Lipid-based microparticles for TB inhaled therapy: physical properties and cell internalization

Tuberculosis (TB) disease is caused by Mycobacterium tuberculosis that survives and replicates within human alveolar macrophages and is characterized by a long chronic stage of infection and progressive pathology mainly compromising (90% of cases) the respiratory system. Current TB therapies have exploited conventional routes of administration, such as oral or intramuscular, based on high and frequent dosages to maintain the drug therapeutic concentration in infection site because of poor drug permeability, poor drug bioavailability and pre-systemic clearance. An alternative acceptable therapy to systemic treatments involves inhalation route delivering the drug directly to the desired site, enabling a rapid onset of the action and avoiding the long period of the current treatment and the first-pass metabolism, as well as the use of high doses of drug resulting in drug resistance onset and in severe side effects on other organs. Inhaled TB therapy can presuppose the development of micro- or nanoparticles acting as drug carriers toward the alveolar region in the deepest lung so inducing the endocytosis process of alveolar macrophages being many antimicrobials difficult to cross cell membranes (1-3). Lipid-based particulate systems have been poorly investigated for TB inhaled therapy (4) though they were generally recognized as safe, poor liable to swell upon contact with the moisture located into the lungs and, consequently, to release the drug before the target site. Among the lipid-based particulate systems, Solid Lipid Microparticles (SLM), constituted by a solid lipid core stabilized by a surfactant at the surface, exhibit several favourable properties as production without organic solvents and long-term stability. In the present study, SLM loaded with rifampicin, a first-line anti-TB drug, were developed by the melt emulsification technique and evaluated in a perspective of an inhaled therapy for the treatment of TB infection. The lipid-based microparticles designed as rifampicin carrier showed features proper to be delivered from a DPI device, to deposit onto alveolar epithelium and to be internalized by macrophages in which Mycobacterium tuberculosis resides.