الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
Recently, delivery of pharmaceuticals through the airways proved to be a promising approach for treatment of local diseases, as well as systemic disorders. Both intranasal and pulmonary routes have many unique characteristics which qualify them to overcome many obstacles in drug delivery such as: large surface area, high blood supply and highly permeable membranes. By virtue of these distinct anatomical features, both routes offer rapid onset of action, improved bioavailability and better patient compliance achieved through dose reduction and thus minimal adverse effects. In addition, these routes are superior to other routes of drug delivery because of being non-invasive and avoidance of first pass metabolism.
However, each of these routes faces some obstacles that complicate drug delivery and cannot be overcome by conventional delivery systems. Major challenges that face the intranasal route are: limited volume of administration, enzymatic degradation and low residence time in the nasal cavity due to MCC. Drug delivery through the pulmonary route is challenging due to MCC, clearance by alveolar macrophages, in addition to enzymatic degradation.
In the current era, the application of nanotechnology in drug delivery has overcome many obstacles and various types of nano-sized delivery systems have been developed. Nanocarriers offer many advantages to nasal and pulmonary drug delivery including: high drug loading, increasing drug residence time and prevention of drug degradation. Moreover, the diversity of nanocarriers allows them to be tailored to obtain a certain release pattern. Nanocarriers include many classes such as: polymeric NPs, micelles, liposomes, SLNs, NLCs, NEs and others. In the last decades, NEs have received a great deal of attention in drug delivery due to its ease of preparation, high solvent capacity, excellent stability and enhancement of drug permeation through different biological membranes.
The present thesis aimed at development of NE formulations of TD suitable for treatment of ED and PAH. Patients administering TD for treatment of ED complain from a delayed onset of action. Thus, the objective was to develop an optimum NE formulation to be delivered through the intranasal route. Screening of different excipients was carried out to select the appropriate excipients followed by characterization of the selected formulations. The safety of the developed formulations on the nasal mucosa was evaluated through histopathological examination and biochemical analysis. Also, the biological efficacy was investigated through biochemical analysis of cGMP. In case of PAH, no liquid dosage form of TD has been developed for treatment of children. Thus the goal was to formulate a NE formulation of TD that can remain stable upon dilution with water to be delivered through nebulization to children. Screening of excipients for proper selection of ingredients and characterization of the
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selected formulations were carried out. The safety of the optimum formulations was evaluated in-vitro as well as in-vivo in animals.
CHAPTER ONE
INTRANASAL TADALAFIL NANOEMULSIONS FOR TREATMENT OF ERECTILE DYSFUNCTION.
This chapter dealt with preparation and characterization of NE formulations of TD to be administered through the intranasal route in order to achieve a rapid onset of action during treatment of ED. Preliminary screening of excipients was carried out for selection of the appropriate oily phase, surfactant and co-surfactant. Excipients were screened based on both solubility studies and emulsification efficiency. Construction of pseudo-ternary phase diagrams was carried out and an optimum system was designated. An o/w and a w/o NE formulations were selected according to the amount of surfactant and co-surfactant present in the formulation as well as drug loading. The optimum o/w formulation (F4) was composed of 10% Capmul MCM EP, 30% water and 60% Labrasol/Transcutol HP (1:1, w/w). On the other hand, the composition of the optimum w/o formulation (F6) was 50% Capmul MCM EP, 10% water and 40% Labrasol/Transcutol HP (1:1). The saturation solubility of TD in both formulation F4 and F6 were 9.74 and 9.95 mg/mL, respectively.
Isotropic nature of the optimized formulations was confirmed by cross-polarized light microscopy, refractive index and %T. The pH and viscosity of the formulations were measured to determine whether their values were appropriate for nasal application. Further characterization of the formulations was carried out in terms of globule size, PdI, zeta-potential, TEM and accelerated stability study. The safety of the formulations on nasal mucosa was verified ex-vivo on freshly excised nasal mucosa through histopathological examination as well as in-vivo in rats through biochemical analysis of TNF-α and caspase-3. The biological efficacy of the formulations was tested in-vivo through biochemical analysis of cGMP in rat penis after 2-hour intranasal administration of the formulations. Long-term stability study was carried out for 3 months to test the stability of the selected formulations at RT. Formulations were evaluated in terms of physical appearance, globule size, drug content and %T.