Formulation Development of Morphine Sulfate Sustained-Release Tablets and Its Bioequivalence Study in Healthy Thai Volunteers

Abstract

The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4-102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one.

Mesoporous Polydopamine Nanoparticles Attenuate Morphine Tolerance in Neuropathic Pain Rats by Inhibition of Oxidative Stress and Restoration of the Endogenous Antioxidant System

“…The in vitro release of morphine from MPDA was studied in phosphate buffer saline at physiological pH ( Figure 6 a). Approximately 70% of morphine is released from the MPDA after 8 h in a sustained fashion without any initial burst release and is comparable with commercial morphine sustained-release formulations developed for human use [ 55 ].…”

In silico (computed) modelling of doses and dosing regimens associated with morphine levels above international legal driving limits

“…First, parameters were developed to match maximum concentration (C max ), time to achieve maximum concentration (T max ), area under the curve (AUC) and plasma/time shape parameters, with clearance and volume of distribution used from the mean of reported data. 22,[33][34][35][36] Second, the predicted and measured plasma concentrations across the dose range at steady state were compared. [35][36][37] This represented the best available population data for the dosing of morphine with slight over prediction being built into the model to ensure conservative clinical application ( Figure 1).…”

“…[35][36][37] Our model used one immediate-release and one modified-release formulation, based on collated published pharmacokinetic data. 22,[33][34][35][36] Clinically differing formulations and circumstances will lead to differing absorption kinetics between formulations, potentially leading to differing doseconcentration relationships in individuals. These findings offer an insight into the changing pharmacokinetic relationship with age and the effect an average dose will have and will help guide the clinician.…”