Pharmaceutical Manufacturing Handbook: Production and

GENERATIONS OF OIL-IN-WATER NANOSIZED EMULSIONS 1333
Promonocyte (bone marrow)
FIGURE 2
Monocyte (blood)
Macrophages (tissues) highly phagocytic
Connective tissue (histiocyte)
Liver (Kupffer cell)
Lung (alveolar macrophage)
Spleen (free and fixed macrophages, sinusoidal lining cell)
Lymph node (free and fixed macrophage)
Bone marrow (macrophages, sinusoidal lining cell)
Serous cavity (peritoneal macrophage)
Bone tissue (osteoclast)
Nervous system (microglia)
Mononuclear phagocyte system.
phases from the parenterally administered emulsions. It is thus reasonable to say
that the resultant oily hydrophobic particles of the emulsions would also be taken
up by macrophages independent of an opsonization process. An opsonization
process is the adsorption of protein entities capable of interacting with specifi c
plasma membrane receptors on monocytes and various subsets of tissue macrophages
(see Figure 2 ), thus promoting particle recognition by these cells. Classical
examples of opsonic molecules include various subclasses of immunoglobulins [36,
37] , complement proteins such as C1q and generated C3 fragments (C3b, iC3b) [38] ,
apolipoproteins [36, 37] , von Willebrand factor, thrombospondin, fi bronectin [39] ,
and mannose - binding protein. When given by other parentral routes, for example,
intraperitoneally, subcutaneously, or intramuscularly, the majority of emulsion droplets
enter the lymphatic system and eventually the blood circulation where particles
behave as if given intravenously. Liver, spleen, and bone marrow uptake is signifi -
cantly lower. Indeed, relative to the emulsion droplet size, lymph nodes take up a
much greater (over 100 - fold) proportion than any other reticuloendothelial system
(RES) tissue.
There is increasing interest in developing injectable emulsions that are not cleared
quickly from the circulation when they are designed to reach non - RES tissues in
the vascular system or extravascular sites of action or to act as circulating drug
reservoirs. Earlier approaches for making long - circulating emulsions concentrate
mainly on changes in the oil phase of the emulsion such as MCT versus LCT [40] ,
use of structured lipids (SLS) having medium - chain (C 8 – C 10 ) fatty acids (SLM) and
short - chain (C 4 ) fatty acids (SLS) [41] , addition of sphingomyelin [42 – 45] and cholesterol
[46] to the emulsion, and use of hydrogenated castor oil (HCO) with at least
20 oxyethylene units (HCO20) [47 – 52] . Using the further established formulation
approaches by which the emulsion droplet surfaces could be altered might, however,
be more realistic and even more useful for a wide array of drug - targeting purposes.
Steric barrier or enhanced hydrophilicity effect exerted by a polyoxyethylene (POE)
chain having surfactants when added as coemulsifi er into the phospholipid -
stabilized fi rst - generation emulsion allows, to some extent, the passive/inverse drug
targeting to the lung, kidneys, and areas of infl ammation [53, 54] . Addition of POE -
based surfactants into the otherwise amphipathic phospholipid - stabilized emulsion