7 research outputs found
Erratum to: Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD
A comparison of drug transport in pulmonary absorption models: isolated perfused rat lungs, respiratory epithelial cell lines and primary cell culture
Purpose: To evaluate the ability of human airway epithelial
cell layers and a simple rat isolated perfused lung (IPL) model to predict pulmonary drug absorption in rats in vivo.
Method: The permeability of seven compounds selected to
possess a range of lipophilicity was measured in two airway
cell lines (Calu-3 and 16HBE14o-), in normal human bronchial
epithelial (NHBE) cells and using a simple isolated perfused
lungs (IPL) technique. Data from the cell layers and
ex vivo lungs were compared to published absorption rates
from rat lungs measured in vivo.
Results: A strong relationship was observed between the logarithm of the in vivo absorption half-life and the absorption half-life in the IPL (r = 0.97; excluding formoterol). Good log-linear relationships were also found between the apparent first-order absorption rate in vivo and cell layer permeability with correlation coefficients of 0.92, 0.93, 0.91 in Calu-3, 16HBE14o- and NHBE cells, respectively.
Conclusion: The simple IPL technique provided a good prediction of drug absorption from the lungs, making it a useful method for empirical screening of drug absorption in the lungs. Permeability measurements were similar in all the respiratory epithelial cell models evaluated, with Calu-3 having the advantage for routine permeability screening purposes of being readily availability, robust and easy to culture
A Biocompatible Synthetic Lung Fluid Based on Human Respiratory Tract Lining Fluid Composition
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A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery
The present study evaluates the effect of L-leucine concentration and operating parameters of a laboratory spray dryer on characteristics of trehalose dry powders, with the goal of optimizing production of these powders for inhaled drug delivery. Trehalose/L-leucine mixtures were spray dried from aqueous solution using a laboratory spray dryer. A factorial design of experiment (DoE) was undertaken and process parameters adjusted were: inlet temperature, gas flow rate, feed solution flow rate (pump setting), aspiration setting and L-leucine concentration. Resulting powders were characterised in terms of particle size, yield, residual moisture content, and glass transition temperature. Particle size was mainly influenced by gas flow rate, whereas product yield and residual moisture content were found to be primarily affected by inlet temperature and spray solution feed rate respectively. Interactions between a number of different process parameters were elucidated, as were relationships between different responses. The leucine mass ratio influenced the physical stability of powders against environmental humidity, and a high leucine concentration (30% w/w) protected amorphous trehalose from moisture induced crystallization. High weight ratio of leucine in the formulation, however, negatively impacted the aerosol performance. Thus, in terms of L-leucine inclusion in a formulation designed for pulmonary delivery, a balance needs to be found between physical stability and deposition characteristics
Inhaled formulation and device selection: bridging the gap between preclinical species and first-in-human studies
Hess deep plutonic crust: exploring the plutonic crust at a fast-spreading ridge: new drilling at Hess Deep
Integrated Ocean Drilling Program (IODP) Hess Deep Expedition 345 was designed to sample lower crustal primitive gabbroic rocks that formed at the fast-spreading East Pacific Rise (EPR) in order to test models of magmatic accretion and the intensity of hydrothermal cooling at depth. The Hess Deep Rift was selected to exploit tectonic exposures of young EPR plutonic crust, building upon results from ODP Leg 147 as well as more recent submersible, remotely operated vehicle, and near-bottom surveys. The primary goal was to acquire the observations required to test end-member crustal accretion models that were in large part based on relationships from ophiolites, in combination with mid-ocean ridge geophysical studies. This goal was achieved with the recovery of primitive layered olivine gabbros and troctolites with many unexpected mineralogical and textural relationships, such as the abundance of orthopyroxene and the preservation of delicate skeletal olivine textures. Site U1415 is located along the southern slope of an intrarift ridge within the Hess Deep Rift between 4675 and 4850 water depths. Specific hole locations were selected in the general area of the proposed drill sites (HD-01B-HD-03B) using a combination of geomorphology, seafloor observations, and shallow subsurface seismic data. A total of 16 holes were drilled. The primary science results were obtained from coring of two ~110 m deep reentry holes (U1415J and U1415P) and five single-bit holes (U1415E and U1415G-U1415I). Despite deep water depths and challenging drilling conditions, reasonable recovery for hard rock expeditions (15%-30%) was achieved at three 35-110 m deep holes (U1415I, U1415J, and U1415P). The other holes occupied during this expedition included two failed attempts to establish reentry capability (Holes U1415K and U1415M) and six jet-in tests to assess sediment thickness (Holes U1415A-U1415D, U1415F, and U1415L). Olivine gabbro and troctolite are the dominant plutonic rock types recovered at Site U1415, with minor gabbro, clinopyroxene oikocryst-bearing troctolite, clinopyroxene oikocryst-bearing gabbro, and gabbronorite. These rocks exhibit cumulate textures similar to those found in layered basic intrusions and some ophiolite complexes. All lithologies are primitive, with Mg# between 0.76 and 0.89, falling within the global range of primitive oceanic gabbros. Spectacular modal and/or grain size layering was prevalent in >50% of the recovered core, displaying either simple or diffuse boundaries. Magmatic foliation largely defined by the shape-preferred orientation of plagioclase and olivine is moderate to strong in intervals with simple modal layering but weak to absent in the troctolite series and largely absent in the multitextured lay-ered series. The abundance of orthopyroxene in these primitive rocks was unexpected and deviates from the standard model for mid-ocean-ridge basalt crystallization. Pres-ervation of delicate skeletal olivine grains suggests that at least part of the recovered section of the lower crust was not subjected to significant hypersolidus or subsolidus strain. The metamorphic mineral assemblages record the cooling of primitive gabbroic lithologies from EPR magmatic conditions (>1000°C) to zeolite facies conditions (2 km beneath the sheeted dike-plutonic transition and thus represents the lower half to a third of the EPR plutonic crust. The orientation of the magmatic fabrics and magnetic inclinations of the core suggest that Site U1415 is composed of a series of 30-65 m thick blocks that likely formed by mass wasting. Sampling three or four blocks of relatively fresh rocks proved advantageous, as it facilitated observations of two distinct types of layering and troctolite units with varying grain size, lithologic associations, and textures. The mineralogical and textural relationships show that in several respects the Oman ophiolite is not the ideal model for fast-spreading ocean crust and call into question some aspects of both of the end-member accretion models that were to be tested. The results of the IODP Hess Deep Expedition 345 provide a reference section for primitive fast-spreading lower crust that did not exist before. This highlights the necessity of ocean drilling to address questions related to the origin and evolution of the lower ocean crust