الفهرس 
general introductionOnly 14 pages are availabe for public view
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Abstract
Vesicular systems are one of the favorable drug delivery systems for specific targeting of drugs to certain organs. These systems have gained a lot of attention owing to their distinct advantages in enhancing bioavailability of drugs and reduction of their dosing frequency. Furthermore, they exhibit prolonged and controlled action. Different vesicular systems have been prepared and used in ocular delivery, among which are niosomes, liposomes and spanlastics.
Among the promising herbal drugs displaying therapeutic potential for ocular diseases is baicalin, which is a bioactive flavonoid with a proven antioxidant activity. The solubility and stability of baicalin are pH dependent; being unstable in basic medium. Therefore, the aim of our study was to incorporate baicalin in various vesicular systems including liposomes, niosomes, penetration enhancer vesicles, transfersomes and their pro forms to enhance its permeability and stability in the eye and modulate its therapeutic efficacy in ocular diseases such as cataract.
The work in this thesis is divided into two chapters
Chapter 1: Preparation and characterization of different vesicular systems of baicalin
This chapter deals with formulation and characterization of baicalin vesicles. The vesicles (liposomes, niosomes, penetration enhancer vesicles and transfersomes) and their provesicular forms were prepared by thin film hydration method. They were characterized through the following studies: EE%, pH, particle size, zeta potential, PDI, in vitro release and transmission electron microscopy. Physical stability of baicalin preparations stored at 2-8oC for 3 months were conducted as well through monitoring the changes in
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particle size, zeta potential, polydispersity, EE% and in vitro release. DPPH antioxidant assay and the effect of gamma radiation sterilization on the particle size and entrapment efficiency of the selected vesicular formulations were also studied. The quantitative analysis of baicalin was done using HPLC.
The results of this work revealed the following:
1- Baicalin liposomes, penetration enhancer vesicles containing labrasol, transfersomes containing Na taurocholate and Na glycocholate and their pro forms were successfully prepared using the thin film hydration method.
2- The pH values of the prepared formulae ranged from (4.55- 5.01) which were suitable for maintaining the stability of baicalin in the eye.
3- Particle size of the prepared vesicular systems of baicalin ranged from (667- 2712 nm) depending on the presence of cholesterol and preparation of the formulations in pro forms, in addition to the type of bile salt used in preparation of transfersomes.
4- All of the prepared vesicles were charged, with zeta potential values ranging from (-14 to -31.5 mV), which were indicative of suitable stability against vesicle aggregation and fusion.
5- The EE% of baicalin in vesicular systems ranged from (25.96- 99%) owing to the hydrophobicity of the drug, suggesting its optimum incorporation within the lipid bilayers.
6- Different EE % values were obtained for baicalin depending on the composition of vesicles, the presence of cholesterol, their preparation in pro forms and the type of bile salt (in case of transfersomes).
7- The highest cumulative percent released of baicalin (89.22%) from different vesicular systems after 8 hours was observed with the pro formula V10 having labrasol penetration enhancer in its composition, while the slowest release rate of baicalin was observed with formulation V11 which contains labrasol and cholesterol, where only 46.24% of the drug was released after 8 hours.
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8- Formulae V1 (liposomes), V9 (PEVs), V12 (Pro PEVs), V15 (transfersomes) and V16 (Pro transfersomes) showed good storage properties as manifested by very slight changes in particle size, EE% of baicalin, and the cumulative percent released of baicalin after 3 months storage.
10- Transmission electron microscopy displayed the sealed spherical structures of baicalin vesicular systems containing baicalin.
9- Formulae V1, V9, V12, V15 and V16 displayed significantly better antioxidant activity compared to the ascorbic acid reference.
11- Formulae V1 (liposomes), V9 (PEVs) and V15 (Transfersomes) were selected for conduction of in vivo studies in rabbits.
Chapter 2: Histopathological and in vivo pharmacokinetic evaluation of the selected baicalin formulations
In this chapter, the in vivo pharamacokinetic behavior of baicalin vesicles was compared to baicalin control solution by measuring the concentrations of baicalin in rabbits‘ aqueous humor at different time intervals. Draize test (ocular irritancy) was also conducted on the eyes of rabbits. Histopathological assessment of the selected formulae was done on the excised eye balls of rabbits. The specimens were collected on glass slides, stained by hematoxylin and eosin (H&E) stain and then examined under light electric microscope for histopathological abnormalities when compared to the normal control. For the pharmacokinetic study, drug-free aqueous humor was obtained using a small needle inserted across the cornea. Samples were collected in vials, stored in freezer at −20 ◦C for later analysis for constructing a calibration curve using an HPLC method. Instillation of selected formulations (V1, V9, V15) and baicalin control solution was done on forty eight rabbits at specific times of 5, 15, 30, 60, 120, 240 and 360 minutes after drug instillation. Aqueous humor samples were collected and stored at -20 Celsius for further analysis by HPLC. The pharmacokinetics of each formula
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was compared to that of baicalin control solution. The maximum drug concentration (Cmax, ug/mL) and the time to achieve this peak (Tmax, min.) were calculated. The areas under the concentration– time curves (AUC 0-∞) were also calculated by the linear trapezoidal rule.
The results of this work revealed the following:
1- The selected vesicular system formulae (V1, V9 and V15) didn‘t show any ocular irritation or histological changes when compared to the normal control. Thus, they were proven safe for ocular administration.
2- The transfersomal formulation (V15) showed the shortest Tmax (15 min) similar to baicalin control solution (15 min), followed by the liposomes (30 min) then the penetration enhancer vesicles with labrasol (60 min).
3- The Cmax were 4.0736 ± 0.241 μg/ml, 2.313± 0.111 μg/ml for ocular liposomes (V1) and baicalin PEVs (V9) respectively, while they were 1.503± 0.0491 and 2.228 ± 0.128 μg/ml for baicalin transfersomes (V15) and the control solution respectively.
4- A significant increase in AUC0-∞ was observed in PEVs, liposomes and Na taurocholate transfersomes when compared to that of baicalin control solution.
5- The superiority of baicalin vesicular formulations was demonstrated compared to baicalin control solution, as manifested by longer ocular residence time and more than 4 folds increase in bioavailability.
from the previous findings, it can be deduced that baicalin vesicular systems adopted in this thesis (liposomes, PEVs, transfersomes) were promising for ocular delivery owing to their high permeability into the eye tissues as well as their great capability in improving the stability and ocular bioavailability of baicalin.
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References