Engineering of multiparticulate systems to modify the drug release across orally disintegrating tablets

Al-Hashimi, Nihad (2021) Engineering of multiparticulate systems to modify the drug release across orally disintegrating tablets. (PhD thesis), Kingston University, .


Background and Aim: Orally disintegrating tablets (ODTs) combined with multiparticulate formulations of modified-release (MR) properties are considered more efficient medicinal options than traditional immediate-release formulations. ODTs & MR multiparticulates provide ease of medicinal use for dysphagic patients allowing a modified drug release to reduce the undesirable side effects, and the frequent daily dose would be eliminated, thus enhancing patient compliance. Nevertheless, the compaction of multiparticulates is challenging, causing polymeric damage leading to a loss in integrity and a rapid drug release. This project aims to prepare ODTs-MR of indomethacin (IND) and propranolol hydrochloride (PRH) by enhancing mechanical properties and the parameters of ODTs and multiparticulates production. Methods: Two developed and validated HPLC methods (according to ICH guidelines) were utilized to detect and quantify indomethacin (IND) and propranolol hydrochloride (PRH) release from the prepared formulations. The direct compression method was used to prepare ODTs, extrusion spheronization and spray drying to prepare the multiparticulates. The mechanical properties of ODTs and multiparticulates were assessed using texture analysis and hardness testing. Through the project, all formulations were examined using disintegration time, dissolution studies (pH 1.2 and 6.8), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and stereomicroscope. Results and discussion: IND loaded microparticles of Eudragit L100 were successfully delayed IND release in pH 1.2 buffer using acetone as a solvent. The low value of YM, using the appropriate solvent type and setting feed concentration at 5% w/v, was appropriate for modifying IND release. Similarly, Eudragit L100 was used to prepare IND loaded pellets. Lactose and mannitol (63, 125 and 500 µm) ODTs comprised of IND loaded pellets disintegrated in less than 30 seconds with acceptable mechanical properties of less than 1.5 MPa and an adequate elastic profile. Also, ODTs-pellets from lactose and mannitol delayed IND release in acidic media to less than 1.07% at 120 minutes while released more than 93% at 120 minutes in phosphate buffer (pH 6.8). Furthermore, the tensile strength of IND�pellets of Eudragit L100 (45, 63 and 90 µm) was directly proportional to YM (p<0.05), offering enough support to maintain their integrity under compression. In addition, the in vitro release study showed a delayed release of IND in the acidic media (pH 1.2) and an immediate release in the buffer media (pH 6.8). On the other hand, the matrix system was unapplicable to delay PRH release from Eudragit RS based pellets despite changing the ratio and type of plasticisers. However, PRH pellets of reservoir system using Eudragit RS, Eudragit RL and combination of Eudragit RS: RL (1:1) w/w showed that the mechanical properties of the coated pellets differ significantly from the uncoated batch (p<0.05). Besides, ODTs reservoir-pellets were able to modify PRH release to ≤ 53.9% in acidic media and ≤ 47.2 % in phosphate buffer for 30 minutes, while the uncoated pellets released > 75% of PRH. Alongside, EDEM® successfully simulated the compaction process and showed that increasing compression force at the beginning of compression strengthens the interparticulate bonds at the surfaces resulting from the low surface roughness. Conclusion: Matrix system to sustain IND release was achieved using Eudragit L100 microparticles and pellets embedded in the ODTs. The lowest percentage of propranolol release was attained from the reservoir system of Eudragit RS and RL pellets embedded in the ODTs. All formulations of ODTs disintegrated in less than 30 seconds. A balance between Young’s modulus and tensile strength is essential to enhance the integrity of the multiparticulates and, eventually, drug release

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