Optimized Taste-Masked Microparticles for Orally Disintegrating Tablets as a Promising Dosage Form for Alzheimer’s Disease Patients

The objective of this research was to optimize the tasted-masked microparticles for orally disintegrating tablets containing donepezil hydrochloride using quality risk assessment and design of experiment approaches. The double emulsion solvent evaporation technique using aminoalkyl methacrylate copolymer (AMC) was used to prepare taste-masked microparticles. Factors affecting the quality of the taste-masked microparticles were analyzed using an Ishikawa diagram.

A risk-ranking approach was used to rank the formulation and process risks. Furthermore, the effect of AMC quantity, stirring time, and volume of outer water phase on various responses, such as particle size, the amount of drug dissolved at 5 min (Q₅) in simulated saliva fluid, and mean dissolution time (MDT) in simulated gastric fluid, was investigated using the Box-Behnken design. The optimized microparticles were then used to prepare orally disintegrating tablets (ODTs) and evaluated by in vitro and in vivo testing. The results demonstrated that particle size was influenced by the AMC amount and stirring time. Q₅ was significantly affected by the amount of AMC and the volume of the outer water phase.

On the other hand, these two factors had a positive effect on MDT. The optimized microparticles had a particle size of 174.45 ± 18.19 µm, Q₅ of 5.04%, and MDT of 5.97 min. The ODTs with taste-masked microparticles showed acceptable in vitro dissolution with an MDT of 5 min. According to the results of a panel of six human volunteers, they greatly improved palatability.

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Materials: DPH (lot number 000000085) was kindly supplied by Pharma Nueva Co., Ltd., Bangkok, Thailand. AMC (Eudragit^® E PO, lot number G170331544) was kindly provided by Evonik Röhm GmbH, Darmstadt, Germany. PVA (lot number 16796TJV), molecular weight of 85,000 Da to 124,000 Da, and degree of hydrolysis of 87% to 89%, was purchased from Sigma-Aldrich, St. Louis, MO, USA. Mannitol (lot number 302004308) was purchased from Shandong Tianli Pharmaceutical Co., Ltd., Shandong, China. Spray dried lactose monohydrate (Supertab^® 11SD, lot number 23034009) was purchased from DMV-Fonterra Excipients GmbH & Co., Goch, Germany. Microcrystalline cellulose (Comprecel^® M101D+, lot number C2006037) was purchased from Mingtai Chemical Co., Ltd, Taoyuan City, Taiwan. Crospovidone (Polyplasdone^® XL, lot number 0002434812) and polyvinyl pyrrolidone K-30 (PVP K-30; lot number 002377911) were from Ashland Chemical Inc., Wilmington, DE, USA. Magnesium stearate (Kemilub^® EM-F-V) was purchased from Italmatch Chemicals, Genova, Spain. All other chemicals and solvents used in this study were of reagent grade or high-performance liquid chromatography grade and were used as received.