Influence of dissolution medium buffer composition on ketoprofen release from ER products and in vitro-in vivo correlation.

The purpose of this work was to investigate the influence of dissolution medium composition on the in vitro release of ketoprofen from a series of ER products and the impact of the different buffer media on the in vivo-in vitro (IVIV) relationship. The products investigated were coated micro bead preparations having increasing levels of coating to retard drug release. Four common dissolution media; USP phosphate buffers of pH 7.2 and 6.8, phosphate (modified isotonic) buffer pH 6.8 and a fasted state simulated intestinal fluid without lipid components (FaSSIFLF) of pH 6.5, were employed in the USP 2 apparatus. Release profiles were compared to the corresponding in vivo release profiles, obtained following deconvolution of the plasma level versus time profiles obtained from a 10-subject five-period cross-over study. Despite the relative similarity in composition of the media employed, significant differences in release profiles were observed reflecting media differences in buffer capacity, ionic strength and pH. As a consequence, the quality and shape of the IVIV relationship changed significantly, the only apparent IVIVC incorporating all four ER products, which was non-linear, was obtained using the phosphate (modified isotonic) buffer of pH 6.8. This data was fitted, using a non-linear least squares method, by the equation of Polli et al. [J. Pharm. Sci. 85 (1996) 753] and gave an alpha parameter estimate of 2, consistent with initial dissolution being more rapid in vitro than in vivo. The systematic shift in profiles, particularly with buffer capacity, underlines the sensitivity of IVIV relationship to medium composition and hence the current difficulties in making a rational choice of an appropriate single dissolution medium.

Steady-state pharmacokinetic comparison of a new, extended-release, once-daily morphine formulation, Avinza, and a twice-daily controlled-release morphine formulation in patients with chronic moderate-to-severe pain.

Extended-release morphine formulations are widely used in the management of chronic pain. Avinza (morphine sulfate extended-release [MSER, Morphelan]) is a new, once-a-day, extended-release morphine formulation designed to reach target concentrations rapidly and maintain concentrations throughout a 24-hour period. The primary objective of this study was to compare the 24-hour steady-state pharmacokinetic (PK) profiles of morphine and its metabolites (morphine-6-glucuronide [M6G] and morphine-3-glucuronide [M3G]) following ingestion of MSER once-a-day and MS Contin (controlled-release morphine sulfate [CRM]) twice-a-day in patients with chronic moderate-to-severe pain. Ten patients with chronic moderate-to-severe pain were recruited into an open-label, multiple-dose, nonrandomized, two-period, single-center study. All patients were stabilized for a minimum of 7 days on a twice-daily dose of CRM associated with an optimal balance between pain control and side effects. Patients were then switched to the closest equivalent once-daily dose of MSER for a minimum of 10 days. Twenty-four hour steady-state PK profiles were obtained on the last day of each treatment period and additional clinical and safety assessments were performed. PK data were normalized to a 100-mg total daily dose prior to statistical analysis. Nine of the 10 patients completed the entire study. MSER and CRM demonstrated similar bioavailability (AUC) of morphine and its metabolites. Compared to CRM, MSER demonstrated a 19% lower maximum concentration (C(max)), a 66% higher minimum concentration (C(min)), and a 44% lower peak-to-trough fluctuation (%FI) over the 24-hour period. In addition, MSER maintained concentrations above 50% and 75% of the C(max) longer than CRM. Clinical efficacy and safety were comparable for MSER and CRM. Once-daily MSER approaches maximum morphine concentration more quickly, approximates maximum concentration longer, and demonstrates less fluctuation in morphine concentration during a 24-hour period than CRM dosed twice daily. The pharmacodynamic implications of this profile deserve further study.

Pharmacokinetic evaluation of a sprinkle-dose regimen of a once-daily, extended-release morphine formulation.

BACKGROUND: Morphine sulfate extended-release (MSER) uses a drug-delivery technology that allows once-daily dosing. It is possible to open the MSER capsule and sprinkle the contents on soft food, a potentially useful alternative to the intact capsule in patients who have difficulty swallowing. OBJECTIVE: This study compared the bioavailability of MSER and its metabolites morphine-3-glucuronide and morphine-6-glucuronide after administration of MSER in a sprinkle-dose regimen relative to an intact capsule swallowed whole. METHODS: This was a randomized, open-label, single-dose, crossover study, with a 7-day washout period between the 2 dosing days. Healthy volunteers were randomized to receive an intact 60-mg MSER capsule swallowed whole or the contents of a 60-mg MSER capsule sprinkled on applesauce. Blood samples were collected and analyzed for concentrations of morphine and its active glucuronide metabolites. Pharmacokinetic (PK) parameters were calculated and bioequivalence assessed. Bioequivalence was concluded if the 90% CIs of the ratio of log-transformed values for maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were within 80% to 125%. RESULTS: Of 30 subjects enrolled, 28 completed the study and were eligible for PK evaluation. Two subjects were withdrawn for reasons unrelated to study treatment. The plasma concentration-time profiles of morphine and its metabolites were superimposable after administration of the 2 regimens. Cmax and total systemic exposure-based on AUC from time 0 to the last quantifiable concentration (AUC(last)) and AUC from time 0 to infinity (AUC(infinity))-were comparable between treatments. The 90% CIs for morphine AUC(last), AUC, and Cmax ratios were 98 to 109, 96 to 106, and 95 to 117, respectively. Similar 90% CIs were obtained for the morphine metabolites. CONCLUSION: In this study in healthy volunteers, sprinkling the entire contents of an MSER capsule onto applesauce and swallowing without chewing was bioequivalent to swallowing an intact MSER capsule.