الفهرس 
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Abstract
The Respiratory System, As Well As The Skin, Is Organs In Direct Contact With The Environment And They Represent Possible Doors For The Entrance Of Therapeutic Agents Into The Body. Because Of The Increasing Incidence Of Pulmonary Diseases With High Mortality And Morbidity, Pulmonary Drug Delivery Is Emerging As A Non-Invasive And Attractive Approach For The Treatment Of Several Pathologies. Pulmonary Drug Delivery Of Poorly Water Soluble Drugs Is An Accepted Route Of Drug Administration For The Management Of Lung Conditions And Diseases As Well As An Evolving Route Of Administration For The Systemic Delivery Of Agents.
Nanosizing Refers To The Reduction Of The Particle Size Of The Active Pharmaceutical Ingredient (Api) Down To The Sub-Micron Range. The Nanoparticles Are Stabilized With Polymers Or Surfactants In Nanosuspensions Which Can Be Further Processed Into Standard Dosage Forms, Such As Dry Powder Inhaler, Suitable For Lung Administration. These Nanoformulations Offer Increased Dissolution Rates For Drug Compounds With Poor Aqueous Solubility (Bcs Class Ii And Iv) And Consequently Enhance Their Bioavailability. This Thesis Investigates A General Method For Producing Micron Sized Dry Powders For A General Class Of Drugs, Poorly Water Soluble Small Molecule Drugs, (Bcs Class Ii) For Their Use In Pulmonary Drug Delivery. The Model Drug Used In This Study Was Voriconazole. Voriconazole (Bcs Class Ii) Was Used As A Model Drug To Study The Effect Of Nanoparticles Agglomerates On The Dissolution Rate Since The Rate Limiting Step Of Absorption For This Class Of Drugs Is The Dissolution Rate. The Objective Of This Study Was To Deliver The Second Generation Triazole (Voriconazole) To Lung Via Inhalation Rather Than By Injection Or Oral Route. In Addition To Improving Solubility Of Voriconazole And Enhancing Its Bioaviability. Nanoagglomerates Were The Platform For Dry Powder Administration Of The Drug For Treatment Of Serious Fungal Infections.
Accordingly, The Work In This Thesis Is Divided Into Two Main Parts:
Part (1) Preparation And characterization Of Voriconazole Nanoparticles
Different Nanoparticles Formulations Containing Two Types Of Edge Activators At Different Ratio Were Prepared Using Emulsification Evaporation Technique. Nanoparticles Were Formulated By Emulsification Of The Drug Using Edge Activators, Which Was Followed By Recovering Of The Particles By Precipitation In Antisolvent . The Prepared Nanoparticles Were characterized According To Their Size Distribution, Zeta Potential, Thermal Analysis Using Both Differential Scanning Calorimetry (Dsc), And X-Ray Diffraction (Xrd), Fourier Transform Infrared Spectroscopy (Ftir), In Vitro Release Profile, Cytotoxicity Studies And Cascade Impaction To Evaluate The Aerodynamic Properties Of The Nanoparticles. The Results Revealed That Nanoparticles Size Was (353 Nm), While Their Zeta Potential Was (- 30.7mv). Voriconazole Nanoparticles Showed Higher Cumulative Drug Release Than The Pure Powder, Which Were Significant At (P< 0.05). The Aerodynamic characterization Of The Nanoparticles Resulted In Significantly Smaller Mass Median Aerodynamic Diameter (Mmad) (P<0.05) And Higher Fine Particle Dose (Fpd) (P<0.01), Fine Particle Fraction (Fpf) (P<0.01) And Total Emitted Dose (Ted) (P<0.01) Than The Pure Powder.
Part (2) Preparation And characterization Of Voriconazole Nanoagglomerates
Controlled Agglomeration Of The Nanosuspenions Was Carried Out By Destabilization Of The Negative charge On The Surfaces Of The Particles. This Was Achieved When Ionic Interaction Of A Diluted Polyethyleneimine Solution Was Used To Neutralize The Strong Negative charges That Take Place On The Surface Of The Nanosuspension. The Prepared Nanoagglomerates Were characterized According To Their Size Distribution, Zeta Potential, Thermal Analysis Using Both Differential Scanning Calorimetry (Dsc), And X-Ray Diffraction (Xrd), Fourier Transform Infrared Spectroscopy (Ftir) In Vitro Release Profile, Cytotoxicity Studies And Cascade Impaction To Evaluate The Aerodynamic Properties Of The Nanoparticles. The Results Revealed That Nanoagglomerates Size Was (2.7 µm), While Their Zeta Potential Was - (20.9mv). Voriconazole Nanoagglomerates Showed Higher Cumulative Drug Release Than The Pure Powder, Which Were Significant At (P< 0.05). The Aerodynamic characterization Of The Nanoagglomerates Resulted In Significantly Smaller Mass Median Aerodynamic Diameter (Mmad) (P<0.05) And Higher Fine Particle Dose (Fpd) (P<0.01), Fine Particle Fraction (Fpf) (P<0.01) And Total Emitted Dose (Ted) (P<0.01) Than The Pure Powder. The Agglomerates Had A Higher Emitted Dose And A Higher Fpd.
The Results Indicated That Nanoparticle Agglomeration Is A Viable Means Of Creating Dry Powders With Suitable characteristics For Pulmonary Drug Delivery As An Alternative To More Expensive And Less Controllable Formulation Strategies. The Results Suggest That Using The Combination Of Edge Activators And The Diluted Osmogenic Polycationic Polymer Solution (Pei) Provides Porous Voriconazole Nanoagglomerates In A Respirable Range, Which Is Proved Successful In Enhancing Both The Deposition And The Dissolution Of Water Insoluble-Drugs In The Lung.