Inhalable dry powders of rifampicin highlighting potential and drawbacks in formulation development for experimental tuberculosis aerosol therapy

ABSTRACT

Introduction

Recently, tuberculosis was reported as the leading cause of death from a single infectious agent. Standard therapy includes administration of four first-line antibiotics, i.e. rifampicin, isoniazid, ethambutol, and pyrazinamide over a period of at least 26 weeks, which in case of rifampicin oftentimes is accompanied by unwanted side effects and variable bioavailability that compromise a positive therapeutic outcome. As the main site of infection is the lungs, it is desirable to develop a therapeutic formulation to be administered via the pulmonary route.

Areas covered

This work presents a literature review on studies investigating inhalable dry powder formulations including rifampicin in the context of an experimental tuberculosis therapy, with a special focus on aerosol performance.

Expert opinion

It was found that formulation approaches involving different strategies and functional excipients are under investigation but as of now, no formulation has managed to leap into commercial clinical testing. Reasons for this might not primarily be associated with a lack of suitable candidates, but amongst others a lack of suitable in vitro models to assess the efficacy, therapeutic benefit, and cost-effectiveness of the candidate formulations.

KEYWORDS:

• Tuberculosis
• rifampicin
• NGI
• DPI
• aerosol testing
• inhalable therapy

Article highlights

• Tuberculosis infections remain one of the most frequent causes of death globally, being the leading cause of death from a single infectious agent and the current regimen show different limitations.

• Pulmonary administration of suitable antibiotic substances is a promising strategy for tuberculosis treatment and due to its well documented and long history of use, and its suitable overall tolerability, rifampicin is probably the most promising candidate to be re-formulated for this route of administration.

• Many different formulation approaches including, e.g. polymeric micro- and nanoparticles, solid lipid nanoparticles, or excipient-free microparticles, targeting different aspects related to the complex pathophysiology and route of administration were proactively investigated over the past 20 years.

• Apart from one tolerability study, none of these formulations yet has lept into clinical testing.

• Amongst others, a lack of data showing the efficacy of experimental formulations in relevant in vivo models might be associated with the stagnation in development observed.

• The use of disposable dry powder inhalation devices might offer advantages over reusable ones, limiting the risk of (re-) contamination of the patients and other groups involved.

This box summarizes the key points contained in the article.

Acknowledgments

The authors are grateful for the financial support of the Federal Ministry for Economic Affairs and Energy (GER, BMWi) in the framework of the EIDEG project (grant no. 03ET1489C).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.