selected DFP-loaded CLN were also subjected to physical stability study and sterilization by gamma irradiation.
Modified chitosan with higher degree of deacetylation was obtained after 2h of deacetylation with 50% NaOH. FT-IR spectra of both modified chitosan (low and high Mw) clearly show that chitosan was successfully deacetylated. Low Mw chitosan, at all concentrations tried (1, 3, and 5% w/v), was convenient for the preparation of CLN. The 3 and 5 %(w/v) high Mw chitosan concentration were so viscous that cannot be electrostatically attracted to the LNC instead a visible agglomeration of particles occurred. Only 1% (w/v) concentration of high Mw chitosan was appropriate for the preparation of CLN.
Narrow PS distribution for the formulations prepared with low Mw chitosan (1 and 3%w/v) ranging from 0.033 to 0.094 indicating good polydispersity while in case of 5% chitosan, it is clearly observed that some agglomeration occured. Particle aggregation was observed for LNC coated with high Mw chitosan. The highest ZP values (+7.29 – +9.46 mV) were obtained upon using low Mw chitosan at 3%w/v concentration. The 3% low Mw chitosan was found optimum for coating the LNCs due to the highest surface charges of the formed NPs confirming particle repulsion and thus system stability, in addition to optimum increase in PS, yet below 60 nm, with good polydispersity, ranging from 0.052 to 0.094. The measured viscosities of the selected CLN dispersions are considered convenient for ocular use. The drug release pattern of DFP-loaded CLN were best fitted with either first-order or zero-order release kinetics. The CLN formulae demonstrated about 2.5-fold increase in mucoadhesive force relative to the respective uncoated LNCs. The stored and sterilized chosen preparations showed non-significant alterations of their physical properties. Based on the obtained results, it can be concluded that the developed CLN represent a promising ocular nanocarrier for the delivery of the anti-inflammatory drug DFP.