Nanosuspensions in drug delivery

Key Points Nanosuspension formulation technology has evolved to meet the needs posed by the numerous water-insoluble drug candidates emerging from high-throughput drug screening programmes that emphasize fit into hydrophobic receptor pockets. Although there are numerous other technologies that can be used, nanosuspensions are ideally suited for drugs with a high crystal energy, which renders them insoluble in lipid as well as aqueous vehicles. The solid state of the nanosuspension confers high weight per volume loading, which is ideal for depot delivery in which administration volume is constrained and high drug levels must be administered. The reduced particle size entails high surface area, thereby increasing the dissolution rate to overcome solubility limited bioavailability. Surfactants, utilizing electrostatic and steric stabilization mechanisms, coat the nanoparticles, thereby preventing their agglomeration and ensuring pharmaceutical stability. Methods of manufacture involve crystallization, building nanocrystals up from the supersaturated solution state, as well as making larger particles smaller by homogenization or milling. Pharmacokinetic profiles for injectables vary from rapidly soluble in the blood, to slowly dissolving, after which macrophage uptake and subsequent release greatly prolong drug delivery, while minimizing peak height. For several drug classes, this leads to improved safety, which permits higher dosing and improved efficacy. Regional delivery confers increased efficacy to local target organs, while minimizing systemic toxicity, and has been demonstrated for the central nervous system, lungs and topically. Numerous solubility-related issues in oral administration of drugs can be resolved, and include increased rate and extent of absorption, reduced variability of absorption, faster onset of action, higher peak drug level, improved dose proportionality and reduced fed/fasted effects. A surprisingly large proportion of new drug candidates emerging from drug discovery programmes are water insoluble, and therefore poorly bioavailable, leading to abandoned development efforts. These so-called 'brickdust' candidates can now be rescued by formulating them into crystalline nanosuspensions. In the process of overcoming issues involving solubility, additional pharmacokinetic benefits of the drugs so formulated have come to be appreciated. As such, insolubility issues of the past have provoked a paradigm change, which now offers novel solut