The development of peptide-based pharmaceutics is a hot topic in the pharmaceutical industry and in basic research. However, from the research and development perspective there is an unmet need for new, alternative, solid-phase peptide synthesizers that are highly efficient, automated, robust, able to synthetize peptides in parallel, inexpensive (to obtain and operate), have potential to be scaled up, and even comply with the principles of green chemistry. Moreover, a peptide synthesizer of this type could also fill the gap in university research, and therefore speed the advancement of peptide-based pharmaceutical options. This paper presents a Tecan add-on peptide synthesizer (TaPSy), which has operational flexibility (coupling time: 15–30 min), can handle all manual synthesis methods, and is economical (solvent use: 34.5 mL/cycle, while handling 0.49 mmol scale/reactor, even with ≤3 equivalents of activated amino acid derivatives). Moreover, it can carry out parallel synthesis of up to 12 different peptides (0.49 mmol scale in each). TaPSy uses no heating or high pressure, while it is still resistant to external influences (operating conditions: atmospheric pressure, room temperature 20–40 ˚C, including high [>70%] relative humidity). The system's solvent can also be switched from DMF to a green and biorenewable solvent, γ-valerolactone (GVL), without further adjustment. The designed TaPSy system can produce peptides with high purity (>70%), even with the green GVL solvent alternative. In this paper we demonstrate the optimization path of a newly developed peptide synthesizer in the context of coupling reagents, reaction time and reagent equivalents applying for a synthesis of a model peptide. We compare the results by analytical characteristics (purity of raw material, crude yield, yield) and calculated overall cost of the syntheses of one mg of crude peptide using a specified set of reaction conditions.

Curcuminoids (CUs) of antitumor and various other potential biological activities have extremely low water solubility therefore special formulation was elaborated. New fast dissolving reconstitution dosage forms of four CUs were prepared as fibrous form of 2-hydroxypropyl-β-cyclodextin (HP-β-CD). In the electrospinning process HP-β-CD could act both as solubilizer and fiber-forming agent. The solubilization efficiency of the CU-HP-β-CD systems was determined with phase-solubility measurements. The electrospun CUs were amorphous and uniformly distributed in the fibers according to XRD analysis and Raman mappings. The fibrous final products had fast (<5 min) and complete dissolution. In typical iv. infusion reconstitution volume (20 mL) fibers containing 40-80 mg of CU could be dissolved, which is similar to the currently proposed dose (<120 mg/m2). The in vitro cytostatic effect data showed that the antitumor activity of the CU-HP-β-CD complexes was similar or better compared to the free APIs.

Laser Assisted Metal-Polymer Joining Technologies (LAMP) are widely used to create hybrid structures for different purposes. If the laser beam is transported to the connected surfaces from the polymer's side, the polymer has to be adequately transparent on the wavelength of the applied radiation to avoid degradation and to ensure effective and efficient adhesion. The transparency can be affected by the components and the structure of the polymer. The long-term goal of our research is to identify, assess and quantify the connection between the type and the amount of reinforcing fibers and the quality of metal-polymer joining. In this paper, we introduce the key findings of the first experiments aimed at joining steel and poly(methyl-methacrylate) reinforced with different amounts of cellulose fibers. We identified the optimal values of some laser technology parameters (e.g. power, velocity) that affect the strength and the visual appearance of joining.

Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate (AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate drug administration for patients with late-stage prostate cancer. Two four-sequence, four-period randomized crossover investigations were undertaken to establish the pharmacokinetic profiles of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS (250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng × h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large pills.

