Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products

Abstract

Drug nanocrystals are a formulation principle for systemic and also intracellular delivery of poorly soluble drugs. Their production by bottom up techiques (precipitation - hydrosols, Nanomorph) and by top down techniques (bead milling - NanoCrystal (R), high pressure homogenization - DissoCubes (R), NANOEDGE (R)) is briefly described, representing the first generation of nanocrystals. The second generation, the smartCrystal (R), is produced by combination processes. They are featured by e.g. increased physical stability and/or smaller sizes (<100 nm), favourable when exposed to the destabilizing electrolytes in biological fluids and for uptake by cells by pinocytosis. The lab scale processes were successfully transferred to industrial scale by using discontinuous bead mills and high capacity homogenizers (top down), precipitation can be performed by static blenders. According to the nanotoxicological classification system (NCS), the nanocrystals belong to class I, being highly tolerable. They can be produced using only regulatorily accepted excipients. Both ease the way to the patient and market. Nanotoxicity studies confirm the good tolerability. The nanocrystal products on the market are no direct intracellular delivery systems. They transport drug to the biological barrier and then promote penetration and permeation of drugs in molecular form through barriers and cellular membranes (cellular delivery mechanism I). Formulations based on the cellular uptake of nanocrystals are still in development (cellular delivery mechanism II). Examples are iv. targeting to endothelial cells of the blood-brain barrier and the loading of blood cells (monocytes, erythrocytes) to use these cells as transport vehicles for the nanocrystals. By now, very little work has been done to study and actively modulate the intracellular fate of nanocrystals.