Designing a unique feedback mechanism for hydrogel-forming microneedle array patches: a concept study

Although microneedle array patch (MAP) technology is reaching ever closer to regulatory approval, it remains imperativethat approaches to further improve patient acceptance are still explored. Addressing this perception, a water-flled reservoirwas incorporated into a hydrogel-forming MAP system to provide a novel feedback mechanism. To confrm successful MAPskin insertion, the end user would both hear and feel the rupture of the water-flled reservoir. Interestingly, a 50-µL waterflled reservoir ruptured at 30.27±0.39 N, which has previously been shown as the mean application force for MN insertionin human subjects following appropriate instruction. Importantly, no signifcant diference in % cumulative permeation ofFITC-dextran 10 kDa and fuorescein sodium after 24 h was observed between a 50-µL reservoir and the current method ofapplication that has been successfully used in both in vitro and in vivo studies (p>0.05). Therefore, as drug delivery was notafected, this proof-of-concept study has shown that a water-flled reservoir feedback mechanism has the potential to serveas a viable tool for consistent MAP skin insertion

Influence of molecular weight on transdermal delivery of model macromolecules using hydrogel-forming microneedles: Potential to enhance the administration of novel low molecular weight biotherapeutics

With a view to improve the current monoclonal antibody-based therapies dominating the pharmaceutical market, low molecular weight (MW) protein-based macromolecules, such as recombinant antibody fragments, typically within the range of 10–70 kDa, have been developed. Previously, our group successfully delivered Avastin®, a monoclonal antibody (mAb) across the skin using hydrogel-forming microneedles (MN). However, it is thought that this delivery system can be further enhanced using novel, lower MW biomolecules. To address this perception, in the current study, FITC–dextran of different MWs (10, 70 and 150 kDa) was used to model the transdermal delivery of low MW biotherapeutics and mAbs with MWs of approximately 150 kDa. Conversely, fluorescein sodium was the compound selected to model hydrophilic, low MW drugs. As expected, fluorescein sodium produced the greatest cumulative permeation (637.4 ± 42.69 μg). The amounts of FITC–dextran 10 kDa and 150 kDa which permeated across neonatal porcine skin in vitro were 462.17 ± 65.85 μg and 213.54 ± 15.19 μg after 24 h, respectively. The results collated here suggest that the delivery of emerging novel biotherapeutics, via ‘super swelling’ hydrogel-forming MNs, have the potential to result in greater permeation across human skin, compared to the delivery of mAbs delivered via the same route

Enhancing the Transdermal Delivery of ‘Next Generation’ Variable New Antigen Receptors Using Microarray Patch Technology: a Proof-of-Concept Study

Heavy chain only binding proteins, such as variable new antigen receptors (VNARs), have emerged as an alternative to the highly successful therapeutic monoclonal antibodies (mAb). Owing to their small size (» 11 kDa)and single chain only architecture, they are amenable to modular reformatting and can be produced using inexpensive expression systems. Furthermore, due to their low molecular weight (MW) and high stability, theymay be suitable for alternative delivery strategies, such as microarray array patches (MAPs). In this study, thetransdermal delivery of ELN22-104, a multivalent anti-hTNF-a VNAR, was examined using both dissolving andhydrogel-forming MAPs. For dissolving MAPs, the cumulative in vitro permeation of ELN22-104 reached a plateau after 2 h (12.24 § 0.17 mg). This could be important for bolus dosing. Assessing two hydrogel-formingMAPs in vitro, PVP/PVA hydrogel-forming MAPs delivered significantly higher drug doses when compared to‘super swelling’ MAPs, equivalent to 43.13 § 10.36 mg and 23.13 § 5.66 mg, respectively (p < 0.05). Consequently, this study has proven that by modifying the MAP system, the transdermal delivery of a VNAR acrossthe skin can be enhanced. Furthermore, this proof-of-concept study has shown that transdermal delivery of‘next generation’ biotherapeutics is achievable using MAP technology

The Role of 3D Printing Technology in Microengineering of Microneedles

Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation of complex MN prototypes with high accuracy and offers customizable MN devices with a desired shape and dimension. Moreover, 3D printing shows great potential in producing advanced transdermal drug delivery systems and medical devices by integrating MNs with a variety of technologies. This review aims to demonstrate the advantages of exploiting 3D printing technology as a new tool to microengineer MNs. Various 3D printing methods are introduced, and representative MNs manufactured by such approaches are highlighted in detail. The development of advanced MN devices is also included. Finally, clinical translation and future perspectives for the development of MNs using 3D printing are discussed

HPLC-MS method for simultaneous quantification of the antiretroviral agents rilpivirine and cabotegravir in rat plasma and tissues

The antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) are approved as a combined treatmentregimen against human immunodeficiency virus (HIV). To fully understand the biodistribution of these agentsand determine their concentration levels in various parts of the body, a simple, selective and sensitive bioanalytical method is essential. In the present study, a high performance liquid chromatography method with mass spectrometry detection (HPLC-MS) was developed for simultaneous detection and quantification of RPVand CAB in various biological matrices. These included plasma, skin, lymph nodes, vaginal tissue, liver, kidneysand spleen, harvested from female Sprague Dawley rats. The suitability of the developed method for each matrixwas validated based on the guidelines of the International Council for Harmonisation of Technical Requirementsfor Registration of Pharmaceuticals for Human Use (ICH) on bioanalytical method validation. Analytes wereextracted from biological samples employing a simple one-step protein precipitation method using acetonitrile.Samples were analysed using an Apex Scientific Inertsil ODS-3 column (4.6 mm × 250 mm, 5 µm particle size),maintained at 40 ◦C, on a HPLC system coupled with a single quadrupole MS detector. RPV was detected at amass-to-charge ratio (m/z) of 367.4 and CAB at 406.3. Separation was achieved using isocratic elution at 0.3 mL/min with a mixture of acetonitrile and 0.1% (v/v) trifluoroacetic acid in water (81:19, v/v) as the mobile phase.The run time was set at 13 min. The presented method was selective, sensitive, accurate and precise for detectionand quantification of RPV and CAB in all matrices. The developed and validated bioanalytical method wassuccessfully employed for in vivo samples with both drugs simultaneously

Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy

Purpose Whilst signifcant progress has been made to defeat HIV infection, the efcacy of antiretroviral (ARV) therapyin the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectablenanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user.To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA andCAB LA via self-disabling dissolving microarray patches (MAPs).Methods Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, withvarious nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robustand were capable of penetrating ex vivo skin with intradermal ARV deposition.Results In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profles, with therapeuticallyrelevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study,repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout theduration of the study.Conclusions These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPVand CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one thatis capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis

Neutrino Quasielastic Scattering on Nuclear Targets: Parametrizing Transverse Enhancement (Meson Exchange Currents)

We present a parametrization of the observed enhancement in the transverse electron quasielastic (QE) response function for nucleons bound in carbon as a function of the square of the four momentum transfer ($Q^2$) in terms of a correction to the magnetic form factors of bound nucleons. The parametrization should also be applicable to the transverse cross section in neutrino scattering. If the transverse enhancement originates from meson exchange currents (MEC), then it is theoretically expected that any enhancement in the longitudinal or axial contributions is small. We present the predictions of the "Transverse Enhancement" model (which is based on electron scattering data only) for the $\nu_\mu, \bar{\nu}_\mu$ differential and total QE cross sections for nucleons bound in carbon. The $Q^2$ dependence of the transverse enhancement is observed to resolve much of the long standing discrepancy in the QE total cross sections and differential distributions between low energy and high energy neutrino experiments on nuclear targets.Comment: Revised Version- July 21, 2011: 17 pages, 20 Figures. To be published in Eur. Phys. J.

Extreme Ultra-Violet Spectroscopy of the Lower Solar Atmosphere During Solar Flares

The extreme ultraviolet portion of the solar spectrum contains a wealth of diagnostic tools for probing the lower solar atmosphere in response to an injection of energy, particularly during the impulsive phase of solar flares. These include temperature and density sensitive line ratios, Doppler shifted emission lines and nonthermal broadening, abundance measurements, differential emission measure profiles, and continuum temperatures and energetics, among others. In this paper I shall review some of the advances made in recent years using these techniques, focusing primarily on studies that have utilized data from Hinode/EIS and SDO/EVE, while also providing some historical background and a summary of future spectroscopic instrumentation.Comment: 34 pages, 8 figures. Submitted to Solar Physics as part of the Topical Issue on Solar and Stellar Flare

A CsI(Tl) Scintillating Crystal Detector for the Studies of Low Energy Neutrino Interactions

Scintillating crystal detector may offer some potential advantages in the low-energy, low-background experiments. A 500 kg CsI(Tl) detector to be placed near the core of Nuclear Power Station II in Taiwan is being constructed for the studies of electron-neutrino scatterings and other keV-MeV range neutrino interactions. The motivations of this detector approach, the physics to be addressed, the basic experimental design, and the characteristic performance of prototype modules are described. The expected background channels and their experimental handles are discussed.Comment: 34 pages, 11 figures, submitted to Nucl. Instrum. Method

From Coherent Modes to Turbulence and Granulation of Trapped Gases

The process of exciting the gas of trapped bosons from an equilibrium initial state to strongly nonequilibrium states is described as a procedure of symmetry restoration caused by external perturbations. Initially, the trapped gas is cooled down to such low temperatures, when practically all atoms are in Bose-Einstein condensed state, which implies the broken global gauge symmetry. Excitations are realized either by imposing external alternating fields, modulating the trapping potential and shaking the cloud of trapped atoms, or it can be done by varying atomic interactions by means of Feshbach resonance techniques. Gradually increasing the amount of energy pumped into the system, which is realized either by strengthening the modulation amplitude or by increasing the excitation time, produces a series of nonequilibrium states, with the growing fraction of atoms for which the gauge symmetry is restored. In this way, the initial equilibrium system, with the broken gauge symmetry and all atoms condensed, can be excited to the state, where all atoms are in the normal state, with completely restored gauge symmetry. In this process, the system, starting from the regular superfluid state, passes through the states of vortex superfluid, turbulent superfluid, heterophase granular fluid, to the state of normal chaotic fluid in turbulent regime. Both theoretical and experimental studies are presented.Comment: Latex file, 25 pages, 4 figure