الفهرس 
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Abstract
Loratadine (LTD), A Tricyclic, Piperidine Derivative Of Antihistamines, Is A Non-Sedative Second Generation H1 Receptor. It Acts By Suppressing The Action Of Histamine Receptor In The Nose And Conjunctivae, Resulting In Disappearing Symptoms As Itching, Congestion, Rhinorrhea, Tearing, And Sneezing. It Is Rapidly Absorbed Following An Oral Administration, With Bioavailability Of Only 40% As It Undergoes First Pass Metabolism. It Has Poor Water Solubility And Low Permeability So It Classified As Class II Of The Biopharmaceutical Classification System (BCS). The Oral Bioavailability Of The Drug Was Found To Be Very Limited And Show High Degree Of Intra- And Inter-Subject Variability And Lack Of Dose Proportionality. Because It Is Weakly Ionizable Base And Its Solubility Is Ph Dependent; Decrease Exponentially With The Increase In Ph, Its Pharmacokinetic Parameters Show Variation Under Fed And Fasting Conditions.
A New Class Of Liposomes Termed Transferosomes Was First Described By Cevc And Has Been The Subject Of Numerous Patents And Literature Reports Since The 1990s. These Belong To The Category That Is Variously Termed As Deformable, Highly Deformable, Elastic Or Ultra-Flexible Liposomes Or Vesicles. Although It Is Generally Accepted That The Permeation Of Conventional Liposomes Is Limited To The Outer Layers Of The Stratum Corneum, Thus Providing A Drug- Or Cosmetic-Localizing Effect Within The Skin, Transferosomes Are Claimed To Permeate As Intact Vesicles Through The Skin Layers To The Systemic Circulation. Transferosomes Or Deformable Vesicles Are Reported To Improve In Vitro Skin Delivery Of A Range Of Drugs And In Vivo Penetration To Achieve Therapeutic Amounts That Are Comparable With Subcutaneous Injection. As With Liposomes, Transferosomes Are Composed Of Phospholipids Such As Phosphatidylcholine, But Also Contain Surfactants, Such As Sodium Cholate, Deoxycholate, Span 80 And Tween 80. The Surfactant Acts As An Edge Activator That Destabilizes The Lipid Bilayers And Increases The Deformability Of The Vesicle.
The Buccal Route Has Been A Very Attractive Route For Scientists, Probably Because Of Its Mucus Membrane High Permeation Which Is 5-8 Folds If It Is Compared To Skin. In Addition, Oral Trans Mucosal Route Provide An Alternative Route For Drugs That Undergoes Extensive First Pass Metabolism, And Degradation In The Gastrointestinal Tract By Gastric Fluids. Besides, It Gives A Faster Onset Of Action Resulting In Improved Bioavailability. Moreover, It Has High Patient’s Compliance Because Of It Is An Easy Way For Self-Medication And Suitable For Dosage Forms Administration And Removal
The Aim Of The Work In This Thesis Is To Verify The Following Hypothesis And Achieve The Following Specific Aims:
Hypothesis: Transferosomal Vesicles Enhance Rate And Extent Of Dissolution And Consequently In Vivo Absorption Of Poorly Soluble Drugs.
Specific Aims: To Evaluate Potential Of Buccal Carbopol Hydro Gel Uploaded With Loratadine Transferosomal Vesicles To Enhance Rate And Extent Of Loratadine Absorption And Decrease Inter-Variability Among Patients.
Accordingly, The Work In This Thesis Is Divided Into Three Main Chapters:
Chapter 1: Optimization, Preparation And characterization Of Loratadine Buccal Carbopol Hydrogel.
Chapter 2: Formulation, Statistical Optimization, In Vitro characterization Of Transferosomal Loratadine
Cahpter 3: Bioequivalence Study Of The Carbopol Hydrogel Containing Optimized Loratadine Transferosomes And Claritin® Tablets
Chapter 1: Optimization, Preparation And characterization Of Loratadine Buccal Carbopol Hydrogel.
The Aim Of The Work In This Chapter Was To Prepare An Optimize Loratadine Buccal Carbopol Hydrogel With Highest Release, Muccoadhesion And Drug Content Through Using 23 Full Factorial Design To Investigate Potential Effects Of Carbopol 934 Concentration, Enhancer Type And Addition Of Poloxamer 188.
