Inhalable Mannosylated Rifampicin–Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy

Abstract

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)–curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy.

State of the Art on Developments of (Bio)Sensors and Analytical Methods for Rifamycin Antibiotics Determination

“…RIF is the most powerful first-line anti-TB drug, characterized as a highly effective, orally administered and non-toxic compound, as part of the combined therapy approach recommended by the WHO [ 23 ]. RIF has an effectiveness of about 95% in cases of TB caused by susceptible strains [ 47 ], with a daily oral administration of the standard 600 mg single dose [ 24 , 48 ] or of a dose corresponding to 10–20 mg RIF/kg body weight [ 49 , 50 ]. Alone or in combination with other drugs, it represents the main treatment for infections (produced by various microorganisms), such as TB ( Mycobacteria tuberculosis ), osteomyelitis ( Staphylococcus aureus ), meningococcal disease ( Neisseria meningitidis ), leprosy ( Mycobacterium leprae ), gonorrhea ( Neisseria gonorrhoeae ) [ 51 ], Legionnaire’s disease ( Legionella pneumophila) [ 19 , 28 ] and even HIV [ 52 , 53 ].…”

“…Moreover, RIF causes orange coloration in urine, sweat and tears [ 28 ]. All of these negative aspects can lead to treatment failure and to the occurrence and even prevalence of (multi)-drug-resistant TB [ 48 , 69 ], especially in patients with HIV infection [ 56 , 70 ].…”

“…After freeze-drying, the drug-loaded polymeric nanomicelles (~108 nm) were stable after dilution in simulated interstitial lung fluid, being suitable for nebulization and drug delivery to the deep lung. The studies revealed that mannose enhanced the microbicidal activity of the inhaled micellar nanoformulation, while curcumin contributed with its anti-inflammatory and potential anti-microbial effects [ 48 ].…”

“…RIF is the active principle of several pharmaceuticals, most of them being in solid form because there is a lack of liquid or aqueous RIF pharmaceutical dosage forms due to low water solubility and high chemical instability [ 48 ]. However, the pharmaceutical industry has very strict regulations regarding the quality and stability of the products, with methods of analysis being decisive to monitor the composition of both final and intermediary products, throughout the whole fabrication process.…”

A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation

“…Various drug delivery systems are reported in the literature for inhaled delivery of rifampicin, such as microparticle systems, liposomes, solid lipid nanoparticles (SLN), polymeric nanoparticles, porous particles, nanoaggregates, and nanocomposites (Table 2). Recently, micellar systems, such as polymeric micelles and nanomicelles, also have gained attention as a promising formulation approach for inhaled delivery of rifampicin [55,56]. Such formulations have shown good retention after intra-tracheal administration in animal models (Table 2).…”