الفهرس 
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Abstract
Atopic Dermatitis (AD) Is A Common, chronic, Recurrent And Pruritic Dermatological Condition With A Variety Of Functional Abnormalities. It Is characterized By Dry Skin And Has A Decreased Ceramide Level.
Nicotinamide Or Vitamin B3, That Is Also Called Niacinamide, Is An Amide Form Of Vitamin B3, Another Vitamin B3 Form Is Nicotinic Acid (Niacin) Which Is Converted To Nicotinamide In The Body. Vitamin B3 Is An Essential Water Soluble Vitamin That Is Not Stored In The Body. Therefore, It Is Important To Regularly Take Vitamin B3 And Tryptophan.
The Importance Of Topical Nicotinamide For The Skin Appearance Improvement May Be Linked To Its Action In The Synthesis Of Lipids As Sphingolipid, Free Fatty Acid, Cholesterol, And Ceramide In Addition To Barrier Layer Proteins As Keratin, Involucrin And Filaggrin, Thus, Reducing Transepidermal Water Loss. Thus It Is One Of The Promising Agents For Reducing The Symptoms Of Atopic Dermatitis.
Due To Short Retention Of Nicotinamide In The Skin Which Was Reported To Be Only 20 Min. The Aim Of This Work Is To Increase The Retention Of Nicotinamide Inside The Skin For The Treatment Of Different Skin Conditions. This Goal Would Be Achieved Using Lipid Vesicles Approach With Surface charge Modification.
The Work In This Thesis Is Divided Into Three Chapters:
Chapter 1: Preparation And Optimization Of Ethosomal Formulations Of Nicotinamide
Chapter 2: Formulation And characterization Of Topical Nicotinamide Thermosensitive Gels.
Chapter3: In-Vivo Evaluation Of Anti-Eczematic Effect Of Nicotinamide Thermosensitive Topical Gels In Animal Models.
Chapter 1: Preparation And Optimization Of Ethosomal Formulations Of Nicotinamide
The Aim Of This Chapter Was To Formulate Ethosomal Formulations Of Nicotinamide For Increasing The Retention Capacity Of Nicotinamide Into The Skin. Box-Benkhen Statistical Design (Using Design Expert Software) Was Applied And Three Factors Were Assigned At Three Levels; Percentage Of Phophatidyl Choline (X1, 2-3%), Percentage Of Propylene Glycol (X2, 0-5%) And Percentage Of Alcohol (X3, 30-55%). Seventeen Formulations Were Generated from The Design With 5 Center Point Formulations. Ethosomes Were Formulated By Cold Method. Formed Ethosomes Were characterized For Their Percent Entrapment Efficiency (%EE), Vesicle Size (Nm) And Percent Drug Released (%DR). from The Proposed Responses, Relationship Equations Were Generated. from Linear Regression, It Was Noted That Increasing Phospholipid Concentration Lead To A Decrease In Vesicles Size Which Came In Contrary To The Previous Findings, While Increasing Ethanol Concentration Lead To A Decrease In Vesicles Size, This Situation Is Observed Parallel To The Increase Of PG. Increasing Phosphatidyl Choline Concentration Lead To A Decrease In %Drug Release While Increasing Ethanol And Propylene Glycol Concentrations Individually Lead To Increased %DR But Their Combined Effects Showed A Negative Effect On NIC Release from Vesicles. Regarding% EE, Increasing Phosphatidyl Choline Percentage Lead To Increased Vesicle Rigidity While Increasing Ethanol And Propylene Glycol Concertations Simultaneously Lead To A Decrease In EE% Due To Increasing Fluidity And Leakage Of Vesicles. Nine Formulations Were Generated from The Design For Validation. Plotting Values Of Expected %DR Against Observed Values Resulted In A Correlation Coefficient Of 0.9567 Which Validated The Design Outputs. Also, Plotting The Data For %DR Against Cumulative Amount Of Nicotinamide Permeated Lead To A Correlation Coefficient Of 0.8315, Indicating That Increasing %DR Lead To An Increase In The Permeated Fraction Of Drug. Three Optimum Formulations Were Generated from The Designs And Evaluated For The Effect Of Positive charge Inducer (Stearyl Amine). It Was Noted That Increasing The Amount Of Stearyl Amine In The Ethosome Formulations Lead To An Increase In Vesicle Size And A Decrease In %DR. In Terms Of Permeation, It Was Noted That There Was A Reverse Proportion Between Increasing Stearyl Amine Concentration And The Amount Of NIC Released from The Vesicles And Hence Increasing Its Retention. These Findings Were Fortified By LCSM Images Which Indicated The Retention Of Vesicles Inside The Skin. Formulations NIC 6 And NIC 9 Were Chosen For Incorpting Into Topical Thermosenstive Gels As They Achieved The Highest Drug Amount Retained In Skin (1.389±0.68 And 1.469±0.48 Mg) Respectively.
