The advantages of an inhaled anti-TB therapy over parenteral or oral administration are inherent to drug delivery directly to the alveolar macrophages, in which M. tuberculosis survives, bypassing gastrointestinal barriers and hepatic metabolism, so obtaining rapid clinical response, decreased dose, dose frequency, treatment period, side-effects and drug-resistance. Moreover, since 75-80% of TB cases remain localized in the lungs, inhalation therapy could also arrest TB dissemination to other organs by maximizing drug concentration at the infected sites in the lungs, also achieving therapeutic but non toxic systemic levels of drugs. Concerning inhaled anti-TB therapy, very limited marketed, pre-clinical and clinical trials are available, although successful results of few research studies on volunteers. Recently, the scientific research has revived an interest in the administration of anti-TB drugs by inhalation especially due to the advent of multi-drug-resistance (MDR-TB) and extensively drug resistant (XDR-TB) strains. However, studies with dried powder formulations are relatively scarce although the benefits of a DPI device compared with MDI or nebulizers: no propellants, no coordination between the patient and the device, drug stability owing to its dry state which makes DPIs suitable for developing countries in warm climates, higher drug payload delivery, portability, and patient compliance. The inhalation of antibiotics alone fails in its attempt to reach alveoli owing to negative powder physical properties. Moreover, inhaled antibiotics alone showed poor uptake by alveolar macrophages (AM) in cell line studies (Hirota et al., 2009). Technological approach to obtain powder fluidization, deaggregation and flowability with proper breathability to target the most distal lung airways, and capacity to be taken up by alveolar macrophages are needed. Among the strategies aiming to make antibiotics breathable, particle engineering on drug alone (controlled crystallization, different morphology by spray-drying technique), or on drug embedded into microcarriers (liposomes, microparticles) were proposed. Microparticles could modify drug flowability acting on their density, surface features and interparticle cohesive forces, drug release and AM phagocytosis. Microparticles were found also able to activate AM innate bactericidal mechanism. Among the breathable microparticulate systems, most of the studies have focused on polymeric microparticles or liposomes, and less attention has been paid to Solid Lipid Microparticles (SLM) although their advantages in terms of stability. Based on these assumptions, biocompatible, biodegradable and eco-friendly processable SLM loaded with rifampicin, a first-line anti-TB drug, able to be taken up by AM and induce intracellular bactericidal effect were designed in a perspective of an inhaled therapy by means a DPI device for the treatment of TB infection. SLM were previously in vitro characterized showing proper aerodynamic size, drug bactericidal activity maintenance, low cytotoxicity and good capacity to be taken up by murine macrophage cell lines J774 (Maretti et al., 2014). In the present work parameters affecting interparticle forces such as sample water dilution before the freeze-drying process, quick freezing at lower temperature, and cryoprotectant use were evaluated in order to improve the powder breathability.
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|Data di pubblicazione:||2015|
|Autori:||Maretti, Eleonora; Porcheddu, Eleonora; Imbuluzqueta, Edurne; Balducci, Anna Giulia; Buttini, Francesca; Sacchetti, Francesca; Romagnoli, Marcello; Leo, Eliana; Iannuccelli, Valentina|
|Titolo:||Inhaled SLM for anti-TB therapy by DPI device: process parameters affecting freeze-drying and breathability|
|Appare nelle tipologie:||Abstract in Atti di Convegno|
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