Brian K. Johnson

Flash nanoprecipitation of organic actives and block copolymers using a confined impinging jets mixer

Current address: Chemical Engineering R&D, Merck and Co., Rahway, NJ 07065, USA.A new technology to form nanoparticles of hydrophobic organic actives at high concentration and yield, as well asmethodstocharacterizetheprocess,arepresented.InFlashNanoPrecipitation,anorganicactiveandanamphiphilicdiblock copolymer are molecularly dissolved in an organic phase and mixed rapidly with a miscible anti-solvent toafford precipitation of the active with a tunable, narrow submicron particle size distribution from 1µmto80nm.The enabling components are a novel ‘analytical’(quantified mixing time) confined impinging jets (CIJ) mixer formillisecond stream homogenization and amphiphilic diblock copolymers which alter the organic nucleation andgrowth, provide steric stabilization for the particles, and offer a functional surface for the particle. Applications inenhanced pharmaceutical delivery, dye preparation, and pesticide formulation are specifically targeted.Manuscript received: 7 May 2003.Final version: 15 July 2003.Theproductionofsubmicronparticlesofhydrophobic,water-insoluble organic compounds at high solids loading is impor-tant in applications involving pharmaceuticals, dyes, andpesticides. For pharmaceuticals the rate of dissolution ofhydrophobic compounds can be controlled by the particlesurface area, and therefore the particle size. For drugs used incancer therapy the immature vasculature in the cancer tumorallows passive targeting of the drug if particle sizes are in therange of 100–200nm. In addition, all of the particles must bebelow 220nm to allow sterile filtration. The colour intensityfor pigments and insoluble dyes increases with decreasingparticle size, as does the resolution for ink jet printing appli-cations.While it is relatively easy to produce small inorganicparticles owing to their higher surface energy and charge sta-bilization,thoseoforganicsaresignificantlymoredifficult.

Long-term safety and tolerability of aripiprazole once-monthly in maintenance treatment of patients with schizophrenia.

The aim of this study was to evaluate the safety and tolerability of aripiprazole once-monthly (ARI-OM) for the maintenance treatment of schizophrenia. This long-term, pivotal study had four phases: oral conversion (phase 1, 4–6 weeks); oral stabilization (phase 2, 4–12 weeks); ARI-OM stabilization with coadministration of oral aripiprazole in the first 2 weeks (phase 3, 12–36 weeks); and a 52-week, randomized [phase 4, ARI-OM vs. placebo (2 : 1)], double-blind, maintenance phase. Safety was assessed across study phases by the time of first onset of adverse events, as were objective measures of extrapyramidal symptoms, fasting metabolic parameters, and body weight. Patient enrollment was phase 1=633; phase 2=710, of whom 210 entered phase 2 directly; phase 3=576; and phase 4=403 (ARI-OM, n=269; placebo, n=134). Adverse events (>5%) in any phase were insomnia, headache, anxiety, akathisia, increase in weight, injection-site pain, and tremor. Headache, somnolence, and nausea had a peak first onset within 4 weeks of treatment initiation. The incidence of extrapyramidal symptoms was similar in all phases. There were no unexpected changes in weight or shifts in fasting metabolic parameters across all study phases. ARI-OM had a safety and tolerability profile comparable with oral aripiprazole in maintenance treatment of schizophrenia.

Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study.

OBJECTIVE To evaluate efficacy, safety, and tolerability of long-acting injectable antipsychotic aripiprazole once-monthly 400 mg (AOM 400) as maintenance treatment for bipolar I disorder (BP-I). METHODS In a double-blind, placebo-controlled, 52-week randomized withdrawal study conducted from August 2012 to April 2016, patients with a DSM-IV-TR diagnosis of BP-I currently experiencing a manic episode were stabilized sequentially on oral aripiprazole and AOM 400 and then randomized to AOM 400 or placebo. The primary end point was time from randomization to recurrence of any mood episode. Other end points included proportion of patients with recurrence of any mood episode and recurrence by mood episode type. RESULTS Of 266 randomized patients, 64 (48.1%) of 133 in the AOM 400 group and 38 (28.6%) of 133 in the placebo group completed the study. AOM 400 significantly delayed the time to recurrence of any mood episode compared with placebo (hazard ratio: 0.45; 95% CI, 0.30 to 0.68; P < .0001). Significantly fewer patients (P < .0001) experienced recurrence of any mood episode with AOM 400 (35/132; 26.5%) compared with placebo (68/133; 51.1%), with the effects observed predominantly on manic episodes (P < .0001). Patients were not depressed at study entry, and between-group differences in depressive episodes were not significant (P < .864). The treatment-emergent adverse events (incidence > 5%) that were reported at higher rates with AOM 400 than placebo were weight increase, akathisia, insomnia, and anxiety. CONCLUSIONS AOM 400 delayed the time to and reduced the rate of recurrence of mood episodes and was generally safe and well tolerated. These findings support the use of AOM 400 for maintenance treatment of BP-I. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01567527.