Chapter 2: Formulation And characterization Of Nicotinamide Thermosensitive Topical Gels
The Aim Of This Chapter Was To Formulate And characterize Thermosensitive Topical Gels Containing Optimized Ethosomal Formulations. Achieving Thermosensitivy Was Done By Incorporating Poloxamer 407 As Geling Agent Plus Adding Polyox®WSR301 Polymer As An Adhesive Agent. Poloxamer 407 Was Assigned At A Concentration Of 18% While Polyox® Was Incorporated At Three Levels Of 0.25, 0.5 And 1%. Nine Gel Formulations Were Prepared By The Cold Method, Three Of Them Contained Ethosomal Free Nicotinamide While The Other Six Formulations Were Prepared Form Ethosomal Formulations NIC6 And NIC9. characterization Of The Formulated Gels Included Viscosity, Gelation Temperature, Release And Permeation Experiments. It Was Found That Increasing Temperature from 5 To 32o C Resulted In A Significant Increase In Viscosity In All Gel Formulations. While Increasing Polyox® Concentration Lead To Decreased Release And Permeation Parameters In All Gel Formulations Due To Increased Viscosity. In Addition, Increasing Polyox® Concentration Lead To A Decrease In Retained Nicotinamide Fraction In The Skin. Formulations G4 And G7 Were selected To Be Evaluated For Their Anti-Eczematic Effect In-Vivo Using Atopic Eczema Animal Model In The Next Chapter.
Chapter 3: In-Vivo Evaluation Of Anti-Ezematic Effect Of Nicotinamide Thermosensitive Topical Gels In Animal Models
The Aim Of The Third Chapter Was To Study The Effect Of The Topically Applied Optimized Ethosomal Gel Formulations Of Nicotinamide On Tri-Nitrochlorobenzene (TNCB) Atopic Dermatitis Animal Model. The Study Was Carried Out On 30 Adult Male Albino Rats. The Rats Were Assigned To Six Groups; +Control, -Control, Placebo, Free Drug Gel, Ethosomal Drug Gel Formulations G4 And G7. Each group Was Sensitized By An Epicutaneal Application Of 300µl Of 7% TNCB Dissolved In Acetone/Olive Oil 4:1 To Shaved Abdominal Skin 7days Before The First Elicitation. from Day 0, 300µl Of 1% TNCB Solution Was Then Applied To Their Shaved Back Skin For Up To 18days At 1-Day Intervals. Afterwards, The Histopathological Study Conducted On Rat’s Skin And Blood Samples Were Collected from Each group And Analyzed For Ige Levels
During The Study Period , No Signs Of Inflammation Or Dry Skin Were Observed In Both Groups Received Positively charged Ethosomal NIC Gels (G4 And G7)When Compared With Control, Placebo, And Free Drug Gel. Regarding Ige Concentration, Gel Formula (G7) Achieved A Significant Reduction In Ige Titer (12.05 ± 2.85 Ng/Ml) Compared To Other Formulations (P<0.05).from The Results Shown In This Chapter, We Concluded That Incorporating NIC Into Ethosomal Gel Formulations Resulted In Elevated Levels Of NIC In The Skin And Hence, Improved Efficiency In Ameliorating Atopic Dermatitis Symptoms In Animal Models. Future Studies Will Open The Door To A New Marketed Product For Treatment Of Atopic Dermatitis And Other Inflammatory Skin Conditions.