Developing a robust in vitro release method for a polymeric nanoparticle: Challenges and learnings.

Nanomedicines have emerged as a promising approach for targeted therapeutic delivery and specifically as a beneficial alternative to conventional cancer therapies as they can deliver higher concentrations of chemotherapeutic agents at the tumour site compared to healthy tissue, thus providing improved drug efficacy and lower systemic toxicity. Long acting injectables are increasingly becoming the focus of pharmaceutical research, as they can reduce dosing frequency and improve the life quality of patients. Development of an in vitro release (IVR) method for modified release nanomedicines is challenging because of the uniqueness and range of different formulation design approaches, as well as the complex nature of drug release mechanisms which may result in inherent variability. Regulatory guidance on the development of dissolution or release methods for parenteral products is limited relative to oral products. This article details the extensive in vitro release method development work conducted on a polymeric nanoparticle to develop the release media composition and selection of suitable apparatus and sampling technique to separate the released drug from the formulation. The aim was to develop a suitably robust analytical method that generated clinically relevant in vitro release data.

Advanced in silico modeling explains pharmacokinetics and biodistribution of temoporfin nanocrystals in humans.

Foscan®, a formulation comprising temoporfin dissolved in a mixture of ethanol and propylene glycol, has been approved in Europe for palliative photodynamic therapy of squamous cell carcinoma of the head and neck. During clinical and preclinical studies it was observed that considering the administration route, the drug presents a rather atypical plasma profile as plasma concentration peaks delayed. Possible explanations, as for example the formation of a drug depot or aggregation after intravenous administration, are discussed in current literature. In the present study an advanced in silico model was developed and evaluated for the detailed description of Foscan® pharmacokinetics. Therefore, in vitro release data obtained from experiments with the dispersion releaser technology investigating dissolution pressures of various release media on the drug as well as in vivo data obtained from a clinical study were included into the in silico models. Furthermore, precipitation experiments were performed in presence of biorelevant media and precipitates were analyzed by nanoparticle tracking analysis. Size analysis and particle fraction were also incorporated in this model and a sensitivity analysis was performed. An optimal description of the in vivo situation based on in vitro release and particle characterization data was achieved, as demonstrated by an absolute average fold error of 1.21. This in vitro-in vivo correlation provides an explanation for the pharmacokinetics of Foscan® in humans.

A comparison of two biorelevant in vitro drug release methods for nanotherapeutics based on advanced physiologically-based pharmacokinetic modelling.

As a growing number of nanotherapeutics enters the market, improved analytical techniques for measuring the drug release are required. Biorelevant release tests have become a standard in the prediction of in vivo pharmacokinetics but also in quality control of novel dosage forms. In the present study, two methods for testing the drug release from nanocarriers, namely the filtration technique and the dispersion releaser technology, have been investigated. Initially, the in vitro release rates were determined using two different biorelevant media. Additionally, the effect of each method on a simulated in vivo pharmacokinetic profile was studied using advanced PBPK modelling. The two methods resulted in slightly different release profiles. Applying the filtration method, an early plateau of 91.0 ±â€¯5.3% was reached at the first sampling time point. In comparison, the release rate steadily increased to a maximum of 100.9 ±â€¯4.1% when the dispersion releaser technology was used. Sensitivity analysis revealed how these differences translated into the PBPK-based simulation. A change in the total dissolution rate of 10% resulted in cmax values of +1.6% and -11.0%, respectively, when using input data obtained with the dispersion releaser. Data obtained by filtration translated into cmax values of ±1.8%.