Pharmacokinetics of Morphine Sulfate Orodispersible Tablets and Bioequivalence with Immediate-Release Oral Morphine Sulfate Formulations in Healthy Adult Subjects Under Fasting Conditions: Single-Dose Comparative Bioavailability Studies.

Abstract

An orodispersible tablet (ODT) formulation of morphine sulfate has been developed to provide a novel alternative for patients with severe pain requiring opioids. This formulation has been developed in a range of doses (1-30mg), enabling relief from severe pain to be achieved and maintained with the lowest possible morphine dose for each patient. The ODT formulation is particularly suitable for patients with swallowing difficulties. The aim of this study was to compare the pharmacokinetics and bioequivalence of the ODTs with reference formulationsof morphine sulfate. Three randomized, single-dose, laboratory-blinded, phase I, crossover studies were conducted in adult healthy volunteers under fasting conditions. The pharmacokinetics of a 30mg morphine sulfate ODT were compared with those of equivalent doses of currently marketed oral immediate-release formulations: tablets (Sevredol®), capsules (Actiskenan®), and a solution (Oramorph®). The bioequivalence of 30mg and 10mg doses of the ODTs and tablets was then assessed in two further studies. Subjects were asked to complete a product appreciation questionnaire for two morphine formulations (ODT and solution). A total of 104 subjects were included across the three studies. The pharmacokinetics of the ODTs were assessed in 100 subjects and were found to be similar to those of the reference formulations. The time to maximum plasma concentration (Tmax) for the ODTs was 0.8h, within the range observed for the reference formulations (0.75-1.25h). Maximum plasma concentrations (Cmax) for the ODTs were 7.7±2.7ng/mL for the 10mg dose and 26.1±10.0ng/mL for the 30mg dose. These values were similar to those obtained for the 10mg and 30mg tablets (8.0±2.9ng/mL and 28.5±11.9ng/mL, respectively), and for the 30mg capsule (29.9±13.0ng/mL). A higher Cmax was observed for the solution (37.9±16.5ng/mL). Plasma exposure to morphine (area under the plasma drug concentration-time curve [AUC]) after ODT administration was similar to that observed for the reference formulations: 39.8±14.8ng·h/mL and 115.5±34.6ng·h/mL for the 10mg and 30mg ODTs, versus 40.7±13.5ng·h/mL and 117.4±31.5ng·h/mL for the 10mg and 30mg tablets, and 121.8±32.0ng·h/mL and 121.0±35.7ng·h/mL for the 30mg solutionand capsule, respectively. Bioequivalence of the 30mg and 10mg ODTs and tablets, assessed in 83patients across two studies, was demonstrated for both the Cmax and AUC from time zero to time t (AUC0-t). No serious or unexpected drug-related events were reported. A product appreciation questionnaire concluded that both ODTs and oral solution products were considered pleasant by most of the subjects. The ODTs were safe, well tolerated, and showed similar pharmacokinetics to those of the reference formulations. The development of a range of doses of morphine sulfate ODTs may provide a new alternative for the oral administration of immediate-release morphine for pain management in pediatric, geriatric and adult populations with swallowing problems.