Factors related to drug and Formulation affecting alcohol dose dumping in modified release oral drug products

ABSTRACT/SUMMARY Dose dumping, which is defined as ‘‘unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the drug contained in a modified release dosage form’’ can have dangerous effects. Currently, the FDA recommends to assess the risk of alcohol-induced dose dumping for opioid and non-opioid drugs with a narrow therapeutic index, such as metoprolol succinate (β-blocker) and venlafaxine HCl (antidepressant). Especially, prolonged-release formulations, which offer a reduced dosing frequency and a prolonged therapeutic effect due to higher drug amounts, are of specific interest. If the opioid drugs-containing dosage form is consumed with ethanol, the drug release can increase immediately, resulting in an overdose and leading to respiratory depression followed by hypoxia and even death. Regarding non-opioid drugs, alcohol might enhance sedation (through synergistic interactions), decrease in motoric skills and may lead to orthostatic hypotension. However, not many research studies have been reported in the literature on alcohol-induced dose dumping. It is important to understand effect of formulation, excipients and manufacturing method on the vulnerability of modified released formulation to dose dumping by alcohol. Ideally, the modified release formulation should be rugged, not vulnerable to alcohol-induced dose dumping for safety and efficacy points of view. The objectives of this project are to mechanistically and systemically understand the effect of formulation composition, formulation design, excipients properties, manufacturing methods and processes parameters on alcohol-induced dose dumping. The team has extensive experience on alcohol-induced dose dumping, abuse deterrent, and meth-deterrent formulations development, evaluation of formulation vulnerability to abuse and dose dumping, understanding and development of metrics for comparison and evaluation of abuse deterrence and alcohol-induced dose dumping properties, and classification of formulation vulnerability and ruggedness to abuse and dose dumping at DPQR (Division of product Quality and Research at FDA). Following are the specific aims of the proposal: Aim I: Mechanistically understand the effect of drug-related factors on alcohol-induced dose dumping from extended release formulations; Aim II: Mechanistically understand the effect of formulation- related (composition and design) factors on alcohol-induced dose dumping from extended release formulations; and Aim III: Mechanistically understand the effect of manufacturing method and process-related factors on alcohol-induced dose dumping from extended release formulations. This proposal focusses on fundamental understanding of excipients properties, manufacturing methods and process parameters that may contribute vulnerability to dose dumping due to alcohol. This basic understanding about the alcohol-induced dose dumping will help the agency in framing the policy regarding vulnerability and ruggedness of a formulation. Outcome will be disseminated in the public domain, which can be utilized by industry, academia and regulatory agency.