الفهرس 
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Abstract
Itopride Hcl Is A Novel Prokinetic Agent; It Has Anticholinesterase Activity As Well As Dopamine D2 Receptor Antagonist. Itopride Hcl Is The Drug Of The Choice In Treatment Of Non Ulcer Dyspepsia (NUD), Gastro-Esophageal Reflux Disease (GERD), Gastritis, Diabetic Gastroparesis And Functional Dyspepsia.
Sustained Release Describes The Delivery Of Drug from The Dosage Forms Over An Extended Period. It Also Implies Delayed Therapeutic Action And Sustained Duration Of Therapeutic Effect. Variability In Gastrointestinal Transit Time Is A Concern For Oral Controlled Drug Delivery Systems. Drugs With A Narrow Absorption Window In The GI Tract Are Particularly Susceptible To Variation In Both Bioavailability And Time To Achieve Peak Plasma Levels. If Successful, Gastroretentive Controlled Release Formulations Could Offer A Potential Solution To The Problem By Offering A Prolonged Gastric Residence Time.
Thus, The Work In This Thesis Is Divided Into Five Chapters:
Chapter I
Compatibility Studies Between Itopride Hydrochloride And Commonly Used Additives For Sustained-Release Dosage Forms
In This Chapter DSC And FT-IR Techniques Were Used To Study The Compatibility Of Itopride Hcl With Certain Formulation Excipients Namely; Hydroxypropyl Methylcellulose (HPMC 15000), Sodium Carboxymethylcellulose (Nacmc), Ethylcellulose (EC), Eudragit RSPM, Avicel PH101, Magnesium Stearate And Carbopol 934p.
In This Work Samples Of The Drug Alone, Excipient Alone As Well As Their Corresponding Physical Mixtures (1:1 W/W) Were Prepared By Mixing.The DSC Thermograms Of The Samples Were Obtained With Thermal Analyzer.
The Work In This Chapter Is Presented Under The Following Headings:
1- Differential Scanning Calorimetry (DSC)
The Tested Samples Were Sealed In Flat– Bottomed Aluminum Pans .The Pans Were Heated Over The Temperature Range Of 0 – 300oc. The DSC Thermograms Of The Products Were Obtained With Thermal Analyzer Equipped With Advanced Computer Software Programs At A Scanning Rate Of 20 Oc Min-1.
The Combination Of Itopride Hcl With Each Of The Investigated Excipients Still Shows The characteristic Features Of The Drug And The Used Excipients, Indicating Compatibility Between The Drug And These Excipients. As Expected, Some Changes In Peak Height To Width Ratio Can Be Seen Because Of Possible Differences In The Sample Mixture Geometry And The Dilution Factor.
2-Fourier Transform Infrared Spectroscopy (FTIR)
The FT-IR Spectra Of The Physical Mixture Of Itopride Hcl With The Studied Excipients. There Is Superposition Of The characteristic Bands Of The Drug And The Studied Excipient. It Is Clear That The Same characteristic Bands Of The Drug Are Appeared With Slight Reduction In Intensity That May Be Attributed To The Dilution Effect Of The Excipients In The Studied Physical Mixtures. In Addition, The FT-IR Absorption Spectra Of These Physical Mixtures Show The Same characteristic Bands Of Itopride Hcl Without Frequency Shift, Which Indicate That No Chemical Interaction Between The Drug And The Used Excipients Could Be Detected.
Chapter II
Formulation And Evaluation Of Itopride HCL Sustained Release Floating Tablets.
In This Chapter Floating Tablets Of ITO HCL Were Prepared Using Certain Hydrophilic Polymers In order To Sustain Release Of This Highly Water Soluble Drug And Sodium Bicarbonate As Gas Forming Agent. The Polymers Used Were A Mixture Of HPMC 15000, Ethylcellulose Or Eudragit Rspm In A Ratio Of 1:1.
