الفهرس 
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Abstract
Mucoadhesion And Mucoadhesive Drug Delivery Systems Are Topics Of Current Interest In Pharmaceutical Product Development. Mucoadhesive Drug Delivery Systems Are Delivery Systems That Utilize The Property Of Bioadhesion Of Certain Polymers. Mucoadhesive Buccal Drug Delivery Systems Offer Many Advantages Over Conventional Systems Such As Ease Of Administration, Rapid Termination Of Therapy And Administration To Unconscious Patients. Buccal Mucosa Provides Direct Entry Of Drug Molecules Into Systemic Circulation, Thus Avoiding Hepatic First Pass Effect.
Betahistine Dihydrochloride (BH.2hcl), An Anti-Vertigo Histamine Analogue Used In Treatment Of Ménière’s Disease, Undergoes Extensive First-Pass Metabolism And Suffers from Short Biological Half-Life.
The Aim Of The Present Work Was To Develop And Estimate Controlled Release Mucoadhesive Buccal Tablets Of BH.2hcl With A Unidirectional Drug Flow To Overcome This Encumbrance.
The Work In This Thesis Is Divided Into Three Chapters:
Chapter 1: Formulation And Evaluation Of BH.2hcl Buccal Mucoadhesive Tablets.
Chapter 2: Stability Study Of The selected BH.2hcl Buccal Mucoadhesive Formulation.
Chapter 3: Bioavailability Study Of The selected BH.2hcl Buccal Mucoadhesive Formulation.
Chapter 1
Formulation And Evaluation Of BH.2hcl Buccal Mucoadhesive Tablets
The Work In This Chapter Includes Formulation Of Twelve BH.2hcl Controlled Release Mucoadhesive Buccal Tablets With Unidirectional Drug Flow Formulations By Direct Compression Using Mucoadhesive Polymers Like Guar Gum, Hydroxypropyl Methyl Cellulose K4M, Sodium Carboxy Methyl Cellulose And Their Combinations. The Tablets Were Coated from All Surfaces Except One Surface With A Solution Of 5% (W/V) Cellulose Acetate And 1% (W/V) Dibutyl Phthalate To Give Unidirectional Drug Flow. Different Permeation Enhancers Like 2% Sodium Deoxycholate, 2% Sodium Cholate Hydrate (SCH) And 5% Menthol Were Tested.
The Flowability Of Formulations Powders Were Determined By Measuring Angle Of Repose, Carr’s Index And Hausner’s Ratio.
The Prepared BH.2hcl Mucoadhesive Buccal Tablets Were Evaluated For Weight Variation, Uniformity Of Tablet Thickness And Diameter, Content Uniformity, Friability, Hardness, Surface Ph, Swelling, Mucoadhesion Strength, Ex Vivo Residence Time, In Vivo Testing Of The Mucoadhesive Delivery Systems, In Vitro Release Study, Ex Vivo Permeation Study, DSC And FTIR Studies.
The Results Revealed The Following:
• All The Powders Of The Formulations Showed Angle Of Repose Θ In The Range 21.9° To 26.57°, Hausner Ratio Value Close To One And The Values Of Carr’s Index For All The Formulations Were < 21 Indicating A Good Degree Of Flowability.
• Weight Variation Test: All The Prepared BH.2hcl Mucoadhesive Buccal Tablets Showed Acceptable Weight Variation Range from 149.6 ± 0.98 Mg To 151.9 ± 0.36 Mg.
• Uniformity Of Tablet Thickness And Diameter: Thickness Of The Developed Formulations F1 To F12 Varied from 1.58 ± 0.06 Mm To 1.69 ± 0.11 Mm, While The Values Of The Tablet Diameter Were In The Range Of 10.03 ± 0.052 To 10.13 ± 0.021 Mm.
