Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Trends of microneedle technology in the scientific literature, patents, clinical trials and internet activity.

The powerful and intriguing idea that drives the emerging technology of microneedles-shrinking the standard needle to a micron scale-has fostered an entire field of microneedle study and subsequent exponential growth in research and product development. Originally enabled by microfabrication tools derived from the microelectronic industry, microneedles are now produced through a number of methods in a variety of forms including solid, coated, dissolvable, and hollow microneedles. They are used to deliver a broad spectrum of molecules, including small molecules, biomolecules, and vaccines, as well as various forms of energy into the skin, eye, and other tissues. Microneedles are also being exploited for use in diagnostics, as well as additional medical, cosmetic, and other applications. This review elucidates the relative roles of different aspects of microneedle technology development, as shown through scientific papers, patents, clinical studies, and internet/social media activity. Considering >1000 papers, 750 patents, and almost 80 clinical trials, we analyze different attributes of microneedles such as usage of microneedles, types of microneedles, testing environment, types of patent claims, and phases of clinical trials, as well as which institutions and people in academia and industry from different locations and in different journals are publishing, patenting, and otherwise studying the potential of microneedles. We conclude that there is robust and growing activity in the field of microneedles; the technology is rapidly developing and being used for novel applications to benefit human health and well-being.

Enzymatically oxidized phospholipids restore thrombin generation in coagulation factor deficiencies.

Hemostatic defects are treated using coagulation factors; however, clot formation also requires a procoagulant phospholipid (PL) surface. Here, we show that innate immune cell-derived enzymatically oxidized phospholipids (eoxPL) termed hydroxyeicosatetraenoic acid-phospholipids (HETE-PLs) restore hemostasis in human and murine conditions of pathological bleeding. HETE-PLs abolished blood loss in murine hemophilia A and enhanced coagulation in factor VIII- (FVIII-), FIX-, and FX-deficient human plasma . HETE-PLs were decreased in platelets from patients after cardiopulmonary bypass (CPB). To explore molecular mechanisms, the ability of eoxPL to stimulate individual isolated coagulation factor/cofactor complexes was tested in vitro. Extrinsic tenase (FVIIa/tissue factor [TF]), intrinsic tenase (FVIIIa/FIXa), and prothrombinase (FVa/FXa) all were enhanced by both HETE-PEs and HETE-PCs, suggesting a common mechanism involving the fatty acid moiety. In plasma, 9-, 15-, and 12-HETE-PLs were more effective than 5-, 11-, or 8-HETE-PLs, indicating positional isomer specificity. Coagulation was enhanced at lower lipid/factor ratios, consistent with a more concentrated area for protein binding. Surface plasmon resonance confirmed binding of FII and FX to HETE-PEs. HETE-PEs increased membrane curvature and thickness, but not surface charge or homogeneity, possibly suggesting increased accessibility to cations/factors. In summary, innate immune-derived eoxPL enhance calcium-dependent coagulation factor function, and their potential utility in bleeding disorders is proposed.

Self-assembled carrageenan/protamine polyelectrolyte nanoplexes-Investigation of critical parameters governing their formation and characteristics.

The aim of this work was to investigate the feasibility of cross-linker free polyelectrolyte complex formation at the nanoscale between carrageenan (CAR) and protamine (PROT). The properties of CAR/PROT nanoparticles (NPs) were dependent on the carrageenan type: kappa (KC), iota (IC) and lambda (LC), concentration of components, addition of divalent cations, weight mixing ratio (WMR) of constituents and mode of component addition. In the case of 0.1% w/v solutions, IC-based NPs had the smallest particle sizes (100-150nm) and low polydispersity indices (0.1-0.4). A decrease in the solution concentration from 0.1% to 0.05% w/v enabled the formation of KC/PROT NPs. All carrageenans exhibited the ability to form NPs with surface charge ranging from -190 to 40mV. The inclusion of divalent cations caused an increase in the particle size and zeta potential. Infrared analysis confirmed the presence of a complex between CAR and PROT and showed that IC chains undergo structural changes when forming NPs. Colloidal stability of NPs was related to the initial surface charge of particles and was time- and pH-dependent. IC was found to be the most suitable type of CAR when forming nanoplexes with PROT.