Ropinirole hydrochloride for amyotrophic lateral sclerosis: A single-center, randomized feasibility, double-blind, placebo-controlled trial

ABSTRACTBackgroundWe previously used an induced pluripotent stem cell-based drug repurposing approach to demonstrate that ropinirole hydrochloride (ropinirole) attenuated amyotrophic lateral sclerosis (ALS)-specific pathological phenotypes. Here, we assessed the safety and feasibility of ropinirole in ALS patients to verify its efficacy.MethodsWe conducted a randomized feasibility trial of ALS. Twenty participants with ALSFRS-R scores greater than 2 points were randomly assigned using dynamic allocation to receive ropinirole or placebo for 24 weeks in the double-blind period. Upon completion, participants could choose to participate in the following 24-week open-label active extension period. The primary outcomes were safety and tolerability. The secondary outcomes for the feasibility trial objective were the change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score, composite functional endpoint, combined assessment of function and survival, event-free survival, and time to ≤50% forced vital capacity (blinded outcome assessment). This study is registered with the UMIN Clinical Trials Registry, UMIN000034954.FindingsTwenty-one participants were randomized into two groups (ropinirole group; n=14) and received ropinirole (n=13) or placebo (n=7) and the data of all participants were analysed using mixed-effects models for repeated measures together. Overall, the incidences of adverse events, most of which had been reported previously, were similar within both groups. Notably, the incidence of gastrointestinal disorders (mainly, temporary mild nausea and diarrhoea) was high at 76·9% in the ropinirole group (14·3% in the placebo group). Regarding the feasibility of verifying efficacy, there were no significant differences in the ALSFRS-R score and combined assessment of function and survival scores during the double-blind period for 6 months, while the participants in the ropinirole group had lived an additional 27·9 weeks without disease progression events compared with the placebo group (log-rank test, 95% confidence interval, 4·3–37·4) at 12 months (secondary outcome).InterpretationRopinirole is safe and tolerable for patients with ALS and this trial indicates feasibility for a subsequent large-scale trial.FundingThis study was funded by The Japan Agency for Medical Research and Development and K Pharma Inc.

Developing an Improved UHPLC Method for Efficient Determination of European Pharmacopeia Process-Related Impurities in Ropinirole Hydrochloride Using Analytical Quality by Design Principles

This article presents the development of a reversed-phase ultra-high-performance liquid chromatographic method for determining process-related impurities in ropinirole hydrochloride drug substance applying the analytical quality by design approach. The current pharmacopeial method suffers from selectivity issues due to two coelutions of two pairs of impurities. The development of a new method began with preliminary experiments, based on which the Acquity UPLC BEH C8 was selected as the most appropriate column. The effects of six different critical method parameters (CMPs) were then investigated using a fractional factorial screening design. Column temperature, the ratio of methanol in mobile phase B, and gradient slope turned out to be highly significant CMPs in achieving critical resolutions, and they were further evaluated using a central composite face-centered response-surface design. Mathematical models were created by applying a multiple linear regression method. Based on the elution order of an unknown degradation impurity and impurity C, two design spaces were established, and for each design space an optimal combination of CMPs was determined. The method developed was validated for precision, accuracy, linearity, and sensitivity, and it was proven suitable for determining nine process-related impurities of ropinirole.

Development and In Vitro Evaluation of Buccal Effervescent Tablet Containing Ropinirole Hydrochloride

The buccal delivery is an attractive route to improve the clinical efficacy of ropinirole hydrochloride (RH) for the treatment of Parkinson and restless syndrome since this drug undergoes extensive first-pass effect, which has only 50% bioavailability after oral administration. The purpose of this study was to develop and optimize the formulation of fast disintegrating buccal effervescent tablets of RH using four types of superdisintegrants. The direct compression method was used to develop four different formulas containing RH using Kyron T-314, crospovidone, croscarmellose sodium, and sodium starch glycolate separately as a superdisintegrant. Sodium bicarbonate and citric acid were added to the formulations to produce effervescence, while sodium carbonate was used as a pH adjusting agent. All the prepared formulas were evaluated, in terms of weight variation, friability, content dose uniformity, hardness, disintegration, and dissolution test. The best formulation was selected for the subsequent study. The obtained results from pre-compression studies were in acceptable range according to British Pharmacopoeia. All formulas passed through the quality control test and significant difference (P < 0.05) was observed for the formula four compared to other formulas, due to the presence of Kyron T-314 as a superdisintegrant in formulation number 4. RH cloud be prepared as a buccal effervescent tablet and superdisintegrant provide fast disintegration of the tablet to exert rapid action.