Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.

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The effect of particle size distribution (PSD) on local voidage has been investigated in a conical fluidized bed containing dried placebo pharmaceutical granule. For each of the five PSDs examined, the static bed height was varied between 0.12 and 0.17 m and the superficial gas velocity was varied between 0.05 and 0.75 m/s. The local voidage was measured using a twin-plane electrical capacitance tomography (ECT) system. A wide PSD containing 12 wt% solids with a 1273 diameter of 2 mm or larger resulted in two different types of gas flow: an annular gas flow up to a gas velocity of 0.50 m/s and a centrally concentrated gas flow above 0.50 m/s. The mixtures containing less coarse material exhibited a centrally concentrated gas flow surrounded by a dense phase at the walls of the bed over the entire range of gas velocities and bed heights examined. Consideration of previous work by other researchers suggests that the behavior of the wide PSD mixture is due to segregation at the lower velocities. The local voidage was sensitive to small changes in static bed height. For the wide PSD mixture at a fixed gas velocity, the gas tended to spread more uniformly over the bed crosssection as static bed height increased. The opposite was true of the other mixtures, i.e., the gas flow became more centralized with increasing bed height.

Electrical capacitance tomographic data collected in a lab-scale fluidized bed used for the drying of pharmaceutical granule have been corrected for the influence of moisture on the permittivity of the drying material. The correction is based on a linear least-squares fit to measurements of capacitance in a packed bed of granule at various moisture contents. X-ray tomography has been used to independently verify this correction procedure. The influence of permittivity models and number of iterations used for the reconstruction of tomograms have also been examined. It has been determined that the Böttcher permittivity model performs best at bed moistures above approximately 5 wt% while the parallel model is superior at bed moisture below this value. The reconstruction technique based on iterative linear back-projection utilized for the reconstruction of ECT data required approximately 50 iterations to successfully reproduce the density behaviour seen in the x-ray tomographs. Instability in the reconstruction technique at higher numbers of iterations indicates that a linear least-squares fit does not completely capture the response of the sensor to moisture changes. For future applications, changes in bed voidage associated with the drying of pharmaceuticals must be addressed and included in this calibration procedure in order to implement this calibration technique throughout the drying process. Nevertheless, the viability of this technique for on-line calibration of an ECT sensor applied to the drying process has been demonstrated.

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Pressure fluctuation measurements collected during the fluidized bed granulation of pharmaceutical granule have been analyzed using the attractor comparison technique denoted as the S-statistic. Divergence of the bed state from the reference during granulation is followed by a return to a condition statistically similar to the original state of the dry fluidized ingredients on drying. This suggests insensitivity of the S-statistic technique to the changes in particle size distribution occurring during the granulation process. Consequently, the monitoring of pressure fluctuations alone may provide an easily implemented technique for the tracking of granule moisture and process end-point determination.