Eight Formulations Were Studied And It Was Found That F2 Was The Optimum Dosage Form With Highest Release 44%, Muccoadhesion Strength 28 Mg And Drug Content 99%, Containing 1% Of Carbopol, 2% Isopropyl Myristate And 2 %Poloxamer 188.
Further Physical characterization Of The Optimimal Formulation Indicated That It Was Elegant And Opaque With No Limps Nor Air Bublbles And Loratadine Was Homogenously Distributed Through Out The Buccal Gel (97%- 101%) In Addition Of Having Ph 6.8 Resembling The Ph Of The Buccal Mucosa ,Viscosity Of 10.356 Cp ± 50 And Loratadine Release from Buccal Gel Was Found To Follow Diffusion-Controlled Mechanism.
Chapter 2: Formulation, Statistical Optimization, In Vitro characterization Of Transferosomal Loratadine
Transfersomes Bearing LTD Were Prepared By Conventional Thin Film Hydration Method And Optimized Using Sequential Quality-By-Design Approach That Involved Placket-Burman Design For Screening Followed By Constrained Simplex Centroid Design For Optimization Of A Tween 80/Span 60/Span 80 Mixture. The Transferosomes Were characterized For Entrapment Efficiency, Particle Size, And Shape. Optimized Transferosomes Were Incorporated In Optimized Buccal Carbopol Hydrogel Gel Obtained from The Previous Chapter. The Gel Was characterized For Rheology, Ex Vivo Permeation Across Chicken Pouch Buccal Mucosa, In Vitro Release, And Mucoadhesion.Optimal Transferosomes characterized By Submicron Size (380 Nm), Spherical Shape And Adequate Loading Capacity (60%) Were Obtained By Using Quasi-Equal Ratio Surfactant Mixture. In Terms Of Amount Permeated, Percentage Released, And Mucoadhesion Time, The Transferosomal Gel Proved Superior To Control, Transferosome-Free Gel.
Cahpter 3: Bioequivalence Study Of The Carbopol Hydrogel Containing Optimized Loratadine Transferosomes And Claritin® Tablets
In This Part, The Buccal Carbopol Hydrogel Containing Optimized Loratadine Transferosomes (Equivalent To 10 Mg Loratadine) Was Subjected To Further In-Vivo Investigations And Compared To The Commercially Available Claritin® 10 Mg Oral Tablets. A Cross Over Design Was Carried Out Using Three Healthy Human Volunteers. Plasma Samples Were Analyzed Using A Sensitive, Reproducible And Accurate LC-MS/MS Method, Developed And Validated Before The Study In Accordance With The International Guidelines. In Addition, In Vitro-In Vivo Correlation Was Also Investigated.
Bioavailability Of The Transferosomal Gel Was Comparable To Claritin® Oral Tablets. However, Inter-Individual Variability In Cmax And AUC Was Reduced By 76 And 90%, Respectively, When The Buccal Gel Was Used. Linear Correlation Of In Vitro Release With In Vivo Buccal Absorption Fractions Was Established With Excellent Correlation Coefficient (R2 > 0.97).
Conclusion:
In Summary, A Buccal Carbopol Hydrogel Was Successfully Developed For LTD, The Concentration Of Carbopol And The Presence Of Poloxamer Were The Most Critical Variables Affecting Muccoadhesion And % Of Drug Released. Also, A Transferosomal Gel Formulation For Buccal Administration Was Successfully Developed For LTD. The Composition Of Hydrophilic-Hydrophobic Surfactant Mixture Plays A Decisive Role In Controlling Transferosome Particle Size And Entrapment Efficiency. Optimal Transferosomes characterized By Submicron Size (380 Nm), Spherical Shape And Adequate Loading Capacity (60%) Were Obtained By Using Quasi-Equal Ratio Surfactant Mixture. In Terms Of Amount Permeated, Percentage Released, And Mucoadhesion Time, The Transferosomal Gel Proved Superior To Control, Transferosome-Free Gel. Bioavailability Of The Transferosomal Gel Was Comparable To Claritin® Oral Tablets. However, Interindividual Variability In Absorption Parameters Was Considerably Reduced When The Buccal Gel Was Used. It Is Concluded That Transferosomal Buccal Gel Is Adequate Delivery System For LTD With Potential Clinical Utility.