RESUMO
Pulmonary delivery and formulation of biologics are among the more complex and growing scientific topics in drug delivery. We herein developed a dry powder formulation using disordered mesoporous silica particles (MSP) as the sole excipient and lysozyme, the most abundant antimicrobial proteins in the airways, as model protein. The MSP had the optimal size for lung deposition (2.43 ± 0.13 µm). A maximum lysozyme loading capacity (0.35 mg/mg) was achieved in 150 mM PBS, which was seven times greater than that in water. After washing and freeze-drying, we obtained a dry powder consisting of spherical, non-aggregated particles, free from residual buffer, or unabsorbed lysozyme. The presence of lysozyme was confirmed by TGA and FT-IR, while N2 adsorption/desorption and SAXS analysis indicate that the protein is confined within the internal mesoporous structure. The dry powder exhibited excellent aerodynamic performance (fine particle fraction <5 µm of 70.32%). Lysozyme was released in simulated lung fluid in a sustained kinetics and maintaining high enzymatic activity (71-91%), whereas LYS-MSP were shown to degrade into aggregated nanoparticulate microstructures, reaching almost complete dissolution (93%) within 24 h. MSPs were nontoxic to in vitro lung epithelium. The study demonstrates disordered MSP as viable carriers to successfully deliver protein to the lungs, with high deposition and retained activity.
Assuntos
Pulmão , Muramidase , Tamanho da Partícula , Pós , Dióxido de Silício , Dióxido de Silício/química , Muramidase/administração & dosagem , Muramidase/química , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Porosidade , Pós/química , Portadores de Fármacos/química , Administração por Inalação , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Humanos , Excipientes/química , Animais , Química Farmacêutica/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , LiofilizaçãoRESUMO
The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.4, 3.9 and 6.3 µm) were analysed after aerosolization in a modified Andersen Cascade Impactor. Systematic control of the release rate of drug loaded into the particles was demonstrated in simulated lung fluid by variation of the mean particle diameter, as well as an enhanced release compared to a commercial micronized formulation. The mesoporous silica formulations all demonstrated an increased release rate of the loaded drug and moreover, under aerosolization from a commercial, low-cost dry powder inhaler (DPI) device, the formulations showed excellent performance, with low retainment and commercially viable fine particle fractions (FPFs). In addition, the measured median mass aerodynamic diameter (MMAD) of the different formulations (2.8, 4.1 and 6.2 µm) was shown to be tuneable with particle size, which can be helpful for targeting different regions in the lung. Together these results demonstrate that mesoporous silica formulations offer a promising novel alternative to current dry powder formulations for pulmonary drug delivery.
Assuntos
Aerossóis , Budesonida , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Tamanho da Partícula , Dióxido de Silício , Dióxido de Silício/química , Dióxido de Silício/administração & dosagem , Budesonida/química , Budesonida/administração & dosagem , Budesonida/farmacocinética , Porosidade , Inaladores de Pó Seco/métodos , Administração por Inalação , Sistemas de Liberação de Medicamentos/métodos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Broncodilatadores/administração & dosagem , Broncodilatadores/química , Broncodilatadores/farmacocinética , Portadores de Fármacos/químicaRESUMO
Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 µm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 µm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9-10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.
Assuntos
Antituberculosos , Clofazimina , Portadores de Fármacos , Pulmão , Nanopartículas , Administração por Inalação , Porosidade , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Nanopartículas/administração & dosagem , Humanos , Pulmão/metabolismo , Clofazimina/administração & dosagem , Clofazimina/farmacocinética , Clofazimina/uso terapêutico , Dióxido de Silício/química , Dióxido de Silício/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Liberação Controlada de Fármacos , Tamanho da Partícula , Tuberculose/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , CamundongosRESUMO
The use of multiagent systems (MASs) in real-world applications keeps increasing, and diffuses into new domains, thanks to technological advances, increased acceptance, and demanding productivity requirements. Being able to automate the generation of mission plans for MASs is critical for managing complex missions in realistic settings. In addition, finding the right level of abstraction to represent any generic MAS mission is important for being able to provide general solution to the automated planning problem. In this article, we show how a mission for heterogeneous MASs can be cast as an extension of the traveling salesperson problem (TSP), and we propose a mixed-integer linear programming formulation. In order to solve this problem, a genetic mission planner (GMP), with a local plan refinement algorithm, is proposed. In addition, the comparative evaluation of CPLEX and GMP is presented in terms of timing and optimality of the obtained solutions. The algorithms are benchmarked on a proposed set of different problem instances. The results show that, in the presence of timing constraints, GMP outperforms CPLEX in the majority of test instances.
