Page 476 - Book Hosokawa Nanoparticle Technology Handbook

APPLICATIONS 6 DESIGN OF NANOPARTICLES FOR ORAL DELIVERY OF PEPTIDE DRUGS
result of hydrogen bonding between etheric groups of medium [32, 33] and the utilization of ionic complex
the graft PEG chains and the proton of the carboxylic formation between peptide and fatty acids [34] have
groups of the PMAA network. At low pH values cor- been proposed so far. According to these methods, the
responding to a gastric juice, the p(MAA-g-EG) nanos- drug content became two to ten times higher than that
pheres remain shrunken, while they swell to a high of the conventional methods, but the absolute drug con-
degree in neutral or basic media. Thus, the loaded pep- tent still remained to be few percent. Similar to the case
tides can be protected by the collapsed hydrogels of liposomes, there are several literatures indicating the
from the acidic environment of the stomach, but effectiveness of non-covalently coating of PLGA
released as the nanospheres pass from the stomach to nanoparticles with muco-adhesive polymers, e.g.,
the upper small intestine because the drastic pH poly(acrylic acid) and chitosan, for the improved intes-
changes causes the hydrogel swell [21–24]. tinal absorption of peptide drugs. As other approaches,
Additionally, the p(MAA-g-EG) nanospheres were attempts were made to covalently attach the PEG chains
molecularly designed to contain PEG tethered chains to the PLGA or acid-anhydride polymers for providing
promoting mucosal adhesion as well as a PMAA muco-adhesive property [36], to introduce hydrophilic
backbone with carboxylic pendant groups which can dextran to PCL nanoparticle with core–corona structure
act as calcium binders leading to inactivation of cer- for further surface-modification with lectins [37], and
tain calcium-dependent luminal enzymes [25] and to prepare self-assembled nanoparticles through the ion-
epithelial tight-junction opening effect [26, 27]. Such pair formation between insulin and .the newly synthe-
multi-functions of the p(MAA-g-EG) nanospheres sized amphiphilic polyesters [38].
were aimed at realizing the enhanced intestinal
absorption of peptide drugs such as insulin and calci- (c) Polysaccharides
tonin. In addition to such molecular design of In addition to synthetic polymers, natural polymers
poly(alkyl(meth)acrylates), composite particle struc- such as polysaccharides have also been widely inves-
tures of nanoparticles are achievable by elaborating tigated as a polymeric source of nanoparticulate car-
polymerization techniques. As such, a novel composite riers for drug delivery. Most polysaccharides are more
nanoparticle consisting of a thermo-sensitive poly(N- or less soluble in aqueous media. Thus, polysaccha-
ispropylacrylamide) (p(NIPAAm)) core having a layer ride-based nanoparticles can be prepared by a precip-
of pH-sensitive p(MAA-g-EG) was prepared by the itation through ion-pair formation with certain
photo-initiated dispersion polymerization method additives (e.g., tripolyphosphate for chitosan [39, 40],
[28, 29]. This core-shell nanoparticle revealed specific calcium ion for pectin [41]) the so-called iontropic
functions including the pro-loading of peptides at an gelation. Addition of counter ionic polymers to poly-
aqueous environment with low temperature, the sup- saccharides is another useful way to make polysac-
pressed release of the loaded peptide in the acidic charide nanoparticles through the polyelectrolyte-based
media and the sustained release of the loaded peptide ionic complexation [42, 43]. Among polysaccharides,
in neutral pH [28, 29]. As another types of chitosan-based nanoparticles has been shown to be
poly(alkyl(meth)acrylate) nanoparticles, hydrophobic endocytosed by in vitro cultured cells [39, 40, 44] and
polystyrene core particles having various hydrophilic also interactive with intestinal absorptive enterocytes
polymer chains were proposed [30]. Comprehensive and/or the Peyer’s patches in vivo [39, 40]. Due to
studies were carried out to evaluate the in vitro and in these properties, the chitosan-based nanoparticles
vivo performances of the proposed nanoparticles as an were also utilized as a delivery system of protein
oral delivery device of calcitonin [30]. Through these (ovalbumin) for the purpose of oral vaccination [45].
studies, introduction of p(NIPAAm) chains to the
polystyrene core was found to be particularly effective (3) Others
to obtain the calcition absorption-enhancing effect Attempts have been made to utilize several nanoporous
after the oral administration of the formulation to rats. absorbents such as carbon-based nanomaterials (car-
bon nanotubes, carbon nanohorns, fullerene, etc.) and
(b) Polyesters porous silicon dioxide (Sylysia 550) as carriers for oral
Biodegradable polyesters, in particular poly(lactic acid), peptide delivery [46]. In order to improve the oral
poly(lactic acid-co-glycolic acid) (PLGA) [31–34] and absorption of erythropoietin (EPO), liquid filled
poly(caprolactone) (PCL) [35] have been widely used nanoparticulate systems (LFNPs) were prepared by
as a constitute of nanoparticles. The preparation of simply mixing these absorbents and EPO along with
nanoparticles using these polyesters is accomplished surfactants and enzyme inhibitors. The in vivo animal
with the methods based on solvent diffusion via an oil- studies revealed that the intestinal absorption of EPO
in-water type emulsion. The use of an aqueous medium after the intra-jejunum administration of EPO-contain-
as a dispersing phase usually leads to low loading effi- ing LFNPs was 5–20 times enhanced in comparison to
ciency because most peptide drugs are water soluble that of the EPO solution. Among the series of LFNPs,
and thus leached out from the polymeric phase readily. the most significant absorption-enhancing effect was
In order to improve the loading efficiency, therefore, found in the LFNPs using carbon nanotubes; the
several methods including the use of non-aqueous bioavailability of EPO was 11.5%.

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