Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 411

Nanocrystals: Production, Cellular Drug
Delivery, Current and Future Products
Rainer H. Müller, Ranjita Shegokar, Sven Gohla, and Cornelia M. Keck
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 ® , high pressure homogenization - DissoCubes ® ,
NANOEDGE ® ) is briefly described, representing the first generation of nano-
crystals. The second generation, the smartCrystal ® , 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 mole-
cular 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 i.v. 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.
Keywords Nanocrystals • Saturation solubility • Dissolution velocity • Dermal
delivery • Oral delivery • Intravenous delivery • Nanotoxicity
R.H. Müller, R. Shegokar, S. Gohla, and C.M. Keck ( * )
Department of Pharmaceutics, Biopharmaceutics and NutriCosmetics,
Institute of Pharmacy/Pharmaceutical Technology, Freie Universität Berlin,
Kelchstr. 31, 12169 Berlin, Germany
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