A bemutatott kutatásban lézersugárral felületkezelt acél minták ball-on-disk típusú koptató vizsgálatának eredményeit mutatjuk be. A lézeres felületkezeléssel létrehozott edzett és nikkel bázisú wolfram karbid tartalmú bevonatolt tárcsák koptató vizsgálatait végeztük el, azzal a céllal, hogy meghatározzuk a kopással szembeni ellenállás változását a kezeletlen acél alapanyagokhoz képest. A kapott eredményekből jól látható, hogy a lézerrel felületkezelt alapanyagok kopásállósága jobb volt, mint felületkezelés nélkül. Az eredményekben bemutatásra kerülnek jellegzetes kopási nyomok, kopási szélességek, mélységek, keresztmetszetek, a lekoptatott tömeg és a súrlódási együttható változása a különböző esetekben.

Target-independent packet processing languages support diverse hardware and software targets by generalizing over the set of primitive operations (extern-functions)available on the target. In P4, the language specification does not specify whether the invocation of an extern function is synchronous or asynchronous - supposedly synchronous by default. However, in some use cases, it makes more sense to invoke such functions in an asynchronous way and let the thread keep processing packets while the extern operation is being performed by a dedicated resource or accelerator device. In this paper, we propose a method for transparent description and efficient implementation of asynchronous extern function calls in P4-programmable software data planes. Our DPDK - based early prototype relies on the concept of coroutines used for saving packet contexts and manual switching between them. The overhead of the proposed solution is analyzed with a packet encryption case study.

Celecoxib (Celebrex®) is the only widely used NSAID that selectively inhibits the COX-2 isoenzyme. Celebrex® is absorbed slowly in the fasted state and food intake further delays absorption. In this work, an amorphous water dispersible granule formulation of celecoxib is described with in vitro characterization, preclinical and clinical data. The formulation exhibited very high passive permeability and apparent solubility, significantly outperforming the micronized celecoxib and the drug product Celebrex®. The granule formulation remained stable for at least 1 year in stability tests. In dog studies, tmax was 1 h with over 50% of Cmax reached within 15 min regardless of food intake. A phase 1 clinical trial was conducted with 12 volunteers at 100- and 200-mg doses. Celecoxib plasma concentrations reached 250 ng/ml, the effective therapeutic plasma level, in less than 15 min regardless of food or dose. The novel celecoxib formulation is rapidly absorbed, demonstrating the potential utility as an acute treatment offering advantages over the currently marketed product.

At the beginning of the research work we encountered two major problems. First, literature for laser beam machining of fibre cement is virtually zero. This fact does not exclude the research of the subject by others, of course, but it may in any case indicate its confidentiality (technological competitive advantage). Second, the exact composition of the fibre cement material is protected, but the boards we use are available from manufacturer by code number, so the experiment can be clearly reproduced. For this reasons, we have decided to use the rigid, classic Design of Experiments method. Based on our previous experience, the effect factors were chosen in the group of Laser power, Cutting velocity, Cutting gas pressure, Focal length, Laser frequency and Cutting gas type, at a total of 17 factor levels. The necessary and sufficient conditions are met by the 2-Factor-Interaction (2FI) fractional factorial experiments, instead of full factorial 6FI experiment series. Based on our very first experiments, it was found that the high-density composite fiber cement material can be cut with laser beam technology. Experiments and related visual and measurement responses clearly define the significant effect factors. The experiments proved our zero hypotheses, the "p-values", derived from the analysis of the response parameters, were below 0.05% (the significance limit usually is 0.1%), for each responses. We answered the questions of the fastest and cheapest technology lineup, to laser beam cut a composite fibre cement board to the desired size, with the expected quality. (C) 2019 Elsevier Ltd. All rights reserved.

Passive wheel speed sensors are widely used in automotive applications where knowledge of the rotational velocity of the rotating axes and resistant to environmental impacts are required. This paper presents a general introduction to wheel speed sensor systems and the underlying physical behaviour are explained with the help of three-dimensional time-stepping finite element method. The 3D field simulations well reflect the dynamics of the magnetic field of the real problem and they provide a quantitative understanding of the output signal behaviour concerning model parameter variations. The sensor geometry is analyzed in detail, featuring a study of the influence of the main parameters. As an outcome of parameter analysis, it was possible to determine the influence of the sensor parameters on the output signal of the sensor. In addition, this study aims to advance the understanding of the physical behaviour of passive wheel speed sensors by three-dimensional nonlinear finite element analysis, which is missing from the literature.

