Project Assistant: Formulation Development of Novel Tuberculosis Compounds into Long Acting Injectables

SDU - University of Southern Denmark

Odense, Denmark

Project background

Long-acting injectables (LAIs) are pharmaceutical products intended for weekly, monthly or with an even lower administration frequency, which provides a continued drug release and thereby a steady exposure of the delivered compound. LAIs are typically administered intramuscularly (IM) or subcutaneously (SC) as oil solutions, in situ forming gels, microspheres, implants, micro- or nanosuspensions, with focus on suspensions in the present work. For individuals suffering of tuberculosis LAIs can provide a huge benefit in disease treatment, due to the long duration time the disease requires.

LAIs have, with huge clinical success, been applied in the treatment of antipsychotic conditions and the area contains some of the most successful LAI formulations seen from a therapeutic perspective. In the 1960s, oil-based parenteral depot formulations, containing antipsychotics, were introduced in the clinical practice. Since then, the micro- and nanosuspension technology has significantly advanced and many of the more recent LAIs are nano-or microsuspensions. Hence, this is currently one of the important technologies in the field of LAIs and also the focus of the present project.

The common approach to manipulate the performance of LAI suspensions release rate relies on changing particle size distribution of the crystalline API. This strategy is fundamentally explained by the Noyes-Whitney equation, which describes the dissolution rate of particles in sink conditions. According to the Noyes-Whitney equation, the dissolution rate is proportional to the total surface area of the drug particles. Some commercial products confirms thus and also a few academical studies have reported correlations between the particle size and the in vivo release, hence it is clearly a point that should be clarified when working with a new compound for a LAI suspension. Aside from particle size, other formulation aspects can significantly impact performance, such as formulation composition and the level of flocculation. In addition, API crystal form properties, such as morphology, level of amorphous contents and residual solvent in the API, may have a significant impact on dissolution, indicating that the selection of version and form is crucial not only for manufacturability and stability purposes, but also for performance.

This project aligns closely with Quality by Design (QbD) principles, emphasizing risk assessment, formulation understanding, and robust design space development, but systematically investigating the formulation impact on in vivo release of LAI suspensions in nonclinical models using the obtained data to generate a risk matrix for in vivo impact of potential particle size variations. A successful outcome of this project will provide a formulation that can be taken to clinical trials for the treatment of tuberculosis with the tools to understand the biopharmaceutical performance of LAI suspensions with the relevant compounds supported by quality tools on the stability.

The work will be conducted in close cooperation with Professor René Holm and other colleagues working on the project.

Qualifications

• We are looking for a candidate with a strong interest in working with pharmaceutical formulation and evaluation focused on formulation and characterization of suspensions;
• The candidate will hold a BSc, a M.Sc. in pharmacy, chemistry, or closely related area;
• Previous experiences with one or more of the following are considered an advantage:
  • formulation design of suspensions;
  • particle size characterization;
  • chemical stability studies;
  • bioanalysis; and
  • in vivo studies.

The candidate must be independent and fluent in English both orally and written.