Development and evaluation of a model characterizing the release characteristics of a new letrozole long-acting injectable formulation

Treating a chronic condition such as breast cancer usually requires daily oral drug administration for extended periods of time, which is associated with non-adherence to the prescribed therapy that may cause disease progression. New delivery strategies such as long-acting injectable (LAI) implants have entered the picture in order to solve oral administration drawbacks while improving bioavailability, plasma levels variability or treatment compliance. This has motivated the development of a new polymeric and biodegradable in situ forming long-acting implant of letrozole. This new formulation is provided as a kit of two syringes (one of them containing letrozole and Poly-Lactic Acid, and the other one containing dimethyl sulfoxide as solvent for reconstitution). Once the formulation is reconstituted and injected into the muscle, the solvent diffuses into tissue fluids and the insoluble polymer precipitates, forming a semi-solid implant that traps the API and allows a sustained drug release. In order to optimize both the formulation and the development process, traditional in vitro dissolution assessment and predictive dissolution modelling were conducted to identify which formulation characteristics show an impact on the kinetics of the release, which may provide a first basis to potentially establish an in vitro-in vivo correlation (IVIVC) with both pre-clinical and clinical data in the future. Two dissolution methods (real-time and accelerated) were used to describe the in vitro dissolution profiles of 15 letrozole LAI formulations differing on their Critical Material Attributes (CMAs). The release profiles were best described using the Weibull distribution and estimating the fraction of the dose loss during injection. The first order rate constant of release (K_D) was increased by 1.87 times in the case of the accelerated conditions, and was 30 % reduced and increased by 1.34 times in the case of higher and lower viscosity of the formulations, respectively. This work allowed for quantitative characterization of the formulation related characteristics responsible for controlling drug release. It provides a new understanding of the formulation that will serve to guide in the development of a robust formulation and to establish product quality control specifications.