The Work In This Chapter Is Presented Under The Following Headings:
1- Formulation Of ITO HCL Floating Tablets:
Twenty One Formulae Were Prepared. The Powder Blend Was Then Compressed Into Tablets Using Single Punch Tablet Machine. The Machine Was Adjusted To Produce Tablets Weighing, Approximately, 350 Mg.
2- Quality Control Tests Of The Tablets:
The Prepared Tablets Were Evaluated By The Following Tests:
(A) Tablet Thickness: The Values Of Tablet Thickness Were In The Range Of 3.4 To 3.6 Mm.
(B) Uniformity Of Weight Variation: All The Prepared Itopride Hydrochloride Floating Tablets Showed Acceptable Weight Variation Range from 350 To 352 Mg.
(C) Content Uniformity: The Drug Concentration Was Not Less Than 96.00% And Did Not Exceed 102.01% Of The Labeled Potency With Standard Deviation Less Than 1%.
(D) Friability: All The Prepared Tablets Showed A Percentage Fine Ranging Around The Acceptable Limit And Did Not Exceed The Permissible Limit Of 1.0%.
(E) Hardness: The Hardness Values Ranged from 4.5 To 8.7 Kg With Standard Deviation Less Than 1%.
3- Determination Of Floating Lag Time And Floating Duration Of The Prepared Tablets:
All The Prepared Tablets Showed Floating Lag Time Of Less Than 0.5 Minute, Good Matrix Integrity And Floating Duration Of More Than 20 Hours.
4- Release Rate Studies:
The Release Of ITO HCL from The Prepared Formulations Was Performed According To The USP XXIV Apparatus 2 (Paddle Method). Studies Were Carried Out At 37± 0.5ºc In 500 Ml Of 0.1 N Hcl For A Period Of 24 Hours. Rotation Speed Was 50 R.P.M.
Results Showed That, ITO HCL Floating Tablets Prepared Using Different Hydrophilic Polymers Sustained Release Of The Water Soluble Drug Over An Extended Period Of Time.
Among The Tested Tablets, It Is Clear That Formula F20 And F21 Complied With The Release Requirements For Sustained-Release Products.
5- Kinetic Analysis Of The Release Data:
The Release Data Were Subjected To Kinetic Analysis Using Linear Regression According To Zero–Order, First–Order, Korsmeyer – Peppas Equation, Hixson–Crowell Model As Well As Higuchi Diffusion Model To Determine The Mechanism Of The Drug Release. It Is Obvious That In All Formulae, The Drug Release Was Found To Follow Higuchi Diffusion Model.
Chapter III
Formulation And Evaluation Of Itopride HCL Sustained Release Mucoadhesive Tablets.
Mucoadhesive Tablets Use A Bioadhesive And Matrix Forming Polymers. The Formulation Method Includes A Simple Approach Of Thoroughly Mixing The Drug And The Polymer. After Oral Administration This Dosage Form Adhere In Contact With Gastric Fluids.
So The Aim Of Work In This Chapter Is To Formulate ITO HCL In The Form Of Sustained Release Mucoadhesive Tablets
The Work In This Chapter Includes:
1-Preparation Of Mucoadhesive Tablets
Tablets Of Fourty Five Formulae Were Prepared By Mixing Of The Drug With The Calculated Amount Of The Polymers. The Hydrophilic Polymers Used Are HPMC 15000, Sodium Alginate And Eudragit Rspm.
2- Physical characteristics Of The Prepared Tablets:
The Prepared Tablets Were Physically characterized By Measuring The Official Parameters Including:
(A) Tablet Thickness: The Values Of Tablet Thickness Were In The Range Of 3.4 To 3.6 Mm.
(B) Uniformity Of Weight Variation: All The Prepared Itopride Hydrochloride Floating Tablets Showed Acceptable Weight Variation Range from 347 To 351 Mg.
(C) Content Uniformity: The Drug Concentration Was Not Less Than 95.00% And Did Not Exceed 101.00% Of The Labeled Potency With Standard Deviation Less Than 1%.
