ANCA-associated vasculitis in childhood: Recent advances

Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort

Characterization of the Mechanisms of Drug Release from Polymer-Coated Formulations using Experiments and Modelling

The main objectives of the work presented in this thesis were to develop new experimental methods to improve the understanding of the release mechanism from a coated formulation and to develop new mechanistic models to describe the release process for pellets coated with a semi-permeable film. Another aim was to characterize the release mechanism from a formulation coated with films made of a blend of a water-insoluble polymer, ethyl cellulose (EC), and a water-soluble polymer, hydroxypropyl cellulose (HPC). The work dealt with free films intended for coating and with coated multiple-unit systems. Two methodologies were mainly used in the study of free films. Electronic speckle pattern interferometry made it possible to discriminate between a semi-permeable and a permeable film. For a permeable film, the effective diffusion coefficient of a drug in the film was determined. A new release cell equipped with a manometer was developed. The combination of pressure and release data made it possible to easily and accurately characterize the release mechanism, to discriminate between semi-permeable and permeable films, and to detect changes in the structure of the film and in the release mechanism during the release. A mechanistic model describing the lag phase of pellets coated with a semi-permeable film undergoing cracking due to hydrostatic pressure build-up was developed. The model was validated against experimentally determined whole-dose release profiles of pellets coated with an EC-based film. The model showed that a small variation in the film thickness has a significant influence on the lag time. A mechanistic model to describe the osmotic pumping release from pellets coated with a semi-permeable film containing water-filled channels was also developed. The model was validated by comparison with experimentally determined release profiles of single pellets coated with a film made of EC and HPC. Via model simulation it was found that the concentration profile in the channels was almost constant. The HPC content of EC/HPC films affects the amount of HPC leached out of the films, and thus the release mechanism. The release mechanism changed from osmotic pumping to diffusion as the amount of HPC increased. When release occurs by diffusion, the effective diffusion coefficient of a drug in the coating is not constant but increases significantly during the release process as a consequence of HPC leaching

The use of holographic interferometry and electron speckle pattern interferometry for diffusion measurement in biochemical and pharmaceutical engineering applications

In this review holographic interferometry and electron speckle pattern interferometry are discussed as efficient techniques for diffusion measurements in biochemical and pharmaceutical applications. Transport phenomena can be studied, quantitatively and qualitatively, in gels, liquids and membranes. Detailed information on these phenomena is required to design effective chromatography bioseparation processes using gel beads or ultrafiltration membranes, and in the design of control led-release pharmaceuticals using membrane-coated pellets or tablets. The influence of gel concentration, ion strength in the liquid and the size of diffusing protein molecules can easily be studied with good accuracy. When studying membranes, the resistance can be quantified, and it is also possible to discriminate between permeable and semi-permeable membranes. In this review the influence of temperature, natural convection and light deflection on the accuracy of the diffusion measurements is also discussed. (c) 2008 Elsevier Ltd. All rights reserved

Electronic speckle pattern interferometry: A novel non-invasive tool for studying drug transport rate through free films

In this work, Electronic Speckle Pattern Interferometry (ESPI) is presented as a non-invasive tool to study drug transport in controlled release systems. ESPI is shown to be a feasible tool to measure drug film permeability via comparison with an ordinary diaphragm cell. A specially designed cuvette was used in the release study: the polymeric film separated the donor and the receiving chambers of the cuvette to create a diffusion cell with no mixing in the two chambers. Thus, the cuvette mimicked a coated system immersed in a stagnant bulk liquid. Concentration profile data were obtained for the two compartments. Using these data, it was possible to visually discriminate between a film subject only to diffusion and a film subject to diffusion as well as osmotic effects. Moreover, using the concentration profile data collected at different time intervals, it was possible to follow the film properties in terms of drug permeability, thus studying bow drug permeability depended on drug concentration. Compared to other measuring techniques, ESPI offers the advantages that no invasive measurements are needed, and that no sampling and calibration are required. Furthermore, the permeability can be measured with no influence of mass transfer in the boundary layers. (c) 2006 Elsevier B.V. All rights reserved

Evaluation of osmotic effects on coated pellets using a mechanistic model

The aim of this study was to develop a simple experimental methodology and to develop a mechanistic model to characterize the release mechanism from pellets developing cracks during the release process with special focus on osmotic effects. The release of remoxipride from pellets coated with an ethyl cellulose film was chosen as a case study. Dose release experiments at different bulk osmotic pressures revealed that the release process was mainly osmotically driven. The model was used to calculate the solvent permeability of the coating, 1.1 x 10(-10) m(2) h(-1) MPa-1 The model was validated by release experiments using similar pellets having different coating thicknesses. The effective diffusion coefficient of remoxipride in the coating was also calculated and found to be 1.7 x 10(-1) m(2) h(-1). A series of experiments was performed in which the osmotic pressure of the receiving solution was changed during the experiment. From the results of these experiments, the area of the cracks in the film, formed by the hydrostatic pressure built up inside the pellets, was estimated to be 3.5 x 10(-5) m(2)/m(2) coating. It could also be deduced that the solvent permeability of the coating film was affected by swelling in the same way at different osmotic pressures. (C) 2006 Elsevier B.V. All rights reserved

Osmotic pumping release from ethyl-hydroxypropyl-cellulose-coated pellets: A new mechanistic model.