Modern welding processes that can easily be automated (such as friction stir welding, laser welding and ultrasonic welding) are gaining popularity in joining metal-polymer hybrid structures. This field of science is intensively studied around the globe, as a dependable, productive joining method that directly produces structurally sound joints between a metal and a polymer structure could unleash unforeseen possibilities in the vehicle industry. In our experiments, we manufactured hybrid steel-poly(methyl-methacrylate) (PMMA) joints with laser welding, using the 2p design of experiment method. We measured the effect of cellulose reinforcing fibres (in varying weight percentages) on the transparency and weldability of the PMMA material and the effect of welding parameters on the mechanical properties of the joints. We also examined the vicinity of the welded seam with scanning electron microscopy.

Sirolimus (Rapamune®) exhibits low bioavailability, high variability and moderate food effect following oral administration. This makes therapeutic blood monitoring of sirolimus concentrations necessary for kidney transplant patients. Furthermore, reaching therapeutic blood sirolimus concentrations in renal cancer patients was found to be challenging when the marketed drug was administered alone. A novel, nano-amorphous formulation of the compound was developed and its pharmacokinetic properties were investigated in a dose escalation study in a first-in-human clinical trial. The effect of food at the highest dose on the pharmacokinetic parameters was also assessed. Each group received one of the escalating doses (0.5–2–10–40 mg) of sirolimus as the novel formulation in the fasted state. Following a 2- to 3-week washout period, the 40-mg group then also received another 40 mg dose in the fed state. Sirolimus whole blood concentrations were determined for up to 48 h. To avoid degradation of sirolimus in the acidic environment in the stomach, 40 mg famotidine was administered 3 h pre-dose in all regimens. The main pharmacokinetic parameters were calculated and data were compared with pharmacokinetic data reported for dose escalation studies for Rapamune®. Thirty-two healthy volunteers were divided into 4 cohorts of 8 volunteers. Dose increments resulted in approximately dose-proportional increases of maximal plasma concentrations (Cmax) and area under the concentration–time curve (AUC)0–48 h up to 10 mg, while less than dose-proportional increases were observed when the dose was increased from 10 to 40 mg. Mean AUCinf at the 40 mg dose in the fasted state was 4,300 ± 1,083 ng·h/ml, which is 28% higher than the AUC reported following the administration of 90 (2 × 45) mg Rapamune® and 11% higher than the exposure reported for 25 mg intravenous pro-drug temsirolimus (3,810 ng·h/ml). At the 40 mg dose, food reduced Cmax by 35.5%, but it had no statistically significant effect on AUC. Inter-individual variability of the pharmacokinetic parameters mostly fell in the 20–30% (CV) range showing that sirolimus administered as the nano-amorphous formulation is a low-to-moderate variability drug. Based on the pharmacokinetic profiles observed, the nano-amorphous formulation could be a better alternative to Rapamune® for the treatment of mammalian target of rapamycin-responsive malignancies. Therapeutically relevant plasma concentrations and exposures can be achieved by a single 40 mg oral dose. Furthermore, the low variability observed might make therapeutic blood monitoring unnecessary for transplant patients taking sirolimus as an immunosuppressant.