Assuntos
Robótica , AlgoritmosRESUMO
Recent industrial developments in autonomous systems, or agents, which assume that humans and the agents share the same space or even work in close proximity, open for new challenges in robotics, especially in motion planning and control. In these settings, the control system should be able to provide these agents a reliable path following control when they are working in a group or in collaboration with one or several humans in complex and dynamic environments. In such scenarios, these agents are not only moving to reach their goals, i.e., locations, they are also aware of the movements of other entities to find a collision-free path. Thus, this paper proposes a dependable, i.e., safe, reliable and effective, path planning algorithm for a group of agents that share their working space with humans. Firstly, the method employs the Theta* algorithm to initialize the paths from a starting point to a goal for a set of agents. As Theta* algorithm is computationally heavy, it only reruns when there is a significant change of the environment. To deal with the movements of the agents, a static flow field along the configured path is defined. This field is used by the agents to navigate and reach their goals even if the planned trajectories are changed. Secondly, a dipole field is calculated to avoid the collision of agents with other agents and human subjects. In this approach, each agent is assumed to be a source of a magnetic dipole field in which the magnetic moment is aligned with the moving direction of the agent. The magnetic dipole-dipole interactions between these agents generate repulsive forces to help them to avoid collision. The effectiveness of the proposed approach has been evaluated with extensive simulations. The results show that the static flow field is able to drive agents to the goals with a small number of requirements to update the path of agents. Meanwhile, the dipole flow field plays an important role to prevent collisions. The combination of these two fields results in a safe path planning algorithm, with a deterministic outcome, to navigate agents to their desired goals.
RESUMO
Breath alcohol screening is important for traffic safety, access control and other areas of health promotion. A family of sensor devices useful for these purposes is being developed and evaluated. This paper is focusing on algorithms for the determination of breath alcohol concentration in diluted breath samples using carbon dioxide to compensate for the dilution. The examined algorithms make use of signal averaging, weighting and personalization to reduce estimation errors. Evaluation has been performed by using data from a previously conducted human study. It is concluded that these features in combination will significantly reduce the random error compared to the signal averaging algorithm taken alone.
Assuntos
Intoxicação Alcoólica/diagnóstico , Testes Respiratórios , Etanol/isolamento & purificação , Algoritmos , Dióxido de Carbono/química , HumanosRESUMO
Measurement of breath alcohol concentration is strongly influenced by timing and the breathing pattern. In particular, shallow expiration and hyperventilation leads to underestimation of the breath alcohol concentration. In the present study, expirograms of alcohol, water and carbon dioxide were recorded in 30 healthy individuals at various breathing manoeuvres (tidal volume, slow maximum and vital capacity expiration, breath holding, and hyperventilation). Estimation of the end expiratory alcohol concentration with the use of simultaneously measured carbon dioxide was shown to reverse the tendency of underestimation at shallow expiration and hyperventilation. These findings indicate that breath alcohol estimations can be performed at shorter expiration time and reduced expired volume compared to existing alcolocks. This is believed to improve their usability and to prevent a possible route for manipulation.
Assuntos
Testes Respiratórios , Depressores do Sistema Nervoso Central/farmacocinética , Etanol/farmacocinética , Mecânica Respiratória , Adolescente , Adulto , Idoso , Dióxido de Carbono/metabolismo , Feminino , Toxicologia Forense , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Detecção do Abuso de Substâncias/métodos , Volume de Ventilação Pulmonar , Capacidade Vital , Água/metabolismo , Adulto JovemRESUMO
Many patients in pre-hospital and emergency care are under the influence of alcohol. In addition, some of the more common pathological conditions can introduce a behaviour that can be mistaken to be related to alcohol inebriation. Fast quantitative determination of the breath alcohol concentration (BrAC) in emergency patients facilitates triage and medical assessment, but shallow expirations performed by non-cooperative patients reduce the measurement reliability. The aim of this study was to evaluate if breath alcohol analysis in non-cooperative patients can be improved with use of simultaneous measurement of the expired carbon dioxide (CO(2)). With prototypes of a handheld breath alcohol analyser based on infrared transmission spectroscopy the alcohol and CO(2) concentration in expired breath from 37 cooperative and non-cooperative patients were measured. The results show that enhanced breath sampling with use of a pump and estimation of the end expiratory BrAC with use of the ratio between the measured partial pressure of CO(2) (PCO2) and a reference value of the alveolar PCO2, provided adequate correlation with the blood alcohol concentration (BAC). This pre-clinical study has shown that breath alcohol analysis in shallow expirations from non-cooperative patients can be improved with use of CO(2) as a tracer gas.