(D) Friability: All The Prepared Tablets Showed A Percentage Fine Ranging Around The Acceptable Limit And Did Not Exceed The Permissible Limit Of 1.0%.
(E) Hardness: The Hardness Values Ranged from 4.5 To 8.8 Kg With Standard Deviation Less Than 1%.
3-Measurement Of Mucoadhesive Strength And Force Of Adhesion
The Mucoadhesive Forces Of The Tablets Were Determined By Means Of Mucoadhesive Measuring Device.
4- Release Rate Studies:
Dissolution Of The Prepared Tablets Was Performed According To The USP XX IV Apparatus 2 (Paddle Method). Studies Were Carried Out At 37 ± 0.5ºc In 500 Ml Of 0.1 N Hcl For A Period Of 24 Hrs. The Paddles Were Made To Rotate At 50 R.P.M.
The Drug Release from Tablet Formulae F25 And F36 Was Complete After 24 Hours, where 100 % Of The Drug Was Released. The Other Formulae Were Successful In Retarding The Drug Release Over 12 Hours Period. The Dissolution Profiles Of Formula F25 Was In Agreement With The Specified Dissolution Requirements. It Is Evident That, As The Bioadhesive Force Of The Polymer Increases The Release Rate And Extent Decreases Significantly.
5- Kinetic Analysis Of The Release Data:
The Kinetic Analysis Of The Dissolution Data Of ITO HCL from Its Prepared Mucoadhesive Tablets Showed That, The Release Data For All Formulae Was Found To Follow Diffusion Model. This Is Probably Due To A Higher Concentration Gradient Through The Gel Layer.
Chapter IV
Stability Studies Of Some selected Itopride Hydrochloride Sustained Release Tablets
Some Floating Tablet Formulae Were selected On The Basis Of The Previous Release Studies. The selected Formulae Were:
from Floating Tablet Formulae:
● Formula F20 : Contained Itopride Hcl 150 Mg And EC: Eudragit Rspm 1:2.
● Formula F21: Containing Itopride Hcl 150 Mg And EC: Eudragit Rspm 2:1.
from Mucoadhesive Tablet Formulae:
● Formula F25: Containing Itopride Hcl 150 Mg And Na Alginate: Eudragit Rspm 1:2.
• Formula F36: Containing Itopride Hcl 150 Mg And Na CMC: Eudragit Rspm 2:1 Prepared Using Direct Compression Technique.
The selected Formulae Were Subjected To The Following Tests:
1- Stability Testing:
The Accelerated Stability Testing Was Carried Out As Follow: The Tablets Of Each Formula Were Placed In Dark Closed Glass Container And Were Stored In Thermostatically Controlled Ovens Adjusted At Different Temperatures, Namely, 30°C, 40°C And 50°C ± 0.5 With Relative Humidity 75% (Maintained Using A Saturated Solution Of Nacl) For A Period Of 6 Months.
The Stored Tablets Were Examined Visually For Any Changes In Colour And/Or Appearance Every Month. The Chemical Analysis Of The Stored ITO HCL Formulae Was Carried Out For The Determination Of The Amount Of Drug Remained In Each Formula After 0.5,1, 2, 3, 4, 5 And 6 Months Using HPLC Stability Indicating Method.
Visual Inspection
None Of The Stored Formulae At Different Temperatures Showed Any Changes In Colour Or Appearance Throughout The Storage Period.
from The chromatogram Of The Drug, The Drug Showed Sharp And Symmetrical Peak With Good Baseline Resolution And Minimum Tailing. An Excellent Correlation Existed Between The Peak Areas And The Concentrations. The Plot Was Highly Linear And The Coefficient Of Determination R2 Value Was 0.9997.
Accuracy And Precision:
The Method Was Accurate And Precise With R.S.D % Value Of Less Than 1%.
