SOLID LIPID MICROPARTICLES FOR INHALED ANTI-TB THERAPY BY DPI: INFLUENCE OF THE PRODUCTION PROCESS ON DRUG STABILITY AND POWDER BREATHABILITY

According to the WHO global report, tuberculosis (TB) remains one of the world’s deadliest communicable diseases. The current therapy involves three/four drug oral regimen, long-term therapy, high and frequent doses so producing several side-effects [1]. To overcome these drawbacks and improve treatment efficacy, the new strategies could involve new formulation design for old drugs. Among these, the shortest-term goal is represented by Drug Delivery Systems (DDS). In this latter context, considering that 75-80% of TB cases remain localized in the lungs, pulmonary route appears the most strategical route [2]. For an efficient drug delivery by Dry Powder Inhaler (DPI) device, several powder properties (particle microsize, irregular shape, low tap density, surface charge, weak adhesion between particles, good flowability) contribute to determining powder aerodynamic performance and, consequently, deposition onto alveolar epithelium, and phagocytosis by alveolar macrophages [3]. Based on these assumptions, Solid Lipid Microparticles (SLM), known to be biocompatible, biodegradable and physically stable were designed as the carrier for rifampicin (RIF). The present research focused on the evaluation of both RIF stability during the production phases and the role of variables relating to freeze-drying process (freezing conditions, sample dilution, cryoprotectants) affecting the powder aerosolization. Considering the complexity of the factors involved in a successful breathable powder, a statistical Design of Experiments (DOE) was adopted to study the critical variables that influence the final product. SLM were obtained by the melt emulsification technique under sonication by using stearic acid and sodium taurocholate as lipid and surfactant, respectively [4]. Loaded SLM were prepared by adding RIF in the melted lipid. All the emulsions were rapidly cooled to room temperature providing SLM that were purified by dialysis and freeze-dried. Freeze-drying was carried out following dilution with water, mixture with cryoprotectant (trehalose or mannitol), and lowering temperature of freezing. SLM exhibited an irregular shape and the following value ranges: size (470 - 1700 nm), PDI (0.32 – 0.94), circularity (0.43 – 0.66), bulk density (0.02 – 0.24 g/cm3), tapped density (0.04 – 0.31 g/cm3) and drug loading level (11.85 – 15.88%). The Emitted Dose and the Fine Particle Mass were between 92.1-103.4% and 0.9-6.83 mg, respectively. DOE approach highlighted the combination of the water dilution before freezing with the cryoprotectant use as the most important parameter to obtain a highly breathable powder as well as the influence of water dilution and freezing temperature on SLM breathability. For a powder to be inhaled by a DPI device, many parameters can guarantee quality and efficacy of the product. The analysis performed demonstrated RIF stability and proved to be efficient in distinguishing the major contribution factors on the final product and identifying the key factors that are helpful for the improvement of SLM production process.