Pharmaceutical Manufacturing Handbook: Production and

GENERATIONS OF OIL-IN-WATER NANOSIZED EMULSIONS 1335
erties, such as the size [68 – 71] , zeta potential (see Sections 7.4.2.3 and 7.4.5 ), and
compositions of phospholipids and oil phase (see the above paragraphs), which may
vary among different products and the batches of each product. The size of particulate
carriers such as liposomes is known to infl uence both the phagocytic uptake by
the mononuclear phagocyte system (MPS) [68 – 70] and the binding of apolipoprotein
(apo) to emulsions [71] . Furthermore, the particle size is a major determinant
of the transfer to extravascular spaces from the blood compartment. The capillaries
of the vascular system can be classifi ed into three categories: continuous, fenestrated,
and discontinuous (sinusoidal) [72] . Particulate carriers including nanosized
emulsions are considered to pass through capillaries and reach extravascular cells
only in organs having discontinuous capillaries such as liver, spleen, and bone
marrow. In such tissues, the extravasation of particles should be regulated by their
size since the largest pores in the capillary endothelium is reported to be about
100 nm [73] . In addition, tumor capillaries have unique characteristics in their structures
and functions in comparison with normal tissues such as muscle [74, 75] , which
results in the enhanced distribution of particulate carriers to tumor tissues [76 – 78] .
The distribution of emulsions within a tumor tissue was also regulated by the size
of particulate carriers [79] . Obviously, because of the submicrometer size range
(175 – 400 nm in diameter) of the emulsions, the more they circulate, the greater their
chance of reaching respective targets. More specifi cally, growing solid tumors as well
as regions of infection and infl ammation have capillaries with increased permeability
as a result of the disease process (e.g., tumor angiogenesis [74] ). Pore diameters
in these capillaries can range from 100 to 800 nm. Thus, drug - containing emulsion
particles are small enough to extravasate from the blood into the tumor interstitial
space through these pores [80] . Normal tissues, by and large, contain capillaries with
tight junctions that are impermeable to emulsions and other particles of this diameter.
This differential accumulation of emulsion - laden drug in tumor tissues relative
to normal cells is the basis for the increased tumor specifi city for the emulsion - laden
drug relative to free (nonemulsion) drug. In addition, tumors lack lymphatic drainage
and therefore there is low clearance of the extravasated emulsion from tumors.
Thus, long - circulating lipid carriers, such as POE/PEG - coated nanosized emulsions,
tend to accumulate in tumors as a result of increased microvascular permeability
and defective lymphatic drainage, a process also referred to as the enhanced permeability
and retention (EPR) effect [81] . Table 2 lists various formulation factors
affecting the metabolism as lipoproteins, the recognition by the MPS, and the elimination
from the blood circulation of both second - and third - generation nanosized
emulsions after parenteral administration.
On the other hand, essential requirements of this “ active ” targeting approach
include identifi cation of recognition features (receptors) on the surface of the target
and the corresponding molecules (ligands) that can recognize the surface. Indeed,
emulsions with appropriate ligands anchored on their surface must be able to access
the target, bind to its receptors, and, if needed, enter it. Furthermore, in order to
bring the colloidal carrier closer to otherwise inaccessible pathological target tissues,
homing devices/ligands such as antibodies and cell recognition proteins are usually
linked somehow onto the particle surfaces. Various methods have been employed
to couple ligands to the surface of the nanosized lipidic and polymeric carriers with
reactive groups. These can be divided into covalent and noncovalent couplings.
Noncovalent binding by simple physical association of targeting ligands to the