Quantitation:
The Percent Remaining Of ITO HCL In The Stored Formulae At 30°C, 40°C And 50°C With Relative Humidity 75% For A Period Of 6 Months Were Calculated. The Data Obtained from HPLC Analysis Were Subjected To Regression Analysis According To Korsmeyer – Peppas Equation, Hixson–Crowell Model, Zero- And First-Order; The Decomposition Of The Drug Follows Higuchi Kinetics.
2- Effect Of Storage At High Temperature And Humidity On The Drug Release:
Aiming To Study The Effect Of Storage At High Temperature And Humidity On The Release Of Itopride Hydrochloride from The selected Formulae, Release Study Has Been Conducted On The Samples Taken from The Stored Formulae At 40°C And 75% Relative Humidity As Described Before. It Is Clear That There Is No Significance Difference In The Rate And Extent Of The Drug Release.
Chapter V
Bioavailability Study Of Itopride Hydrochloride from Some selected Sustained Release Formulations.
In This Chapter, The Pharmacokinetic Parameters Of ITO HCL from The selected Floating Tablet Formula F20 And F21 And Mucoadhesive Formula F25 And F36 Tablets Were Studied In Animals. Also, The Relative Bioavailability Of ITO HCL from The selected Formulae Was Compared To The Commercially Available Ganaton® Tablets.
The Results Of This Study Can Be Given Under The Following Headings:
1- Re-Validation Of The Analytical Method:
The Parameters Essential To Ensure The Acceptability Of The Performance Of An Analytical Method Are Stability Of The Drug In The Matrix Under The Storage Conditions Of The Study, Accuracy, Precision, Sensitivity, Specificity And Reproducibility.
The Developed HPLC Method Was Revalidated To Determine ITO HCL In Plasma.
Calibration Curve:
The Calibration Standards Were Prepared By Adding A Definite Volume Of The Working Standard
The Prepared Itopride Hcl Stock Solution (100µl/Ml) Was Appropriately Diluted With Water To Obtain Working Solutions For Calibration At 200, 400, 1600, 4000, 8000, 16,000, 32,000 And 40,000 Ng/Ml. A 0.5 Ml Of Plasma Sample Was Placed In A 1.5 Ml Centrifuge Tube, 20 µl Of Serial Itopride Hydrochloride Stock Solution, 15µl Of The Prepared Internal Standard Solution And 450µl Of 10% Perchlorate Solution Were Added And Vortexed For 30 Seconds. The Calibration Curve For Itopride Hcl Was Plotted As Peak Height Ratio Versus Concentration (µg/Ml).
Chromatographic Conditions
The Mobile Phase Consisted Of 0.1mol/L Ammonium Acetate: Methanol (30:70, V/V) At A Flow Rate Of 1.1 Ml/Min. Before Analysis, The Mobile Phase Was Filtered And Then Degassed Ultrasonically For 15 Min. Itopride Hcl And Internal Standard Were Detected At An Excitation Wave Length Of 291 Nm And Emission Wave Length Of 343 Nm.
Accuracy And Precision
The Accuracy And Precision Of The Assay Method Was Evaluated. The Method Was Accurate And Precise With R.S.D% Less Than 1.5%.
2- Bioavailability Study:
Protocol
The Study Was Conducted As Single Doses Cross Over Design, With 7-Days Washout Period.
Drug Administration
The Study Was Carried Out Using Six Groups Of Newzeland Rabbits (2.5 Kg) Each group Consists Of 3 Rabbits. group I (Control Group) Was Starved And Only Water Was Allowed. group II Was Administered Floating Tablet Formula F20. group III Was Administered Floating Tablet Formula F21. group IV Was Administered Mucoadhesive Tablet Formula F25. group V Was Administered Mucoadhesive Tablet Formula F36. group VI Was Administered Commercial Tablets (Ganaton ®).The Rabbit Groups II, III, IV, V And VI Were Starved Overnight Before Drug Administration And Continued Fasting Until 4 Hrs Post Dose, With Free Access To Water. Each group Was Given A Drug Dose Of 15 Mg /Kg from Each Of The Tested Preparations; F20 , F21, F25, F36 And Ganaton ®.
