For the first time in more than a decade, the global death toll due to tuberculosis exceeded 1.5 million in 2020, underscoring the need for access to treatments that work better and last longer.
“During the COVID-19 pandemic, we witnessed more deaths due to tuberculosis because of disruption or reallocation of health services, setting us back at least five to eight years in the global fight against tuberculosis,” said Miriam Braunstein, PhD, a professor of microbiology and immunology at the University of North Carolina (UNC) School of Medicine and a member of the UNC Institute for Global Health and Infectious Diseases.
Braunstein is part of a team of scientists from UNC, Case Western University, and Duke University, that has developed a long-acting injectable formulation of a drug (rifabutin) approved for the treatment of tuberculosis, to address the problem. “We think long-acting formulations could be a game-changer, whether it’s for preventative therapy or treatment of disease,” said Braunstein.
Instead of a strict regimen of daily injections, the team’s preclinical experiments show that a single injection of the drug using an upgraded delivery system can last at least four months. The details of the new formulation were published in an article titled, “A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis,” published in the journal Nature Communications. Such long-acting, slow-release formulations have been approved by the FDA for the treatment of cancers, schizophrenia, and opioid dependency. This is the first attempt at using the technology in the treatment of tuberculosis.
“Our approach could dramatically change tuberculosis treatment,” said Martina Kovarova, PhD, an associate professor of medicine at UNC and a senior author of the study. “Affordable long-acting formulations with generic anti-tuberculosis drugs would help ease the burden of this disease on low-income communities around the world where better access to treatment is most needed.”
According to the World Health Organization, tuberculosis, caused by Mycobacterium tuberculosis, affects nearly 10 million people annually with additional latent infections in about one-quarter of the global population that can reactivate, resulting in weakness, weight loss, fever, chest pain, and coughing up blood. The current treatment for tuberculosis involves strict adherence to daily injections with the threat of failure of treatment and drug resistance if medications are missed. The new delivery system could increase compliance to treatment and overcome these threats.
Manse Kim, PhD, a postdoctoral researcher at UNC-Chapel Hill, and Claire Johnson, a graduate student at UNC, both lead authors of the study, combined rifabutin with biodegradable polymers and nontoxic, biocompatible solvents in the new delivery system and injected the formulation subcutaneously in mice of the BALB/c strain.
“Upon injection, the solvent dissipates to surrounding tissues during the polymer phase change leaving formed implants that are composed only of the biodegradable polymers and rifabutin,” Kovarova explained.
The new delivery system also includes amphiphilic compounds that are attracted to both water (hydrophilic) and lipids (lipophilic). This allows the injection of higher loads of rifabutin in a single injection.
“The addition of very small amount of amphiphilic compounds can significantly increase rifabutin solubility,” explained Kovarova. “The concentration of the amphiphilic compound to achieve the maximum rifabutin solubility is different for each compound, suggesting amphiphilic compounds and rifabutin interact in the non-toxic organic solvent, like in water.”
In mice, the injectable implant erodes over the course of 16 weeks, releasing its payload in a sustained fashion throughout. The sustained release of the drug is facilitated by the organized microstructure of the solidified implant that can be regulated by changing the composition of the delivery system.
Kovarova said, “At early time points, all implants showed similar pore sizes on the surface. However, with time, high drug load formulation showed that the implant maintained small pore size longer than the formulation with low drug load because of its higher hydrophobicity.”
In mice exposed to Mycobacterium tuberculosis, the new long-acting delivery system prevented active infection, and in mice with active tuberculosis infections, the single injection cleared the infection from lungs and other tissues. None of the mice showed any adverse effects. However, in the event of any side effects, the subcutaneous implant can be removed readily.
“We think this technology could be leveraged in our battle against tuberculosis worldwide,” said Kovarova. The team is currently conducting additional preclinical research on larger animals before the long-acting rifabutin formulation can be tested in humans in Phase I clinical trials.
