Roles of Cellulosic Polymers and Surfactants in the Stabilization of Drug Nanosuspensions and Redispersibility of Dried Composites

摘要

Almost 40% of the new chemical entities in drug pipeline of pharmaceutical companies have low aqueous solubility, which leads to poor bioavailability in vitro and in vivo. Reduction of drug particle size down to nano-scale has been an effective way of increasing the dissolution rate of poorly water-soluble drugs1. Wet stirred media milling (WSMM) has been commonly used to reduce drug particles to nano-scale. However, nanoparticles are prone to aggregation. Severe aggregation of drug nanoparticles can cause loss of surface area and thus reduce the potential dissolution improvement expected from nanoparticles. To prevent the aggregation in drug nanosuspensions, cellulosic polymers and surfactants are used as stabilizers, also known as dispersants. On the other hand, to ensure chemical and physical stability of nanosuspensions for a long-term storage and meet patient need/demands, drug nanosuspensions are typically dried into nanocomposite microparticles (NCMPs), in the form of powders, which are then incorporated into various solid dosage forms such as tablets, capsules, sachets. Unfortunately, without proper formulation with dispersants, drying of nanosuspensions can also lead to aggregation and loss of large surface area, which in turn can cause poor bioavailability unanticipated from drug nanoparticles2. Moreover, drug nanoparticle recovery during aqueous redispersion of NCMPs can be slow and incomplete, which affects both in vitro and in vivo dissolution3-5. Recent work2,3,5 shows that the presence of surfactant is critical to the full recovery of nanoparticles from NCMPs and their dissolution, whereas that of polymer appears to have positive yet convoluted effects3. In summary, both the physical stability of milled drug suspensions and the redispersibility–dissolution of NCMPs are significantly affected by polymer and surfactants.