HPLC Determination Of ITO HCL In Plasma Samples.
Sample Of 0.5 Ml Of Blood Plasma Was Treated Then Injected To The HPLC Column.
Pharmacokinetic Analysis Of The Data
The Individual Pharmacokinetic Parameters Of ITO HCL Were Calculated By Non-Compartmental Analysis. The Following Parameters Were Derived: The Peak Plasma Concentration (Cmax), The Time To Reach The Maximum Plasma Concentration (Tmax) Both Were Observed Values. The AUC (0-48) And AUC (0-∞) Also Were Calculated By The Linear Trapezoidal Rule, And Extrapolation To Infinity, Respectively. Also, The Overall Elimination Rate Constant (Ke) Was Calculated from The Slope Of The Terminal Elimination Phase Of A Semi-Logarithmic Plot Of Concentration Versus Time, After Subjecting It To Linear Regression Analysis. The Elimination Half Life (T1/2) Was Obtained.
Non-Significant Variation In Half-Life Of The Drug Elimination T1/2 El Values Was Obtained Since It Was 6.485 Hours For The Commercial Ganaton® Tablets While 7.014, 6.823, 6.672 And 7.063 Hours Were The Drug Elimination T1/2 El Values For The Sustained Release Itopride Hcl Floating Tablet Formula (F20, F21) And Itopride Hcl Mucoadhesive Tablet Formula (F25, F36), Respectively. This Indicates That The Sustained Release Formulations Have Extended The Release Of Itopride Hcl Significantly Compared To The Commercial Tablets.
The Peak Plasma Concentration (Cmax) Of Ganaton® Was 7.299 µg /Ml And This Value Was Considerably High. The Sustained Release Formulation Had Cmax Of 5.310, 5.490, 5.985 And 5.724 µg /Ml For The Prepared Sustained Release Itopride Hcl Floating Tablet Formula (F20, F21) And Itopride Hcl Mucoadhesive Tablet Formulae (F25, F36) .This Indicates The Rapid Release Of The Drug from Ganaton® Tablets Compared To The Sustained Release Preparations.
AUC0-24 Hr Of Ganaton® Was Found To Be 47.052 µg.Hr/Ml, Which Attributed To Rapid Absorption And Rapid Elimination from The Body. While On Administration Of The Sustained Release Formulation (F20, F21) And Itopride Hcl Mucoadhesive Tablet Formulae (F25, F36) The AUC0-24 Hr Was Found To Be 89.356, 99.220, 112.369, 113.549, Respectively And Relative Bioavailability FR % In Comparison To Ganaton® Was Found To Be 189.91, 210.87, 241.32 And 238.81 % Indicating The Enhanced Bioavailability Of The Prepared Formulations.
from The ANOVA Results, It Could Be Concluded That There Was A Significant Difference Between The Values Of AUC0-48 And AUC0-∞ Of Formulae (F20, F21) And (F25, F36) When Compared To Ganaton® Tablets. Also, There Was A Significant Difference Between The Values Of T1/2 Of Formulae (F20, F21) And (F25, F36) When Compared To Ganaton® Tablets
Relative Bioavailability
The Percent Relative Bioavailability Of ITO HCL from Floating Formulae (F20, F21) In Comparison To Reference Formulation (Ganaton®) Was Calculated As Follows:
Cmax Of Floating Formulae (F20, F21)
% Relative Bioavailability = ------------------------------------------- X 100
Cmax Of Commercial Tablets
The Results Showed That, The Mean Percent Relative Bioavailability Of The Formula F20 Was 189.91% With Respect To Cmax, Concerning The Formula F21 The Mean Percent Relative Bioavailability Was 210.87% With Respect To Cmax.