الفهرس 
Pharmaceutical Study on Oral Disintegrating Tablet for a Model Drug
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Abstract
Patients presenting with epigastric pain and burning, early satiation, and postprandial fullness without any structural, organic, or systematic pathology are labeled as having functional dyspepsia (FD) which is a common problem whole around the world and often impacts the quality of life and work productivity.
Functional dyspepsia could easily be overlooked as the symptoms overlap with gastro-oesophageal reflux disease and irritable bowel syndrome. The regurgitation of stomach contents and acid into the esophagus caused by the spontaneous and repetitive opening of the lower esophageal sphincter or its improper closure is known as gastro-oesophageal reflux (GERD) which is a chronic case that also impacts on quality of life and work productivity.
Prokinetic drugs enhance gastric emptying, prevent reflux of gastric content, and relieve the symptoms of FD and GERD. Prokinetic drugs are commonly used for treatment of various GIT diseases like Gastro Esophageal Reflux Disease, Functional Dyspepsia and Diabetic Gastroparesis and for control of emesis of varying etiology. Prokinetic drugs have motility enhancing effect on the upper part of GIT, whereas no clinically significant effects on the motility of large intestine have been reported. While taking prokinetic drugs, dose of drugs with inhibitory effects on GIT motility should be reduced without increasing the dose of prokinetic drugs as higher doses bear the risk of iatrogenic inhibition of gastric motility.
Itopride is a prokinetic on the upper and lower GIT which is mediated by its dual mechanism of action as D2 receptor antagonist and cholinesterase inhibitory action.
Itopride can relieve the clinical symptoms and improve the quality of life and mental health status of patients with irritable bowel syndrome (IBS), GERD and FD accompanied by abdominal distension, so it is worthy of clinical promotion.
The bitter taste of itopride HCl is considered a pre-formulation problem. Taste masking changes the nature of powder material and affects rheological characteristics, mechanical strength, and disintegration behavior which are mandatory for the preparation of a pharmaceutical product meeting the official specifications. Itopride HCl is 60% bioavailable due to the first-pass effect. It is metabolized in the liver by N-oxidation to inactive metabolites by the enzyme flavin-containing monooxygenase. Thus, we incorporated itopride HCl in ODTs. The drug release from the Orally Disintegrating Tablets is rapid compared with the conventional tablets.
The work in this thesis was divided into three chapters:
Chapter I: Taste Masking of Itopride HCl using solid dispersion method by solvent evaporation technique.
Chapter II: Formulation and evaluation of Itopride HCl oral disintegrating tablet by direct compression technique.
Chapter III: In-vivo pharmacokinetic study of the optimized ODT against the marketed product GANATON® on rabbits.
Chapter I
Taste Masking of Itopride HCl using solid dispersion method by solvent evaporation technique.
The aim of the work in this chapter is to mask the bitter taste of Itopride HCl to be palatable and ready to be incorporated into ODT using Solid Dispersion by the solvent evaporation method.
The work in this chapter is presented under the following heading:
1. Compatibility studies of Itopride HCl with the formulated additives.
To investigate any possible interactions between the drug and the investigated polymers; Fourier transform infrared spectroscopy (FTIR) is used. Physical mixtures of Itopride HCl and the polymers (mannitol and Eudragit EPO®) in a ratio of 1:1were prepared and subjected to FTIR analysis.
The above-mentioned drug (D), polymer (P), and D/P combinations were carried out using FTIR Bruker 22, UK. The samples were prepared as KBr disks compressed under a pressure of 6 tones/cm2. The wavenumber selected ranged between 500 and 4000 cm-1.
By comparing the IR spectrum of pure Itopride HCl with IR of possible combinations, It was noted that there is no absence of any characteristic peaks, this corroborates the absence of any physiochemical interaction(s) and incompatibility between the drug and polymers.
2. Taste masking of Itopride HCl by Solid Dispersion technique using the Solvent Evaporation method.
Solid dispersions of drug were prepared by solvent evaporation method where drug (Itopride HCl) and polymers (mannitol or Eudragit EPO®) were dissolved in Ethyl alcohol in different Drug: Polymer ratios. Solutions were mixed with constant stirring and solvent was evaporated. Solid dispersion was isolated, after complete evaporation of the solvent.
3. Evaluation of Physicochemical characterization of the Itopride HCl SD blends.
The taste-masked granules were tested for micromeritics prior to compression, many parameters such as bulk density, tapped density, angle of repose, flowability, compressibility index, and Hausner ratio were calculated.
The prepared blends were evaluated for different physicochemical characterizations, all results clearly indicated good flow characteristics of all solid dispersions. It was noted that in the case of using Eudragit EPO®, solid dispersions showed very free-flowing properties as in F4, F5, and F6 while in the case of mannitol, solid dispersions showed free-flowing properties as in F1, F2, F3, F7, F8, and F9. This may be due to the difference between mannitol and Eudragit EPO® in particle size and energy.
