Searching for a long-acting injectable formulation for the antiretroviral dolutegravir

The aim of this study was to engineer a proper particle size to provide plasma dolutegravir concentration maintenance above protein-adjusted 90% inhibitory concentration (PA-IC90) and to evaluate the monthly-acting injectable dolutegravir feasibility for HIV therapy. Liquid antisolvent precipitation technology was used to engineer dolutegravir particles. As a strategy for controlling variations of the habit, particle size and polymorphs of dolutegravir, process intensification was performed using acetone, methanol and dimethyl sulfoxide as solvents and temperature range from 5oC to 30oC. Physical properties of particles were characterized and in vitro drug release was measured. Results revealed that crystal morphology and polymorphic form were independents of solvent and temperature. Concerning solvents, particle sizes were not markedly different. However, results suggested that the higher temperature the higher dolutegravir particle size. Particle size, ranging from 6.48 mum to 17 mum, showed the maximum drug release of 93% in 12 days compared with raw drug that showed a maximum release of only 47.5%. In vivo pharmacokinetic analysis, conducted in Wistar male rats, demonstrated that dolutegravir particles of approximately 13 mum maintained plasma drug concentration above protein-adjusted 90% inhibitory concentration for 26 days.