Engineered microparticles based on drug–polymer coprecipitates for ocular-controlled delivery of Ciprofloxacin: influence of technological parameters

Abstract

Ciprofloxacin is a drug active against a broad spectrum of aerobic Gram-positive and Gram-negative bacteria, for the therapy of ocular infections. It requires frequent administrations owing to rapid ocular clearance and it is a good candidate for ocular controlled release formulations. The preparation of such drug release systems is still a challenge. Ionic interactions between ciprofloxacin and the polyelectrolytes chondroitin sulfate or lambda carrageenan result in coprecipitates that can act as microparticulate controlled release systems from which the drug is released after being displaced by the medium’s ions. In some formulations, Carbopol was added to improve the mucoadhesive properties. The aim of this research was the study of the influence of the technological parameters of the preparation method of coprecipitates on their particle size, with the goal of achieving particles engineered with a size suitable for the ocular administration. Technological parameters taken into account were: concentration of drug and polymer solutions utilized for the preparation of interaction products, possible use of surfactants (kind and concentration), temperature of the solutions and stirring during the process of preparation of the coprecipitates. Preliminary stability study tests were carried out to further characterize the leader formulation. Particle size in suspensions for ocular drug delivery is a critical parameter influencing the quality of the formulation. The results obtained from this study show that chondroitin sulfate coprecipitates present the best characteristics in terms of particle size suitable for ocular administration. A further improvement of the particle size characteristics has been obtained with the addition of surfactants.     

Evaluation of tritium diffusion through the Neutral Beam Injector calorimeter panel

The Neutral Beam Test Facility (NBTF) to be realized in Padoa will test the Neutral Beam Injection (NBI), one of the Heating and Current Drive Systems foreseen for ITER. The NBI is based on the acceleration of hydrogen or deuterium negative ions up to 1 MeV. This work has been aimed at assessing the tritium release from the NBTF in order to provide data for the safety analysis. In particular, the diffusion of the tritium through the neutral beam target material (the CuCrZr alloy calorimeter panels) has been assessed by using literature data of the diffusion coefficient. The tritium generated inside the calorimeter panels moves into both the vacuum and water side: the tritium diffusion flux has been evaluated during the beam-on (200 °C) and the beam-off (20 °C) phases of the NBTF experiments consisting of an interim campaign and a final test. The penetration depth of the tritium through the 2 mm thick CuCrZr alloy material has been also evaluated by using a Monte-Carlo code. As main result, the assessed diffusion flux of tritium during both the beam-on and the beam-off phases are modest. In fact, at the end of the interim campaign (100 days), about the 96% of the all generated tritium (626.5 MBq) exits the calorimeter while the residual tritium inventory (25 MBq) leaves the copper alloy with a diffusion time of about 1 month. At the end of the final test (14 days) about the 99% of the total generated tritium (1.023 × 10⁴ MBq) leaves the copper alloy and the remaining tritium inventory (152.2 MBq) is released by about 32 days. In both the interim campaign and the final test, more than the 99% of the total tritium is transferred into the vacuum side of the calorimeter panel while negligible tritium amounts enter the cooling water system thus showing a very low impact on the environment.     

Ion-beam machining of millimeter scale optics

An ion-beam microcontouring process is developed and implemented for figuring millimeter scale optics. Ion figuring is a noncontact machining technique in which a beam of high-energy ions is directed toward a target substrate to remove material in a predetermined and controlled fashion. Owing to this noncontact mode of material removal, problems associated with tool wear and edge effects, which are common in conventional machining processes, are avoided. Ion-beam figuring is presented as an alternative for the final figuring of small (<1-mm) optical components. The depth of the material removed by an ion beam is a convolution between the ion-beam shape and an ion-beam dwell function, defined over a two-dimensional area of interest. Therefore determination of the beam dwell function from a desired material removal map and a known steady beam shape is a deconvolution process. A wavelet-based algorithm has been developed to model the deconvolution process in which the desired removal contours and ion-beam shapes are synthesized numerically as wavelet expansions. We then mathematically combined these expansions to compute the dwell function or the tool path for controlling the figuring process. Various models have been developed to test the stability of the algorithm and to understand the critical parameters of the figuring process. The figuring system primarily consists of a duo-plasmatron ion source that ionizes argon to generate a focused (~200-mum FWHM) ion beam. This beam is rastered over the removal surface with a perpendicular set of electrostatic plates controlled by a computer guidance system. Experimental confirmation of ion figuring is demonstrated by machining a one-dimensional sinusoidal depth profile in a prepolished silicon substrate. This profile was figured to within a rms error of 25 nm in one iteration.     

Biomimetic Concealing of PLGA Microspheres in a 3D Scaffold to Prevent Macrophage Uptake

Scaffolds functionalized with delivery systems for the release of growth factors is a robust strategy to enhance tissue regeneration. However, after implantation, macrophages infiltrate the scaffold, eventually initiating the degradation and clearance of the delivery systems. Herein, it is hypothesized that fully embedding the poly(d,l ‐lactide‐co‐glycolide acid) microspheres (MS) in a highly structured collagen‐based scaffold (concealing) can prevent their detection, preserving the integrity of the payload. Confocal laser microscopy reveals that non‐embedded MS are easily internalized; when concealed, J774 and bone marrow‐derived macrophages (BMDM) cannot detect them. This is further demonstrated by flow cytometry, as a tenfold decrease is found in the number of MS engulfed by the cells, suggesting that collagen can cloak the MS. This correlates with the amount of nitric oxide and tumor necrosis factor‐α produced by J774 and BMDM in response to the concealed MS, comparable to that found for non‐functionalized collagen scaffolds. Finally, the release kinetics of a reporter protein is preserved in the presence of macrophages, only when MS are concealed. The data provide detailed strategies for fabricating three dimensional (3D) biomimetic scaffolds able to conceal delivery systems and preserve the therapeutic molecules for release.     

Combining Singular-Spectrum Analysis and neural networks for time series forecasting

In this paper, we propose a combination of an adaptive noise-reduction algorithm based on Singular-Spectrum Analysis (SSA) and a standard feedforward neural prediction model. We test the forecast skill of our method on some short real-world and computergenerated time series with different amounts of additive noise. The results show that our combined technique has better performances than those offered by the same network directly applied to raw data, and therefore is well suited to forecast short and noisy time series with an underlying deterministic data generating process (DGP).