Development of Alcohol-Resistant Extended-Release Formulations: Regulatory Considerations and Formulation Strategies

This study was aimed to develop reservoir-type extended-release (ER) formulations resistant to alcohol-induced dose dumping (ADD) using polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP-90).

The ER formulations were developed utilizing water-soluble and water-insoluble core diluents and binders, along with various PVAc with PVP-90 (3:1 w/w) coating levels. In vitro risk mitigation studies were conducted to understand the impact of alcohol on the properties of polymer compositions and their films, including viscosity, swelling, elasticity, and breaking force. The PVAc with PVP-90 (3:1) film exhibited minimal swelling and maintained better integrity in the presence of alcohol.

The ER tablets incorporating water-soluble L-PVP in the core did not exhibit burst release in alcoholic media but showed compromised ADD resistance at lower coating levels. Increasing the concentration of PVP-90 in the core resulted in a slower disintegration rate, with concentrations exceeding 15% preventing full disintegration of tablets within 2 h in 0.1N HCl with 40% alcohol. The optimized formulation, containing 25% PVP-90 in the core and PVAc with PVP-90 coating, minimized ADD risk and maintained an ER release profile even after exposure to accelerated storage conditions (40°C/75% RH) for 3 months.

The study highlights the importance of core and coating compositions in achieving ADD resistance. However, risk mitigation strategies including a new recommended dissolution method revealed that formulations meeting FDA guidelines could still exhibit dose dumping after just 2 h of alcohol exposure. This finding suggests the need to review regulatory standards for ADD resistance and harmonize requirements between agencies like EMA and US FDA to develop a relevant in vitro method for assessing ADD in modified release formulations.