Impact of ethanol on continuous inline diafiltration of liposomal drug products.

Liposomal drug products are playing an increasing role in the field of drug delivery. With this increased demand comes the need to increase the capabilities and capacity of manufacturing options. Continuous manufacturing techniques present a significant opportunity to address these needs for liposomal manufacturing processes. Liposomal formulations have unique considerations that impact translation from batch to continuous process designs. This article examines aspects of converting to a continuous design that were previously viewed as inconsequential in a batch process. The batch process involves the removal of ethanol (EtOH) through tangential flow filtration (TFF). EtOH was found to reduce the permeability of the hollow fibers used for TFF. This effect was determined to have minimal impact on the overall batch process design but considerable influence on the design of continuous TFF such as inline diafiltration (ILDF). Using a pilot scale setup, EtOH was found to decrease permeability in an inverse manner to EtOH concentration. Further assessment found that dilution of the EtOH levels prior to diafiltration can significantly reduce the amount of ILDF stages needed and that a continuous design requires less buffer to the commensurate batch design.

Absence of long-term structural and functional cardiac abnormalities on multimodality imaging in a multi-ethnic group of COVID-19 survivors from the early stage of the pandemic.

Aims: Many patients with coronavirus disease-2019 (COVID-19), particularly from the pandemic's early phase, have been reported to have evidence of cardiac injury such as cardiac symptoms, troponinaemia, or imaging or ECG abnormalities during their acute course. Cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) have been widely used to assess cardiac function and structure and characterize myocardial tissue during COVID-19 with report of numerous abnormalities. Overall, findings have varied, and long-term impact of COVID-19 on the heart needs further elucidation. Methods and results: We performed TTE and 3 T CMR in survivors of the initial stage of the pandemic without pre-existing cardiac disease and matched controls at long-term follow-up a median of 308 days after initial infection. Study population consisted of 40 COVID-19 survivors (50% female, 28% Black, and 48% Hispanic) and 12 controls of similar age, sex, and race-ethnicity distribution; 35% had been hospitalized with 28% intubated. We found no difference in echocardiographic characteristics including measures of left and right ventricular structure and systolic function, valvular abnormalities, or diastolic function. Using CMR, we also found no differences in measures of left and right ventricular structure and function and additionally found no significant differences in parameters of tissue structure including T1, T2, extracellular volume mapping, and late gadolinium enhancement. With analysis stratified by patient hospitalization status as an indicator of COVID-19 severity, no differences were uncovered. Conclusion: Multimodal imaging of a diverse cohort of COVID-19 survivors indicated no long-lasting damage or inflammation of the myocardium.

An exploratory investigation of the influence of publication on translational medicine research.

BACKGROUND: Changes in clinical practice are brought about by the weight of clinical evidence for and against an intervention. Clinical evidence of efficacy relies on the dissemination of research results, usually by publication in medical journals which is often seen as a pre-requisite for progression of an intervention through further clinical trials or implementation studies. HOW FAR HAS RESEARCH PROGRESSED ALONG THE TRANSLATIONAL PATHWAY?: We undertook an exploratory exercise to determine where basic and translational medical research is currently published. Original research articles (329 in total) published in high impact general and specialist medical journals were classified into different stages of research within the translational medicine pathway. WHERE IS TRANSLATIONAL RESEARCH PUBLISHED?: The general medical journals had the broadest spread of published research over the translational pathway. The specialist journals tended to be positioned to disseminate the research findings of early stage translational research from basic science results through to early stages of clinical testing. CONCLUSION: It is not possible for one journal to satisfy all the needs of the reader and the author along the translational medicine pathway. For an intervention to progress along the translational pathway background information should be readily accessible in the article. This pathway is currently being actively managed by the funding agencies but the next challenge is to ensure the pathway operates efficiently and does not allow promising innovations to languish and to provide a smoother transition for interventions to reach the clinic in a quicker timescale. It is clear that the dissemination of results in the right place at the right time is crucial to the transition of an intervention from the laboratory to clinical practice.

Does fluoxetine improve recovery after stroke?

The studyFOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet 2019;393:256-74.The study was funded by the UK Stroke Association and the NIHR Health Technology Assessment Programme project number 13/04/30.To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000729/a-commonly-used-antidepressant-doesnt-improve-recovery-after-stroke.

People with chronic obstructive pulmonary disease exacerbations prefer early discharge, then treatment at home.

The studyHome treatment of COPD exacerbation selected by DECAF score: a non-inferiority, randomised controlled trial and economic evaluationEchevarria C, Gray J, Hartley T, Miller J, Simpson AJ, Gibson GJ, Bourke SCPublished on 24 April 2018 Thorax 2018;73:713-22This project was funded by the National Institute for Health Research-Research for Patient Benefit Programme (project number PB-PG-0213-30105).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000691/hospital-at-home-treatment-for-copd-flare-ups.

Can treating vitamin D deficiency reduce exacerbations of chronic obstructive pulmonary disease?

The studyJolliffe D, Greenberg L, Hooper R, Mathyssen C, Rafiq R, de Jongh R, Camargo C, Griffiths C, Janssens W, Martineau A. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019. doi:10.1136/thoraxjnl-2018-212092This project was funded by the National Institute for Health Research Health Technology Appraisal programme (project number 13/03/25).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000737/treating-vitamin-d-deficiency-may-reduce-exacerbations-of-copd.

Negative pressure dressings are no better than standard dressings for open fractures.

The studyEffect of negative pressure wound therapy vs standard wound management on 12-month disability among adults with severe open fracture of the lower limb: the WOLLF randomised clinical trial.Costa ML, Achten J, Bruce J, et al; UK WOLLF CollaborationPublished on 9 October 2018 JAMA 2018;319:2280-8.This project was funded by the National Institute for Health Research Health Technology Assessment Programme (project number 10/57/20).To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000655/negative-pressure-dressings-are-no-better-than-standard-dressings-for-open-fractures.

Laser eye procedure is safe and effective as an early treatment for glaucoma.

The studyGazzard G, Konstantakopoulou G, Garway-Heath E, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet 2019; doi:10.1016/S0140-6736(18)32213-XThis project was funded by the NIHR Health Technology Assessment Programme (project number 09/104/40) and was sponsored by the Moorfields Eye Hospital NHS Foundation Trust.To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000774/early-glaucoma-laser-eye-treatment-trabeculoplasty.

Routine use of progesterone does not prevent miscarriage.

The studyCoomarasamy A, Devall AJ, Cheed V, et al. A randomised trial of progesterone in women with bleeding in early pregnancy N Engl J Med 2019;380:1815-24.This project was funded by the NIHR Health Technology Assessment Programme (project number 12/167/26).To read the full NIHR Signal, go to https://discover.dc.nihr.ac.uk/content/signal-000792/miscarriage-not-prevented-by-routine-use-of-progesterone.

Potential of Continuous Manufacturing for Liposomal Drug Products.

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits (e.g., improved economics, more consistent quality) that come with continuous processing. If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This paper reviews the current state of continuous manufacturing technology applicable to liposomal drug product manufacturing and an assessment of the challenges and potential of this application.