• Content Uniformity: The Mean Percentage Of BH.2hcl Content In Mucoadhesive Buccal Tablets from All Formulations Ranged from 98.0 ± 0.70% To 102.1 ± 0.65% Of The Initial Drug Content Added. The Percentage Deviation Did Not Exceed 2% Indicating Well-Mixed Products.
• Friability Test: All Tablets Formulated With The Different Excipients Showed Percentage Fines Within The Permissible Limit Of 1%.
• Hardness: All The Prepared BH.2hcl Mucoadhesive Buccal Tablets Showed Hardness Values Ranged from 3–4.36 Kg/Cm2 With SD < 2% For All The Prepared Tablets.
• Surface Ph: Surface Ph Of The Prepared Formulations Was Found To Be Close To Neutral Ph. It Was Reported That Neutral Ph Of The Formulations Does Not Cause Any Irritation To The Mucosa. Surface Ph Of All The Formulations F1 To F12 Ranged from 6.04 To 7.68.
• Swelling Study: Formulations Containing HPMC (F1-F3) Showed Lower Values Than Those Containing Guar Gum (F4-F6). Also, The Results Showed That Formulations Containing Polymers With Higher Concentration (F3 And F6) Had Lower Swelling Index. Moreover, Incorporation Of Na CMC Increased The Swelling Index Of The Prepared Formulations (F9-F12). The Highest Swelling Index Was Obtained In Formulation F12 Which Containing A Mixture Of 35% Guar Gum And 15% Na CMC.
• Mucoadhesion Strength And Ex Vivo Residence Time: Formulation F12 Showed The Highest Mucoadhesive Strength While F1 Showed Lowest Mucoadhesive Strength. The Results Of The Mucoadhesion characteristics Of The Prepared Formulations Showed That All Tablets Attached Well To The Buccal Membrane And Most Of The Prepared Formulations Have Good Mucoadhesive Performance.
• In Vivo Testing Of The Mucoadhesive Delivery Systems: The In Vivo Mucoadhesive Performance Test Was Carried Out In Three Healthy Volunteers Aged (20–35 Years). The Volunteers Were Claimed To Note: Adhesion Time, The Strength Of Adhesion, Irritation, Bitterness And Disintegration Of The Mucoadhesive Tablets. Formulations (F1-F3) Suffered from Certain Problems Like Slight Adhesive Strength, Moderate Irritation, Moderate Bitterness, Disintegration And Very Short Adhesion Time. Replacement Of HPMC K4M With Guar Gum In The Formulations (F4-F6) And Formulations (F10-F12) Resulted In Better Parameters (Adhesive, No Or Slight Irritation, No Bitterness And No Disintegration And Reasonable Adhesion Time Of More Than 8 H). On The Other Hand, Formulations (F7-F9) Showed Good Responses But Suffered from Short Adhesion Time Which Ranged from 4.5 To 7 H.
• In Vitro Release Study: For Formulations (F1-F3), It Is Clear That The Extent Of Drug Release Was 99.1, 98.7 And 96.9%, Respectively. On The Other Hand, The Extent Of Drug Release For Formulations (F4-F6) Was 100.5%, 99.9% And 81.4%, Respectively. Formulation F6 Complied With The Release Requirements For The Extended Release Products. The Release Of BH.2hcl from Formulations (F7-F9) Was Found To Be 99.1%, 96.8% And 81.7% After 8 H, Respectively. For The Formulations (F10-F12), The Extent Of The Drug Release Was 81.1%, 60.2% And 54.9%, Respectively.
• Ex Vivo Permeation Study: The Permeation Enhancers, 2% SDC, 2% SCH And 5% Menthol Have Been Incorporated Separately In The selected Formulation F10 Which Gave Optimum Adhesion Time And Adhesion Strength With Minimum Irritation To Volunteers. It Showed Zero-order Release Kinetic And Comply With The Dissolution Requirements For Controlled Release Dosage Forms. SCH (2%) Used In This Work Exerts A Significant Enhancement In The Permeation Of BH.2hcl.