e17036 Background: Zytiga (Abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect. This is attributed to the inadequate and variable dissolution of the compound in the gastrointestinal tract in the fasted state (Geboers, 2016). Recent clinical studies show that abiraterone trough concentration correlates with PSA response and PFS (Carton, 2015), while administration of Zytiga with food resulted in the reversal of PSA progression (Stover, 2015). Doubling the dose of Zytiga at the time of acquired resistance was not effective (Friedlander, 2017) most likely because Zytiga exposure is not linear above 1,000 mg resulting in only a little improvement in drug exposure. To resolve the low bioavailability and food effect we developed a novel AA formulation with improved solubility and dissolution characteristics (Solymosi, 2017) and evaluated its clinical pharmacokinetics and safety in healthy volunteers. Methods: The study was conducted in 11 healthy men aged 47–57 years. All subjects received 3 consecutive single doses of the novel formulation of AA (100 and 200 mg in the fasted state and 200 mg in the fed state). Data was compared with pharmacokinetic and safety data reported for 1,000 mg Zytiga, the marketed drug. Results: The novel formulation of AA allows rapid absorption of the compound with tmax values within one hour. Based on AUC values, a ~250 mg dose of the novel formulation is predicted to give the same exposure as 1,000 mg Zytiga in the fasted state. The significant positive food effect was also eliminated and the variability of exposure was significantly reduced when compared to published Zytiga data. AA administered in the novel formulation was well tolerated with no IMP related safety AEs reported. Conclusions: The novel formulation has two potentially advantageous properties: (1) allows 75% dose reduction with significant reduction of inter-individual variability and no significant positive food effect, and (2) the improved bioavailability could allow increased doses and drug exposures for patients and thereby improve the outcome of abiraterone acetate therapy. Clinical trial information: 2015-002759-83.

Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability. Abiraterone acetate is poorly water soluble which is believed to be responsible for its very low bioavailability in the fasted state and its significant positive food effect. In this work, we have successfully used in vitro dissolution, solubility and permeability measurements in biorelevant media to describe the dissolution characteristics of different abiraterone acetate formulations. Mathematical modeling of fraction dose absorbed indicated that reducing the particle size of the drug cannot be expected to result in significant improvement in bioavailability in the fasted state. In the fed state, the same formulation approach can result in a nearly complete absorption of the dose; thereby, further increasing the food effect. Using a "bottom-up" formulation method we improved both the dissolution rate and the apparent solubility of the compound. In beagle dog studies, this resulted in a ≫>10-fold increase in bioavailability in the fasted state when compared to the marketed drug and the elimination of the food effect. Calculated values of fraction dose absorbed were in agreement with the observed relative bioavailability values in beagle dogs.

Data plane compilation is a transformation from a high-level description of the intended packet processing functionality to the underlying data plane architecture. Compilation in this setting is usually done statically, i.e., the input of the compiler is a fixed description of the forwarding plane semantics and the output is code that can accommodate any packet processing behavior set by the controller at runtime. Below we advocate a dynamic approach to data plane compilation instead, where not just the semantics but the intended behavior is also also input to the compiler. We uncover a handful of runtime optimization opportunities that can be leveraged to improve the performance of custom-compiled datapaths beyond what is possible in a static setting.

Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics. The current study was performed to evaluate the pharmacokinetics and safety of this novel formulation in healthy volunteers.

OpenFlow is an amazingly expressive dataplane programming language, but this expressiveness comes at a severe performance price as switches must do excessive packet classification in the fast path. The prevalent OpenFlow software switch architecture is therefore built on flow caching, but this imposes intricate limitations on the workloads that can be supported efficiently and may even open the door to malicious cache overflow attacks. In this paper we argue that instead of enforcing the same universal flow cache semantics to all OpenFlow applications and optimize for the common case, a switch should rather automatically specialize its dataplane piecemeal with respect to the configured workload. We introduce ESwitch, a novel switch architecture that uses on-the-fly template-based code generation to compile any OpenFlow pipeline into efficient machine code, which can then be readily used as fast path. We present a proof-of-concept prototype and we demonstrate on illustrative use cases that ESwitch yields a simpler architecture, superior packet processing speed, improved latency and CPU scalability, and predictable performance. Our prototype can easily scale beyond 100 Gbps on a single Intel blade even with complex OpenFlow pipelines.