A new mechanistic model of drug release by osmotic pumping and diffusion from pellets coated with a semipermeable film developing pores created by the leaching of water-soluble compounds initially present in the coating, has been developed. The model describes dynamically all the main processes occurring during release, i.e. the inflow of solvent driven by the difference in osmotic pressure across the coating film, dissolution of the drug, swelling of the pellet due to mass accumulation, the build-up of hydrostatic pressure inside the pellet, and the outflow of the dissolved drug through the pores. The model was validated by comparison with the release profile of single metoprolol succinate pellets coated with a film made of ethyl cellulose and hydroxypropyl cellulose (80:20). This system was chosen as it was shown that the release mechanism was osmotic pumping, and that the release occurred through small pores created in the coating by hydroxypropyl cellulose leaching. Insight into the release process was obtained via dose release experiments performed at different osmotic pressures of the release medium, single-pellet release experiments, and a study of the coating before and after immersion in the release medium using scanning electron microscopy. The good agreement found between the predicted release and the experimental data confirmed the validity of the model and its prediction capacity. The model can be used to calculate important variables, e.g. the drug concentration profile in a pore and the pressure build-up inside the pellet

Mechanistic model for drug release during the lag phase from pellets coated with a semi-permeable membrane.

A new mechanistic model of drug release during the lag phase from coated pellets undergoing cracking in the coating due to the hydrostatic pressure built up inside the pellet has been developed. The model describes dynamically all the main release processes occurring during the lag phase in pellets coated with a semi-permeable membrane, i.e. the influx of solvent driven by the difference in osmotic pressure across the coating, dissolution of the drug, swelling of the pellet due to solvent accumulation, build-up of hydrostatic pressure inside the pellet, tensile stress acting on the coating, and the efflux of the dissolved drug. The water uptake is described using irreversible thermodynamics theory, while the tensile stress is described using solid mechanics theory. Importantly, the model allows the prediction of the lag time prior to crack formation. The effect of the pellet size, the pellet shape and the coating thickness on the lag time and on the lag phase release profile has been investigated via computer simulations. The model was validated by comparison with dose release data obtained from pellets coated with an ethyl-cellulose-based film. The good agreement found between the predicted release and the experimental data confirmed the validity of the model

Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems.

The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed

Determination of a diffusion coefficient in a membrane by electronic speckle pattern interferometry: a new method and a temperature sensitivity study

In this work, a method has been developed to easily determine the effective diffusion coefficient (D-e) of a solute in a permeable membrane using electronic speckle pattern interferometry. Fringes are introduced parallel to the direction of diffusion during the diffusion process and D-e can be calculated by simple measurements on the interference pattern. For a fast and convenient determination of D-e, a mathematical expression has been derived from the analytical solution of diffusion in two media separated by a resistance. The D-e obtained when fringes are introduced is in agreement with that obtained when fringes are not introduced. The effect of temperature variation on the optical path of the reference and the object beams has also been investigated. The error introduced into the calculation of D-e, when the temperature oscillation is not taken into account, has been compared for the case when fringes are not introduced during the diffusion experiment and the case when fringes are introduced. In the first case, the relative error can be greater than 100%. Interestingly, in the latter case, the error caused by temperature oscillation is considerably reduced, and no error is introduced if the temperature changes homogeneously over the whole diffusion cell used for the diffusion experiment

Coated formulations: New insights into the release mechanism and changes in the film properties with a novel release cell.

The effect of the blend ratio of water-insoluble ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC-LF), on the properties of sprayed films and on the drug release mechanism of formulations coated with the material was investigated. When the original HPC-LF content exceeded 22%, both the amount of HPC-LF leached out and the water permeability of the films increased drastically when they were immersed in a phosphate buffer solution. The release mechanism of potassium nitrate through EC/HPC-LF films containing 20, 24 and 30% HPC-LF was elucidated in a new release cell equipped with a manometer to measure the pressure build-up inside the cell. A lag phase in the release accompanied by a pressure build-up was observable in all the experiments showing that all the films were initially semi-permeable to KNO(3). However, pressure data revealed that films with 30% HPC-LF became permeable to KNO(3) during the release process due to HPC-LF leaching. Importantly, the blend ratio influenced not only the release rate (which increased as the amount of HPC-LF increased), and the lag time (which increased as the amount of HPC-LF decreased), but also the release mechanism, which changed from osmotic pumping to diffusion as the amount of HPC-LF increased