Ramizol^® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation

Abstract

Objective: Novel antibiotic Ramizol^® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing.

Significance: The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance.

Methods: Ramizol^® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague–Dawley rats.

Results: Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague–Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T_max and T_1/2 when compared to the oral and IV routes.

Conclusions: Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol^®. This formulation will allow further development of Ramizol^® for systemic infection eradication.

Keywords:

• PLGA
• Ramizol^®
• microparticles
• nanoparticles
• in vivo
• pharmacokinetics

Disclosure statement

RAB is an employee, board member and shareholder of Boulos and Cooper Pharmaceuticals.

Additional information

Funding

The authors acknowledge funding from Boulos & Cooper Pharmaceuticals for supporting the project.