Global Regulatory Landscape for Aggregate Safety Assessments: Recent Developments and Future Directions.

Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments. We will show how these trends lead to opportunities for closer interdisciplinary collaboration, for bridging the gap between preand postmarketing surveillance, and for a more proactive determination of patient populations with a positive benefit-risk profile for product use. We will conclude by pointing to ongoing and future work that seeks to provide specific solutions for ongoing aggregate safety evaluation.

Sustained release carrier for adenosine triphosphate as signaling molecule.

Adenosine triphosphate (ATP) is a molecule with a fascinating variety of intracellular and extracellular biological functions that go far beyond energy metabolism. Due to its limited passive diffusion through biological membranes, controlled release systems may allow to interact with ATP-mediated extracellular processes. In this study, two release systems were explored to evaluate the capacity for either long-term or short-term release: (i) Poly[(rac-lactide)-co-glycolide] (PLGA) implant rods were capable of ATP release over days to weeks, depending on the PLGA molecular weight and end-group capping, but were also associated with partial hydrolytic degradation of ATP to ADP and AMP, but not adenosine. (ii) Thermosensitive methylcellulose hydrogels with a gelation occurring at body temperature allowed combining adjustable loading levels and the capacity for injection, with injection forces less than 50N even for small 27G needles. Finally, a first in vitro study illustrated purinergic-triggered response of primary murine microglia to ATP released from hydrogels, demonstrating the potential relevance for biomedical applications.

Understanding instability and rupture of poly(alkyl-2-cyanoacrylate) capsules.

INTRODUCTION: Poly(alkyl-2-cyanoacrylates) (PACAs) are degradable biomaterials that are clinically applied as surgical glue and studied as a matrix for particulate drug carriers such as nanoparticles or micro/nanocapsules. The stability of capsule walls is essential to avoid leakage of encapsulated compounds. METHODS: PACA capsules and (co)polymer films were prepared and characterization of their morphologies and thermal properties was performed. RESULTS: Thin-walled capsules that allow for a large internal volume to carry the payload were instable due to the high brittleness of PACA. Strategies to reduce the glass transition temperature (Tg) from values as high as ~ 120 °C included plasticization by solvents and copolymerization approaches. By using the latter, the Tg of commonly used n-butylcyanoacrylate could be reduced up to 30 K, following predictions of mixed-system glass transition temperatures obtained, for example, by the Fox equation. CONCLUSIONS: Thin-walled PACA capsules may allow for large payloads in the field of drug delivery and beyond, but require modifications of the PACA to improve capsule stability by more elastic capsule walls.