Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 412

1 Introduction

Soluble drugs can reach their target in the body (organ, cell, cellular compartment)
by a simple diffusion process of the drug molecules in the body fluids. In contrast
to this, poorly soluble drugs - due to their insolubility in body fluids - need to have
a carrier which carries them to the target, e.g. particulate nanocarriers. Diffusion in
the body fluids is a non-specific, i.e. non-directed process. Soluble drug molecules
distribute regarding distribution velocity and organ pattern according to their
molecular properties (e.g. molecular weight, diffusion coefficient, log P value,
permeability of membranes for the specific molecule, clearance). In contrast to this,
incorporation of a molecule in a nanocarrier allows to target it to specific sites in
the body, certain organs, specific cells within this organ or ideally to a specific cell
compartment.
Such nanocarriers are e.g. micelles, polymeric nanoparticles or lipidic systems
such as nanoemulsions, liposomes, transfersomes, niosomes or lipid nanoparticles
made from solid lipids (e.g. solid lipid nanoparticles (SLN) and nanostructured
lipid carriers (NLC) ( Müller, Shegokar, and Keck, in press ). A basic problem of
these nanocarriers is that very often the loading capacity for drug is relatively low,
especially when drugs are just bound to the surface of a nanocarrier (e.g. dalargin
to the surface of polymeric nanoparticles (Kreuter et al. 1997 )). This is a very
pronounced problem when the aim is to target. Only a limited fraction of the
administered carriers reach the target (assumed 10%). If the loading capacity is
low (e.g. 10%), only a small fraction of the totally administered drug reaches
the organ which might not be enough to reach a therapeutic level for cure of the
disease. Therefore a nanocarrier would be ideal having a loading capacity of
close to 100%.
This is realized by the nanocrystals. They are particles consisting of drug
only without any matrix material as e.g. in polymeric nanoparticles (polymers)
or liposomes (phospholipids). They are only stabilized by an adsorbed surfac-
tant layer or sterically stabilizing polymer layer. Such adsorption layers on
nanoparticles are typically 2-5 nm, maximum about 10 nm in thickness. Considering
cubic nanocrystals of 500 nm size and the adsorption layer as part of the nano-
crystal, this corresponds to maximum just 6% of the volume. Practically the
nanocrystals can simplified be considered as nanocarriers with 100% loading
capacity.
Major prerequisites for use of a nanocarrier in therapy are the possibility of
controlled production, ability to produce on large industrial scale, accordance with
regulatory requirements (e.g. status of excipients), ability for efficient delivery of
drugs, ideally target to the interior of cells, and in case of nanocarriers the increasing
need of data to prove the absence of nanotoxicity. Ideally the nanocarriers used
should belong to class I of the nanotoxicological classification system ( Müller,
Gohla, and Keck, in press ). These issues will be presented and discussed within this
book chapter.