En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase-2 as a Target for Kunitz-Type Inhibitors.

The cell-surface serine protease matriptase-2 is a critical stimulator of iron absorption by negatively regulating hepcidin, the key hormone of iron homeostasis. Thus, it has attracted much attention as a target in primary and secondary iron overload diseases. Here, we have characterised Kunitz-type inhibitors hepatocyte growth factor activator inhibitor 1 (HAI-1) and HAI-2 as powerful, slow-binding matriptase-2 inhibitors. The binding modes of the matriptase-2-HAI complexes were suggested by molecular modelling. Different assays, including cell-free and cell-based measurements of matriptase-2 activity, determination of inhibition constants and evaluation of matriptase-2 inhibition by analysis of downstream effects in human liver cells, demonstrated that matriptase-2 is an excellent target for Kunitz inhibitors. In particular, HAI-2 is considered a promising scaffold for the design of potent and selective matriptase-2 inhibitors.

Multichannel terahertz time-domain spectroscopy system at 1030 nm excitation wavelength.

We present Terahertz (THz) imaging with a 1D multichannel time-domain spectroscopy (TDS) system which operates with a photoconductive array of 15 detection channels excited by a 1030 nm femtosecond fiber laser. The emitter and detector are photoconductive antennas based on InGaAs/InAlAs multi-layer heterostructures (MLHS). We characterized the THz optics and the resolution of the system. The performance is demonstrated by the multichannel imaging of two samples. A simultaneous measurement of 15 THz pulses with a pixel pitch of 1 mm increases the measurement speed of the TDS system by factor 15.

Towards better understanding of the influence of process parameters in roll compaction/dry granulation on throughput, ribbon microhardness and granule failure load.

A key quality attribute for solid oral dosage forms is their hardness and ability to withstand breaking or grinding. If the product is to be manufactured continuously, it can be of interest to monitor the hardness of the material at different stages of manufacturing. Using the controlled process parameters of roll compaction/dry granulation specific compaction force, roll speed and gap width, hardness of the resulting ribbons and granules can be predicted. For the first time, in this study two yield variables (corrected torque of the granulation unit and throughput of material) are used to predict the granules failure load. The increase in granule hardness was monitored in-line when the specific compaction force was increased during the compaction process. This opens the way for in-line control of material hardness, and its use for feedback and feedforward control loops for future continuous manufacturing processes.

Combination of a rotating tube sample divider and dynamic image analysis for continuous on-line determination of granule size distribution.

The granule size distribution is a critical quality attribute of granules. It has a great impact on further packaging or processing. Due to increasing interest in continuous manufacturing techniques, it is of high interest to develop an in-line or on-line tool to monitor the granule size distribution. However, development of an in-line measurement tool for granule size distribution was challenging since large throughput and inhomogeneous product stream are limiting factors for current particle size analyzers. In this study, continuous sampling was tested in conjunction to a continuous on-line method of size determination using dynamic image analysis. A rotating tube sample divider was used to split previously compacted material in representative samples at different ratios and the sample was directly conveyed to the particle size analyzer where the granule size distribution was determined. The method was tested for different granule sizes to determine limits of detection and its ability to detect these changes immediately, as this enables real-time monitoring of the process. This research is the base for development of control tools concerning the granule size distributions for continuous granulation processes.

How relevant is ribbon homogeneity in roll compaction/dry granulation and can it be influenced?

A homogeneous distribution of solid fraction in ribbons is generally assumed to be beneficial during roll compaction/dry granulation. Numerous attempts have been made to increase this homogeneity by modification of the machine, i.e. the roll design and the design of the feeding unit. It has however not been critically tested how relevant this homogeneity really is during subsequent processing. This study investigated two resulting questions: How can process parameters used to increase homogeneity in ribbons and how relevant is this homogeneity for properties of resulting tablets? For that, a statistically designed experiment were performed and ribbon homogeneity analyzed using X-ray micro-computed tomography. Independent from the sealing system used during manufacturing, larger gap widths led to higher homogeneity. The effect of specific compaction force was strongly dependent on the sealing system. When using the cheek plate system, higher specific compaction forces decreased the ribbon homogeneity, while it had no influence when rim rolls were used. In a subsequent study, ribbons of different homogeneity were milled and the resulting granules compressed to tablets. Tablets from homogeneous and inhomogeneous ribbons showed comparable strength and tablet mass variability. Reduced tabletability from highly densified regions of inhomogeneous ribbons was compensated by higher amounts of fines which originate from the more porous regions of ribbons. It was concluded that the relevance of ribbon homogeneity in roll compaction might generally be overestimated.