الفهرس 
General introductionOnly 14 pages are availabe for public view
 |  | from | 226 |  |  |
| | | from | 226 | | |
Abstract
Aims and objectives: This thesis was concerned with the design and evaluation of cubosomes for ocular delivery of BDP, in an attempt to enhance the transcorneal drug permeation and ocular bioavailability following topical administration.
In chapter 1, cubosomes were prepared by the top-down method using GMO oil and two stabilizers (poloxamer 407 and solulan C 24) were used to generate cubosomes. All the prepared cubosomes were characterized regarding their properties as particle size and zeta potential, drug entrapment efficiency, pH, surface tension and viscosity measurements. The morphology was also studied through the normal and polarized light microscope in addition to the transmission electron microscopy. Also, in vitro, ex vivo performance, and stability study of selected formulations were performed.
Results showed that BDP loaded cubosomes were successfully prepared by the top-down method using a well-known stabilizer pol.407 and new alternative stabilizing agent solulan C 24. The characterization of the prepared cubosomes formulations revealed that all formulations have a particle size within the nanoscale range (104 nm – 278 nm) and zeta potential values (-16 mV to - 43.7 mV). The pH of the prepared cubosomes was in a range of (6.5-7.7) which considered tolerable for topical ocular applications. Also, they showed a higher entrapment efficiency EE% ranged from 94.1 to 98.12 %.
In addition, they showed a significantly lower surface tension ranged from 39-43 dynes/cm without the addition of any excipients compare with that of the control BDP-suspension (74.89 dynes/cm). Also, the viscosity measured at the ocular temperature (35 ◦C) ranged from 3.65 cP to 5.85 cP and 3.75 cP to 5.9 cP for cubosomes prepared with pol. 407 and solulan C24 respectively indicating a significant increase in viscosity when compared to the control (0.93 cP).
The bilayer formation was confirmed by the “Maltese crosses” textures under the polarized light microscope. Also, the TEM imaging showed a cubic shaped structures indicating the formation of cubosomes with particle size range agrees with the result obtained by Malvern Zetasizer. The in vitro release study showed a significant increase in the cumulative percentages of drug released from cubosomes formulations compared with that of the BDP-suspension. The mechanism of release of BDP from the cubosomes was Fickian diffusion-mediated release. Furthermore, the ex vivo permeation study using excised bovine corneas through the in-house modified Franz-diffusion cells, showed a significant increase in the apparent permeability coefficient (Papp ) compared to the control formula. Also, the stability study showed good stability of the prepared cubosomes formulations through the 3-month study.
In chapter 2, Cubosomal gel (Cubo-gel) formulations were prepared with different concentrations of hydroxypropyl methylcellulose (HPMC) and carboxymethylcellulose (CMC). The prepared formulations were characterized for pH, viscosity, and in vitro and ex vivo performance. The obtained results revealed that the prepared formulations were of satisfactory pH and the viscosity was found to be directly related to the type, concentrations of the used gelling agent, and the temperature at which it was measured. The in vitro release study showed that the increase in the viscosity of the prepared formulations with either the type or the concentration of the polymer used led to retarded drug release. The in vitro release kinetics showed that BDP was released from Cubo-gel formulations by diffusion and erosion mechanism (n-values range 0.63 to 0.82). The ex vivo permeation study showed a higher Papp and steady-state flux, of Cubo-gel formulations compared to the gel formulated from BDP-suspension.
In chapter 3, evaluation of the optimized cubosomes and Cubo-gel formulations was performed. This includes the study of ocular irritation through the bovine corneal opacity and permeability (BCOP) test. In addition to the in vivo study for the determination of the precorneal residence time of sodium fluorescein loaded formulations. In vivo assessment of ocular bioavailability through measuring the change in the intraocular pressure (IOP) and the anti-inflammatory effect of the selected optimized formulations on endotoxin-induced uveitis in the rabbit model.
Results revealed that all the tested formulations were non-irritant with cumulative BCOP score lower than 0.5 with supportive results obtained from the histopathological examination of corneal sections.
The precorneal residence time test revealed a significant enhancement in the precorneal residence time of cubosomes and Cubo-gels when compared to that of the control. Furthermore, the change in the measured IOP revealed that the BDP loaded cubosomes and Cubo-gel formulations showed enhanced ocular bioavailability compared with the control.
Also, the in vivo assessment of anti-inflammatory activity of cubosomes and Cubo-gel formulations showed a marked reduction in the aqueous humor level of leucocyte, PEG2, and NO in endotoxin-induced rabbit uveitis compared to the effect of the control (BDP-suspension). Supportive results were obtained from histopathological examination of the cross-sections taken from iris and retina of the normal, control, and treated groups after 24 h treatment.