Optimized inhalation formulation of clofazimine and amikacin for targeted treatment of respiratory infections

The invention describes a pharmaceutical composition combining clofazimine and amikacin for inhalation to treat respiratory diseases like tuberculosis. This formulation enhances drug delivery to the lungs, improving efficacy and reducing systemic side effects.

Background

Bacterial infections, particularly those caused by mycobacteria such as Mycobacterium abscessus, Mycobacterium avium, and Mycobacterium tuberculosis, present significant treatment challenges due to the emergence of drug-resistant strains. Current treatment regimens for infections like pulmonary Mycobacterium abscessus involve prolonged use of multiple antibiotics, often leading to systemic toxicities and requiring regular monitoring.

Despite these intensive treatments, success rates are low, and chronic infections can lead to progressive lung function decline, especially in patients with cystic fibrosis. The mycobacteria’s complex cell wall structure and ability to survive within alveolar macrophages contribute to their resistance, as they can inhibit phagosome-lysosome fusion and other cellular processes. Additionally, the formation of necrotizing granulomas and the presence of extracellular aggregates further complicate treatment due to poor drug penetration.

Inhaled antibiotics have been explored to deliver higher drug concentrations directly to the lungs, potentially reducing systemic side effects. However, existing formulations, such as nebulized liposomal amikacin, have shown limited efficacy against certain mycobacterial infections, and resistance to aminoglycosides is increasing.

Combining antibiotics like amikacin with clofazimine has shown promising in vitro synergy, but the oral form of clofazimine is limited by severe side effects, including skin discoloration and gastrointestinal issues. These challenges highlight the need for innovative approaches to effectively deliver and combine these drugs to overcome resistance and improve treatment outcomes.

Technology description

The technology involves pharmaceutical compositions that combine clofazimine and amikacin for inhalation, specifically targeting respiratory diseases caused by mycobacteria, such as Mycobacterium abscessus and Mycobacterium tuberculosis. This formulation is designed to enhance drug delivery directly to the lungs, potentially increasing efficacy while minimizing systemic side effects. The process involves spray drying, where clofazimine is deposited onto amikacin particles, forming a composite particle suitable for inhalation.

This method aims to improve drug penetration and uptake in the lungs, leveraging the observed synergistic antibacterial activity between clofazimine and amikacin. The technology also explores various drug ratios and the use of excipients to optimize pulmonary delivery.

This technology is differentiated by its innovative approach to drug delivery, focusing on direct pulmonary administration to enhance treatment efficacy for mycobacterial infections. Traditional treatments for these infections often involve prolonged systemic antibiotic regimens, which can lead to significant side effects and limited success rates due to poor drug penetration and resistance. By delivering the drugs directly to the lungs, this technology aims to achieve higher local drug concentrations at the infection site, potentially overcoming resistance mechanisms and reducing systemic exposure.

The use of spray drying to create composite particles is a novel strategy that enhances the stability and delivery efficiency of the drugs, making this approach a promising alternative to existing treatments.