The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs

Abstract

Context: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation.

Objective: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development.

Materials and methods: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal.

Results: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ～68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model.

Discussion: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds.

Conclusions: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.     

Probabilistic Seismic Hazard Assessment for Bridgetown-Barbados,Employing Subduction Interface Characteristic Earthquakes

A new probabilistic seismic hazard analysis was performed for the city of Bridgetown, Barbados, West Indies. Hazard computations have been performed using the standard Cornell-McGuire approach based on the definition of appropriate seismogenic sources and expected maximum magnitudes, the authors take into consideration the possibility of large subduction interface earthquakes of magnitude 8.0-9.0 beneath the Barbados accretionary prism via application of a characteristic model and slip rates. The analysis has been conducted using a standard logic-tree approach. Uniform hazard spectra have been calculated for the 5% of critical damping and the horizontal component of ground motion for rock site conditions setting 5 return periods （95, 475, 975, 2,475 and 4,975 years） and spectral accelerations for 34 structural periods ranging from 0 to 3 s. The disaggregation results suggest that the magnitude-distance pair that dominates the hazard yields M 7.4 and 8.6 and a distance of 42.5 km in the Interface Subduction Zone beneath Barbados for the 475 and 975 years RP （return period）, respectively. An event with an M 8.0 at a distance of 107.5 km in the Intraplate Subduction Zone is the second scenario that dominates the hazard for both 475 and 975 years RP.     

Water Resources: The Delaware Basin

Philadelphia is in competition with New York City and Baltimore in staking a claim for the water resources it will need in the next half century and beyond. A new governmental organization having a delegation of both state and federal powers for continuous planning and for unified management and control of the water resources of the entire Delaware River Basin has been proposed; and a federal-state compact for its establishment is being negotiated.     

Acid catalyst influence on the polymerization time of polyfurfuryl alcohol and on the porosity of monolithic vitreous carbon

This study compares the influence of different acid catalysts on the polymerization rate of polyfurfuryl alcohol (PFA) precursor and especially on the respective porosity of Monolithic Vitreous Carbon (MVC) produced from that. Five acid catalysts commonly used were compared: p‐toluenesulfonic (PTLS), hydrochloric, sulfuric, nitric, and phosphoric. A fixed molar concentration of catalyst was diluted in PFA resin under room pressure and temperature. The time dependence of PFA resin polymerization was investigated by optical transmittance of PFA films, and the polymerization degree, characterized by ATR spectroscopy and thermogravimetry. MVC samples prepared with the same PFA resin and each catalyst were carbonized up to 1200 °C, under inert atmosphere. MVC porosity was studied by nitrogen adsorption/desorption, and by SEM and optical microscopy. Higher polymerization degree and higher residual mass were obtained with faster catalysts. No direct relation between the polymerization rate and the acid force was observed. PTLS promoted the fastest PFA polymerization process and the sulfuric acid, the slowest one. MVC samples were obtained by slow carbonization. MVC presented low specific surface S_BET from 1.4 to 7.4 m²/g. Nitric acid catalyst contributed the most to micropores formation. Micrometric apparent porosity was smaller for the catalysts having longer polymerizations times, such as phosphoric and sulfuric acid. Phosphoric catalyst corresponded to the lowest porosity in MVC. As the polymerization time increased, the average size of the micrometric surface pores tended to augment. The MVC macroscopic porosity increased with the S_BET increment. Acid catalysts choice exerted a fundamental role on the porosity of MVC. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43272.     

Laser pyrolyzed organosilazane-based Al/ZrO2 composite coating on stainless steel: Resulting microstructure and mechanical properties

Protective ceramic-based coatings are frequently the most suitable solutions for problems like corrosion and wear. It has been shown that the precursor technology is suitable for the preparation of ceramic coatings by pyrolysis in a furnace. However, the required high temperature for the preparation of the ceramic coatings limits this approach to high temperature-resistant substrates. A very innovative approach to overcome this restriction is the use of laser radiation as a thermal source for the pyrolysis of the preceramic polymer. In this paper, we report on a coating system, for steel substrates, consisting of a polysilazane (Durazane 2250) bond coat and a hard and dense top-coat composed of an organosilazane (Durazane 1800) with tetragonal ZrO₂ particles and aluminum flakes as fillers pyrolyzed using Nd:YVO₄ laser. The aluminum fillers led to a significant increase in absorption of the laser energy leading to the formation of a dense coating with a thickness up to 20 μm and a mainly cellular/columnar-dendritic microstructure. The microstructure, mechanical, and tribological behaviors of these composite coatings are reported and compared to those of laser pyrolyzed glass/ZrO₂-filled polysilazane-based coatings reported in the literature.     

Short fiber-reinforced oxide fiber composites

This paper presents a novel fiber spraying process for the manufacturing of short fiber bundle-reinforced Nextel™ 610/Al₂O₃-ZrO₂ oxide fiber composites (SF-OFC) and its characterization. First, the influence of varying fiber lengths (7, 14, and 28 mm, continuous fibers) and fiber orientations (unidirectional 0°, quasi-isotropic, ±45°) was investigated using hand-laid SF-OFC. Due to the weak matrix, the hand-laid material exhibited a strongly fiber-dominated material behavior, that is, variations in fiber length and orientation had a strong influence on the material properties. Second, the automated sprayed SF-OFC, however, exhibited a random orientation of the fiber bundles, which resulted in in-plane isotropic material properties. Average bending strengths of up to 177 MPa, strains of .39%, and a quasi-ductile fracture behavior were achieved. The strain was, therefore, in the range of fabric-reinforced OFC. While the bending strength of the SF-OFC was somewhat lower than that of fabric-reinforced OFC with the fiber orientation parallel to the loading direction, it was more than two times higher than the strength in 45° direction relative to the fabric reinforcement. Combined with good drapability and lower material costs compared to fabric-reinforced OFC, SF-OFC is, therefore, a promising material for industrial applications.