In vivo Taste Masking Evaluation was also performed where, twelve healthy volunteers (age 18–25) of either gender were chosen (male = 6, female = 6). 100 mg of blends were put in the mouth for 60 seconds before being spat out. Mineral water was utilized to wash each volunteer’s mouth in between the examination of two samples. The bitterness intensity scale was used to record the bitterness instantly, with 1, 2, 3, 4, and 5 indicating least unpleasant, less unpleasant, neutral, more unpleasant, and most unpleasant.
It was noted that by using solvent evaporation method, F5 (1:2) (Drug: EPO) and F8 (1:1:2) (Drug: Mannitol: EPO) were the best formulae for their evaluation to mask the bitter taste with score = 1 Least unpleasant (least bitter).While F6 (1:3) (Drug: EPO) was found to be the most bitter taste with score =5 most unpleasant. The more bitter taste was ranked for (F1,F7 and F9) with score =4 more unpleasant. The neutral taste score was ranked for (F2 and F4) with score =3, while the less bitter score was ranked for (F3) with score =2 less unpleasant.
Chapter II
Formulation and evaluation of Itopride HCl oral disintegrating tablet by direct compression technique.
The aim of the work in this chapter was to formulate and evaluate Itopride HCl oral disintegrating tablets by direct compression technique using different co-processed excipients.
The work in this chapter is presented under the following heading:
1. Preparation of ODTs by Direct Compression Technique
Itopride HCl ODTs were prepared by the best taste-masked formulae (F5 & F8) with different co-processed excipients by direct compression. The powder was mixed using the V-shaped mixer and then compressed into tablets using the single punch tableting machine of compression force 400 kg using a 7 mm flat punch and die set.
2. Evaluation of prepared ODTs
Evaluation of the prepared Itopride HCl ODTs showed that (T10) Prosolv SMCC 90® based formulae which is taste masked by Eudragit EPO® and mannitol in ratio Drug : Mannitol : Eudragit EPO® (1:2:1), was the best prepared ODT which showed a superior dissolution profile, drug content, hardness, and disintegration time. Overall, the in-vitro results showed that the new prepared formula due to its rapid release easily provide effective and efficient tablets of Itopride HCl.
Chapter III
In-vivo pharmacokinetic study of the optimized ODT against the marketed product GANATON® on rabbits.
The aim of this part of the study was using a specific HPLC method to determine ITO in the plasma of rabbits after taking the optimized ODT (T10). This ODT was Prosolv SMCC 90® based formulae which is taste masked by Eudragit EPO® and mannitol in ratio Drug : Mannitol : Eudragit EPO® (1:2:1). This study was done to determine whether the optimized ODT (T10) increased the bioavailability and decreased the onset of action of ITO compared to the commercially available conventional oral tablet, GANATON® (Abbott, Egypt, 50mg).
The work in this chapter is presented under the following heading:
1. Study Design, sample collection & Pharmacokinetic analysis.
Six albino rabbits weighing about 2-2.5 kg, with no previous diseases, in standard settings with commercially available food and cabbage, were included in the experiment.
All rabbits were fasted for 12 hours and given unlimited access to water. The treatment initiated where, all six rabbits were divided equally into two groups and given codes (A, B). group A was given a commercial medicine (Ganaton®50 mg, Abbott, Egypt) that was administered orally to each animal. Whereas group B received the optimized ODT (T10), by placing it in the rabbits’ oral cavities using forceps until completely disintegrated.
Following administration, at various time intervals (0, 5, 15, 30, and 45 minutes), as well as 1, 1.5, 2, 3, 4, 5, and 6 hours later. Blood samples were collected in heparin-containing collectors and centrifuged at 4000 rpm for 15 minutes, after which the separated plasma was transferred to tubes and kept at -80°C until analyzed.
The measured plasma Itopride HCl concentration was plotted versus time and compared to the commercial product Ganaton®.
The peak plasma concentrations (Cmax) of Itopride HCl and the time of its occurrence (Tmax) were estimated using the concentration-time data. The area under the curve from the beginning to the latest time recorded (AUC0−t) was calculated using the linear trapezoidal method.
It was found that by Comparing to orally administered marketed product GANATON® , the optimized orally disintegrating tablet (T10) showed rapid onset of action (30 minutes faster than GANATON®) with an increase in Cmax . Also, the new prepared formula due to its rapid release easily provides effective and efficient tablets of Itopride HCl by the oral route as an ODT that provides by-passing the excessive degradation of drug by first-pass metabolism increasing the oral bioavailability from 60% of marketed drug Ganaton® to 88% for the optimized ODT