Bioequivalence study of two morphine extended release formulations after multiple dosing in healthy volunteers

Aim: Two extended release (ER) formulations of morphine sulphate (30 mg eac h), Oramorph SR (test) and a marketed reference formulation (MST Mundipharm a Retardtabletten), were investigated for their relative bioavailability at steady-state. Methods: The study was designed as a single-centre, open-lab el, two-period crossover, pharmacokinetic comparison in 28 healthy male vol unteers and was completed in 23 subjects. The determination of morphine and its metabolite morphine-6-glucnronide in plasma was done by HPLC with elec trochemical detection after solid-phase extraction. Results: Under steady-s tate conditions in the first dosing interval, mean maximum plasma concentra tions for morphine were 19.1 ng/ml (CV% 41) for Oramorph SR 30 mg and 19.1 ng/ml (CV% 33) for MST-30 Mundipharma Retardtabletten. Geometric mean AUC(0 -12) values were calculated as 108 ngxh/ml (CV% 40) for Oramorph SR 30 mg a nd as 118 ngxh/ml (CV% 30) for the reference formulation. The plasma concen trations of the major metabolite, morphine-6-glucuronide, were found to be generally in a higher range compared to the parent compound. The 90% confid ence intervals of test to reference ratios calculated for all relevant para meters (AUC, C-max, PTF) for both the parent compound and morphine-6-glucur onide were all within the limits of 80-125%. The most frequent adverse even ts (AE > 10%) during Oramorph SR 30 mg treatment were headache (36%), dizzi ness (18%), nausea (21%), vomiting (21%) and pruritus (11%). During treatme nt with MST-30 Mundipharma Retardtabletten, the most frequent AEs were head ache (29%), dizziness (13%), nausea (29%) and vomiting (29%). Conclusion: T he results demonstrate bio-equivalence of Oramorph SR 30 mg and MST-30 Mund ipharma Retardtabletten.