(425) Dissolution studies in the presence of alcohol with an abuse-deterrent, extended-release morphine product candidate

Abstract

Some extended-release (ER) opioid formulations may be prone to rapid drug release (dose dumping) when co-ingested with alcohol, potentially causing toxicity, overdose, and even death. Dissolution testing in the presence of various concentrations of alcohol to assess the potential for dose dumping was conducted with a novel morphine abuse-deterrent (AD), ER, injection-molded tablet (morphine ADER-IMT) product candidate. Morphine ADER-IMT applies proprietary Guardian™ technology (Egalet Corporation, Wayne, PA) that uses a novel plastic injection molding process for manufacturing the tablets. Dissolution of morphine ADER-IMT (15-mg, 60-mg, and 100-mg dosages) was evaluated (n=12) at 37ºC±0.5ºC in 900 mL 0.1 N HCl (pH 1.2; reflecting gastric pH) or buffer (pH 6.8; reflecting intestinal pH) media containing 0, 5, 10, 20, and 40% ethanol, using a standard United States Pharmacopeia apparatus. Morphine release was measured by high-performance liquid chromatography with an ultraviolet detector (285 nm) at 15, 30, 45, 60, 75, 90, 105, and 120 minutes. All dissolution profiles for morphine ADER-IMT 15 mg and 60 mg complied with f2 profile comparison test criteria, indicating comparable dissolution profiles among aqueous (0% ethanol) and ethanol-containing media. The 100-mg dosage demonstrated a significantly slower dissolution in 40% ethanol and therefore did not pass the f2 test. Ethanol in concentrations of 5%–20% had no clear effect on dissolution rates in either pH 1.2 or pH 6.8. However, a trend showing a decrease in dissolution rates for all dosages was observed with increasing ethanol concentrations, and a significant decrease in dissolution rate was observed with 40% ethanol. No evidence of alcohol dose dumping was observed with morphine ADER-IMT, and slower dissolution rates occurred at higher alcohol concentrations. Funded by Egalet Corporation.