Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology.

摘要

A significant percentage of active pharmaceutical ingredients identified through discovery screening programs is poorly soluble in water. These molecules are often difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues, e.g. poor bioavailability, lack of dose proportionality, slow onset of action and other attributes leading to poor patient compliance. In addition, for parenteral products, these molecules are generally administered with co-solvents and thus have many undesirable side effects. Wet media milling is one of the leading particle size reduction approaches that have been successfully used to formulate these problematic compounds. The approach is a water-based media milling process where micron-sized drug particles are shear-fractured into nanometer-sized particles. Nanoparticle dispersions are stable and typically have a mean diameter of less than 200 nm with 90% of the particles being less than 400 nm. The formulation consists only of water, drug and one or more GRAS excipients. Drug concentrations approaching 300-400mg/g can be targeted with the use of minimal amounts stabilizer. Typically, on average, the drug to stabilizer ratio on a weight basis ranges from 2:1 to 20:1. These liquid nanodispersions exhibit acceptable shelf-life and can be post-processed into various types of solid dosage forms. Nanoparticulate-based drug products have been shown to improve bioavailability and enhance drug exposure for oral and parenteral dosage forms. Suitable formulations for the most commonly used routes of administration can be identified with milligram quantities of drug substance providing the discovery scientist an alternate avenue for screening and identifying superior leads. In the last few years, formulating poorly water soluble compounds as nanosuspensions has evolved from a conception to a realization. The versatility and applicability of this drug delivery platform are just beginning to be realized.