الفهرس 
Development and Evaluation of Bilayer Tablet Formulation of a Prokinetic Drug
CONTENTSOnly 14 pages are availabe for public view
 |  | from | 110 |  |  |
| | | from | 110 | | |
Abstract
Mosapride citrate (MOS) is a potent gastroprokinetic agent, used in the treatment of various gastrointestinal disorders.
Gastrointestinal (GI) disorders affect millions of people and are considered a major cause of global morbidity. Mosapride citrate (MOS) is a prokinetic agent with antiemetic effect, as it has 5-HT4 (5-Hydroxytryptamine receptor 4) receptor agonist.
MOS relieves constipation and helps with heart burn, nausea, vomiting, and functional dyspepsia. 5-HT3 (5-Hydroxytryptamine receptor 3) receptor partial antagonistic effect provides MOS with its antiemetic effect.
MOS lacks affinity for dopamine D2, 5-HT1, 5-HT2, or adrenergic receptors subsequently missing any cardiac or nervous adverse reactions due to selective stimulation of serotonin 5-HT4 receptors.
Presently, available tablet dosage formulation of MOS is incapable to achieve the optimum clinical efficacy. As MOS is (BCS class II) class two according to the bioavailability classification system, this means it possesses low solubility and requires dissolution enhancement to increase its bioavailability. The drug also suffers from a short half-life which is around 2.3 hours.
This half- life necessitates frequent dosing for MOS (three times daily), and this certainly, would have a negative effect on patient compliance and patient satisfaction.
A bilayer tablet can solve both problems simultaneously by offering a biphasic release profile with a fast release phase and extended release one. So, the aim of this study was the formulation of mosapride using solid dispersion (SD) techniques and choosing the best system that enhances the solubility and the best system that can extend its release and incorporating both systems separately into individual tablets for choosing the optimal tablet formulation that best serve its function. Finally incorporating both tablet formulations into one bilayer tablet.
The work in this thesis is divided into three chapters:
Chapter I: In-vitro and In-vivo Evaluation of Enhanced Release Mosapride Citrate through Preparation of Triple Solid Dispersion and Tablet Formulation.
Chapter II In-Vitro Evaluation of Controlled Release Mosapride Citrate through Preparation of Solid Dispersion and Tablet Formulation.
Chapter III In-Vitro Evaluation of Mosapride Citrate through Preparation of optimized Bilayer Tablet Formulation.
Chapter I
Amorphous solid dispersion ASD is an old yet trending technique for dissolution enhancement and thus considered as a cornerstone method for improving the bioavailability of poorly soluble drugs.
So, the aim of this chapter was to develop and characterize MOS solid dispersion that enhances its solubility thus overcoming its low bioavailability.
Both binary (SD) and triple solid dispersion (TSD) were prepared with Soluplus® (SOL) and α-Tocopherol polyethylene glycol succinate (TPGs) using solvent evaporation. Optimal systems were chosen according to the best dissolution rate and were compressed into tablets using either, Ac-Di-Sol®, Crospovidone, or chitosan as superdisintegrants.
Results declared that MOS-TSD acquired the highest dissolution rate in terms of t1/2 = 1.5 min.
DSC and XRPD illustrated a partial amorphization of mosapride.
FTIR revealed a possible H bond interaction between drug and carriers. Drug release from MOS-TSD tablets containing Crospovidone showed 60.7% flush release with a t1/2 = 1.4 min.
An ultrasonographic study performed on rabbits revealed that MOS-TSD tablet with optimum carrier combination showed 2.46 -fold increase in duodenal and cecal motility compared to pure MOS and 2.5-fold increase compared to the oral marketed product.
Therefore, the formulation of fast release tablet with surfactant based triple solid dispersion offered a great success in improving the therapeutic efficacy of mosapride.
Chapter II
This chapter utilizes the solid dispersion technique to extend the release profile of mosapride as a very effective method to overcome its short half-life and its need for multiple dosing along the day.
Eight sustained release (SD) systems were prepared with different ratios of hydrophobic polymers (ethyl cellulose Eudragit ® RSPO, Compritol ® 888 ATO and carnauba wax). Systems were evaluated and chosen according to the best dissolution rate and were compressed into tablets using either, chitosan or Carbopol® as binding agents.
Results declared that using ethyl cellulose with mosapride in the ratio 1:5 acquired the most optimum dissolution rate in terms of t1/2 = 12.56 hr.
DSC and XRPD illustrated a partial amorphization of mosapride.
FTIR revealed a possible H bond interaction between drug and carriers.
SR-SD was formulated into a tablet using chitosan as a binding agent and the result of release experiments revealed that only 47.7mg % of mosapride was released after five hours.
This fulfilled the maximum requisite of an optimum sustained release tablet because it had the longest half-life (6.27 hours) in comparison to the tablet prepared using Carbopol® (Half-life 2.85 hours) as a binder.
Chapter III
In this chapter the optimum tablet formulations from chapter one and two were combined to give the bilayer tablet that acted as a dosage with a biphasic release. This dosage form solved the two limitations of mosapride as a drug with low solubility and a short half-life.
The TSD-Tablet formulation powder was thoroughly mixed directly compressed using a 7 mm flat punch via a single-punch tablet machine (Royal Artist, Mumbai, India). The powder was compressed with a low force of compression. The sustained release powder mixture was placed above the intact TSD-tablet layer and compressed with a higher force resulting in the formation of a bilayer tablet.
The bilayer tablet underwent all the quality control testing according to the USP. Tablet hardness, friability, weight variation, and drug content uniformity, were within USP limits.
Disintegration testing was documented as a phase-by-phase disintegration through pictures. This was done to show that although it is a bilayer tablet each layer behaved according to its own additives and that they both did not alter one another’s disintegration properties.
The Instant release layer disintegrated within 30 sec leaving the SR-SD layer intact for around 25 minutes to complete its disintegration.
Dissolution testing for the bilayer tablet showed a biphasic drug release. At five minutes almost 50% of the mosapride was released which is the total amount of mosapride the instant release layer.
Yet over the following four hours only 80 % of the drug in tablet was very slowly and evenly released with a rather longer half-life 7.5 hr. which means that each layer served its purpose and the bilayer drug gave a biphasic release profile.
Linear regression analysis was performed in which release data of MOS from bilayer tablet was fitted to different kinetic models (zero-order, first order, and Higuchi model. The coefficient of determination (R²) was determined for each. Kinetic data were calculated for each layer separately. The first layer showed a zero-order drug release kinetics with a flush 39.53 mg % and a t1/2=5 min. The second layer had a seven and half hour half-life with a zero-order drug release profile as well. The formulation attained the goal giving rise to a preliminary fast and constant release which could support a prompt action. This state was followed by a gradual and constant release profile which was extended over the 4 h with a t1/2 of 7.5 h predicting that it could achieve a constant blood level when tested in-vivo.
To demonstrate the difference in surface topography of both layers, the bilayer tablet was transversely sectioned and examined under the scanning electron microscope.
the morphology of the bilayer tablet appeared to have a considerable difference between the two layers. It can be observed that the first layer had many pores that should allow water entrance and fast disintegration While SEM analysis of the SR layer showed little to no pores, in addition to the presence of the elongated chitosan fibers.