Exploring the relationship between bulk Young's Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds.

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.

Current status of pathogen handling in European laboratories: focus on viral inactivation process.

For handling safely infectious agents, European laboratories must comply with specific EC Directives, national regulations and recommendations from the World Health Organization (WHO). To prevent laboratory acquired infections (LAIs) and pathogens dissemination, a key biosafety rule requires that any infectious material (clinical specimens or research samples) manipulated outside a biosafety cabinet (BSC) must be inactivated unless the lack of infectivity is proven. This inactivation process is a crucial step for biosafety and must be guided by a rigorous experimental qualification and validation procedure. However, for diagnostic or research laboratories, this process is not harmonized with common standard operation procedures (SOPs) but based on individual risk assessment and general international guidelines which can pose problems in emergency situations such as major outbreaks or pandemics. This review focuses on viral inactivation method, outlining the current regulatory framework, its limitations and a number of ways in which biosafety can be improved.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

Impact of long-acting injectable antipsychotics vs. oral medication on relapses of patients with psychosis and bipolar disorder.

Relapse associated with multiple hospital readmissions of patients with chronic and severe mental disorders, such as psychosis and bipolar disorder, is frequently associated with non-adherence to treatment. The primary aim of the study was to compare the effectiveness of long-acting injectable (LAI) treatment, vs. oral medication in reducing readmissions of patients with psychotic or bipolar disorder in a community sample of 164 patients with psychosis and 29 patients with bipolar disorder (n = 193), with poor adherence to oral medication. The mean follow up period was 5.6 years and the number of readmissions were compared for an equal-length period of oral treatment preceding the onset of LAI administration. We observed a significant decrease of 45.2 % in total hospital readmissions after receiving LAIs treatment. The effect was significant both for patients with a pre-LAI treatment history of predominantly voluntary hospitalizations and with predominantly involuntary admissions. In addition, we observed equal effectiveness of first- vs. second-generation LAIs in reducing total hospital readmissions regardless of type of pre-treatment admission history (voluntary vs. involuntary). LAIs appear to be effective in reducing both voluntary and involuntary hospital readmissions in patients with psychosis and bipolar disorder with a history of poor adherence to treatment.

Long-Acting Injectable Antipsychotics-A Review on Formulation and In Vitro Dissolution.

Long-acting injectable (LAI) neuroleptics constitute an effective therapeutical alternative for individuals suffering from persistent mental illness. These injectable pharmaceuticals help patients manage their condition better and improve long-term outcomes by preventing relapses and improving compliance. This review aims to analyse the current formulation aspects of LAI neuroleptics, with particular emphasis on analysis of drug release profiles as a critical test to guarantee drug quality and relevant therapeutical activity. While there is no officially approved procedure for depot parenteral drug formulations, various dissolution tests which were developed by LAI manufacturers are described. In vitro dissolution tests also possess a critical function in the estimation of the in vivo performance of a drug formulation. For that reason, thorough inspection of the in vitro-in vivo correlation (IVIVC) is also discussed.