Symptoms and functioning with aripiprazole once-monthly injection as maintenance treatment for bipolar I disorder

BACKGROUND Effects of maintenance treatment with aripiprazole once-monthly 400mg (AOM 400) on symptoms and functioning were assessed in adults with bipolar I disorder (BP-I) after a manic episode. METHODS Patients were stabilized on oral aripiprazole, cross-titrated to AOM 400, then randomized in a 52-week, double-blind, placebo-controlled, withdrawal phase. Prespecified secondary outcomes are reported: time to hospitalization for mood episode, Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression-Bipolar scale, Functioning Assessment Short Test (FAST), and Brief Quality of Life in Bipolar Disorder questionnaire. Time to hospitalization for mood episode was analyzed using log-rank test and changes from baseline using mixed model for repeated measures or analysis of covariance. RESULTS AOM 400 significantly increased time to hospitalization for any mood episode versus placebo (P=0.0002). YMRS total scores decreased with oral aripiprazole; improvements were maintained with AOM 400. After randomization, YMRS scores changed little with AOM 400 but worsened with placebo (P=0.0016), and MADRS scores, already low at trial initiation, did not differ between groups. FAST score improvements were maintained with AOM 400 but not placebo (P=0.0287). LIMITATIONS Results are generalizable to patients with BP-I stabilized on aripiprazole following a manic episode. CONCLUSIONS Patients with BP-I experiencing an acute manic episode exhibited symptomatic and functional improvements during stabilization with oral aripiprazole and AOM 400 that were maintained with continued AOM 400 treatment but not placebo. AOM 400 is the first once-monthly long-acting injectable antipsychotic to demonstrate efficacy in maintenance treatment of the manic phase of BP-I.

The Safety and Tolerability of Aripiprazole Once-Monthly as Maintenance Treatment for Bipolar I Disorder: A Double-Blind, Placebo-Controlled, Randomized Withdrawal Study

BACKGROUND Aripiprazole once-monthly 400 mg (AOM 400), an atypical long-acting injectable antipsychotic, has demonstrated efficacy and safety in maintenance treatment of bipolar I disorder (BP-I). We further assess safety and tolerability and characterize adverse events (AEs) across the duration of aripiprazole exposure. METHODS Patients with BP-I were stabilized on oral aripiprazole (2-8 weeks), AOM 400 (12-28 weeks), followed by 1:1 randomization of patients meeting stability criteria to a 52-week, double-blind, placebo-controlled withdrawal phase. Treatment-emergent AEs (TEAEs) were collected across study phases. AEs were counted in a phase if they were drug-related and continued from the baseline of that phase. A separate analysis on new-onset akathisia was conducted. RESULTS Among TEAEs occurring in ≥10% of patients during all study phases were akathisia (23.3%) and weight increased (10.6%). Median time to akathisia onset was 20 days after starting oral aripiprazole; median duration was 29 days for the first occurrence; 21/168 patients (12.5%) reporting akathisia experienced >1 episode. Episodes of new-onset akathisia decreased over time, with few events reported in the randomized phase. Weight gain was minimal with oral aripiprazole, generally starting within 3 months after the first AOM 400 injection, and appearing to plateau at 36 weeks. The mean weight gain within any study phase was ≤1.0 kg. Potentially clinically significant changes in metabolic parameters were uncommon. LIMITATIONS Patients on placebo had AOM 400 exposure before randomization. CONCLUSION These findings suggest that AEs with AOM 400 treatment were time-limited and support AOM 400 as a well-tolerated maintenance treatment of BP-I.

2277 – A placebo-controlled study of efficacy and safety of aripiprazole once-monthly for long-term maintenance treatment in schizophrenia

Objective Evaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia. Methods Patients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed. Results 710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p 5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders. Conclusions ARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia 1 .