• Characterization Of Drug And Excipients: The DSC Thermogram Of The Drug Showed One Main Prominent characteristic Endothermic Melting Peak At 149.47 °C. Based On DSC Results, All The Used Additives Were Found To Be Compatible With The Drug. FTIR Results Concluded That All The Excipients Under Test Showed No Signs Of Chemical Interaction With The Drug.
Chapter 2
Stability Study Of The selected BH.2hcl Buccal Mucoadhesive Formulation
Formulation F10 Which Containing A Combination Of 35% Guar Gum And 5% Na CMC Gave Optimum Adhesion Time, Adhesion Strength And Minimum Irritation To Volunteers. It Showed Zero-order Release Kinetics And Complied With The Release Requirements For Controlled Release Tablets. Addition Of 2% SCH Produced A Significant Enhancement In Permeation Of BH.2hcl Across Buccal Mucosa; So It Was selected To Perform Stability Study.
The Stored BH.2hcl Buccal Mucoadhesive Tablets At 40 And 60°C At 75% Relative Humidity In Ovens (Formulation F10 In Addition To SCH) Were Examined Visually For Any Changes In Colour And/Or Appearance Every Week. The Chemical Analysis Of The Stored BH.2hcl Formulation Was Carried Out For The Determination Of The Amount Of Drug Remained In The Tablets After 1, 2, 4, 6, 8 And 12 Weeks Using HPLC Stability Indicating Method.
Release Study And Determination Of Mucoadhesive Strength Were Performed On Tablets Obtained from The Stored Formulation At 40°C And 75% Relative Humidity After 4, 8 And 12 Weeks.
The Results Revealed The Following:
• The Buccal Mucoadhesive Formulation F10 Showed A Predictive Shelf Life Of 3.06 Years.
• The Release Of BH.2hcl from The Stored Tablets Did Not Change.
• There Was Insignificant Change In The Mucoadhesive Strength And Force Of The Stored Tablets.
Chapter 3
Bioavailability Study Of The selected BH.2hcl Buccal Mucoadhesive Formulation
The Study Was Carried Out To Compare The Pharmacokinetics Of BH.2hcl from The Optimized Buccal Tablet (F10 In Addition To SCH, Treatment A) To That Of The Commercially Available Oral Betaserc® 24 Mg Tablet (Solvay Pharmaceuticals) (Treatment B) Following Administration Of A Single Dose (24 Mg) Using Randomized Crossover Design.
In This Study, Six Healthy Male Volunteers (60–70 Kg, Age Between 20 And 30 Years) Were Involved In The Study where They Gave Informed Consent And Were Arbitrarily Divided Into Two Groups Of Equal Size. The Chosen Volunteers Were Non-Alcoholics And Non-Smokers.
Plasma Samples Were Analyzed For BH.2hcl Adopting A Modified Ultra-Performance Liquid chromatography/Tandem Mass Spectrometry (UPLC/MS/MS) Method.
The Results Revealed The Following:
• The Optimized Buccal Formulation And Betaserc® Tablets Showed Mean Peak Plasma Concentrations Of 106.31 And 151.95ng/Ml Obtained Within 6.2 And 2.5 H, Respectively.
• The Mean Areas Under The Plasma Concentration–Time Curves For The Optimized Buccal Formulation And Betaserc® Tablets Were Calculated To Be 1540.33 And 870.23 Ng H/Ml, Respectively.
• The Buccal Formulation Showed A T1/2 Of 6.78 H While Betaserc® Tablets Attained A T1/2 Of 3.1 H.
• The Optimized BH.2hcl Buccal Formulation Exhibited Percentage Relative Bioavailability Of 177% Compared To That Of The Commercially Available Betaserc® Tablets.
• The Developed BH.2hcl Unidirectional Mucoadhesive Buccal Formulation Might Be Beneficial In Supplying Constant Drug Delivery.