(W1130-08-53) Alcohol Resistant Extended Release Multiparticulates Based on EUDRAGIT® NM 30 D

Purpose: The concurrent consumption of alcoholic beverages and oral controlled-release formulations presents significant safety risks, as alcohol can disrupt the release rate-controlling polymeric diffusion layer of modified-release multiparticulates. This disruption can lead to uncontrolled and immediate drug release, commonly referred to as alcohol-induced dose dumping. The presence of alcohol can accelerate the release of the active pharmaceutical ingredient from modified release formulations, resulting in altered systemic exposure. The FDA recommends that sponsors who are developing certain modified release, solid, oral dosage forms conduct in-vitro studies to determine the potential for dose dumping from alcohol in-vivo¹. Creating an alcohol-resistant coating formulation is particularly challenging for coated multiparticulates. Therefore, this study aims to evaluate the alcohol resistance performance of coating systems utilizing EUDRAGIT® NM 30 D for extended release applications.

Methods: Coating with EUDRAGIT® NM 30 D based dispersion: Metoprolol succinate pellets (840-1190 microns) were prepared using wet extrusion and spheronization. Afterwards, the pellets were coated with a formulation containing EUDRAGIT® NM 30 D, and either HPMC (hydroxylpropyl methylcellulose, 3 cps) or HPC-LM (hydroxypropyl cellulose) as well as polysorbate 80. The coating formulation was applied utilizing a fluid bed processor with bottom spray assembly. The post treatment of coated pellets was performed in a tray dryer at 50°C for 24 hours. Three batches of the final coating formulation were investigated to prove reproducibility of process and performance. In vitro dissolution study was used to determine extended release characteristics and alcohol resistance performance using USP apparatus 2 (paddle) at 50 rpm. Dissolution media comprised of 500 mL each, of 0.1 N HCl for 2 hours (without or with 40% v/v ethanol), followed by phosphate buffer pH 6.8 at up to 12 hours, maintained at 37.5ºC. All samples were analyzed via high-pressure liquid chromatography (HPLC) and detected via UV detector. A stability study of EUDRAGIT® NM 30 D coated metoprolol pellets was conducted as per ICH guidelines in closed induction sealed HDPE containers at 40°C/75% RH up to 6 months.

Results: Formulations coated with EUDRAGIT® NM 30 D, combined with cellulosic components (HPMC/HPC-LM) and an appropriate non-ionic emulsifier (polysorbate 80), exhibited favorable extended release characteristics and alcohol resistance properties. The study also explored the impact of different cellulosic components on alcohol resistance, revealing that HPC-LM produced slightly slower release profiles in both non-alcoholic and alcoholic environments compared to HPMC (as shown in figure 1 and 2). The coating weight gain and the type of cellulose employed can serve as effective tools for modulating drug release, enabling the attainment of desired extended release profiles and alcohol resistance. The developed formulations demonstrated reproducible performance in terms of release, alcohol resistance properties and storage stability under accelerated conditions (40°C/75% RH) for up to six months, with a similarity factor exceeding 50 in their release profiles.

Conclusion: This study provides compelling evidence that EUDRAGIT® NM 30 D is highly effective in the formulation of alcohol-resistant extended-release multiparticulates. The formulations demonstrated robustness, maintaining integrity even in a dissolution medium containing 40% v/v alcohol for two hours. This addresses concerns related to alcohol-induced dose dumping and meets regulatory requirements for modified release formulations.

References: 1. “Bioavailability Studies Submitted in NDAs or INDs — General Considerations”, Guidance to Industries U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), April 2022.

Figure 1: Alcohol resistance performance of reproducible batches of EUDRAGIT® NM 30 D+ HPMC formulation

Figure 2: Alcohol resistance performance of reproducible batches of EUDRAGIT® NM 30 D+ HPC formulation