(W1130-03-18) Formulation and Development of Rivastigmine tartrate Sustained-Release Tablets

Purpose: The aim of this study is to develop a sustained-release tablet formulation for rivastigmine tartrate to minimize gastrointestinal side effects that may occur during administration. Rivastigmine tartrate is an acetylcholinesterase inhibitor used in the treatment of Alzheimer's dementia and Parkinson's disease. To achieve controlled drug release, we investigated the potential of utilizing hydroxypropyl methylcellulose (HPMC), Eudragit^® L 100, and Lambda carrageenan as excipients in the design of sustained-release matrix drug delivery systems.

Methods: Preparation of rivastigmine tartrate sustained-release tablet - Rivastigmine tartrate and Fumed silica were sieved (355 μm). Rivastigmine tartrate and MCC were mixed in a PVC bag. HPMC, Eudragit^® L100, Lambda carrageenan, and Fumed silica were sequentially mixed. Each of Blends were mixed for 3 min. Finally, just before tableting, Magnesium stearate was added and mixed for 3 min. Blends were compressed using a rotary tablet press machine (ZP10, Shanghai, China) via direct compression. The tablet manufacturing process is illustrated in Figure 1. Melting Temperature Evaluation - Rivastigmine tartrate, HPMC, Lambda carrageenan and Eudragit^® L 100 were weighed in standard open aluminum pans between 3 and 5 mg respectively. The samples were subjected to a gradual temperature increase from 40 °C to 250 °C at a rate of 10 °C/min, with a nitrogen flow rate of 50 mL/min. Thermograms of rivastigmine tartrate, excipients, and binary mixtures of rivastigmine tartrate with each excipient were obtained using a 1:1 w/w ratio. Preparation of Dissolution Test - Dissolution tests were conducted to evaluate the impact of polymers on the dissolution profile of the tablets. The dissolution media used were pH 1.2 (0.1 N hydrochloric acid) and pH 6.8 (0.20 M tribasic sodium phosphate), following the guidelines provided in the EXTENDED-RELEASE DOSAGE FORMS section of USP DISSOLUTION. The in vitro dissolution was performed using the USP II paddle method at a temperature of 37 ± 0.5 °C, with the paddle rotating at 50 rpm. After the rivastigmine tablets were placed in the dissolution vessels, samples (1 mL) were drawn at predetermined time intervals, and the media was replenished with fresh buffer (1 mL) after each sampling. The collected samples were filtered through a 0.45 µm filter, and their concentrations were analyzed using HPLC.

Results: 1) Differential Scanning Calorimetry (DSC): Figure 2A presents the thermograms obtained when rivastigmine tartrate was mixed with HPMC, Eudragit^® L 100, or Lambda carrageenan. The melting temperature of pure rivastigmine tartrate was determined to be 126.68 °C. Figure 2B shows the peaks observed in the mixtures of rivastigmine tartrate with each polymer. No significant changes in the endothermic peaks were observed, indicating no notable interactions between rivastigmine tartrate and the excipients. 2) Dissolution Test: Figure 3A illustrates the formulation of the sustained-release tablets. In Figure 3B, the dissolution test was performed to compare Formulation 1 containing HPMC with Formulation 2 containing both HPMC and Eudragit^® L 100. The dissolution rate of Formulation 2 decreased after 3 hours, suggesting that Eudragit^® L 100 may reduce the dissolution rate due to electrostatic attraction after the buffer change. Figure 3C demonstrates a significant difference in dissolution rate depending on the amount of Lambda carrageenan. Formulation 3, which contains a small amount of Lambda carrageenan, exhibited a lower initial dissolution rate compared to Formulation 2 without Lambda carrageenan. The effect of Lambda carrageenan is evident in formulation 4, with a higher amount of Lambda carrageenan.

Conclusion: This study aimed to formulate rivastigmine sustained-release tablets, and the properties and functional groups of rivastigmine tartrate were investigated when mixed with HPMC, Eudragit^® L 100, or Lambda carrageenan. The formulation of the tablets varied depending on the presence and quantity of HPMC, Eudragit^® L 100, and Lambda carrageenan.

Acknowledgements: This work was supported by the Mid-Career Researcher Program (No. NRF-2021R1A2C2008834), the Basic Research Infrastructure Support Program (University-Centered Labs-2018R1A6A1A03023718), and the Bio & Medical Technology Development Program (NRF-2022M3A9G8016257) through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT).

Schematic diagram of the direct compression

A, B) DSC data of API, Excipients and Binary mixtures

A) Formulation of Rivastigmine tartrate sustained-release tablets
B, C) Dissolution profiles of Rivastigmine tartrate SR tablets (n=3)