Page 469 - Book Hosokawa Nanoparticle Technology Handbook

6 DESIGN OF NANOPARTICLES FOR ORAL DELIVERY OF PEPTIDE DRUGS APPLICATIONS
injections, often leading to the poor patient compli- location with a range of 1–400 m (the average thick-
ance. Alternatively, oral drug delivery offers painless ness is around 200 m) [9]. Mucus consists of non-
(non-invasive), self-administrable, inexpensive and mucin components and mucin. The non-mucin
convenient usage, and thus can be expected as a components are IgA antibodies, enzymes, surfactants
patient-friendly dosing system. Considerable research and free lipids. Mucin is defined as the stainable
efforts have been thus invested in the development of component of mucus. The major macromolecular
oral drug delivery systems. Above all, use of particu- component of mucin is a group of high-molecular
late carriers, especially ‘nanoparticulate’ carriers has weight glycoproteins; the polydisperse glycoprotein
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attracted much attention in the pharmaceutical field has a molecular weight in excess of 2 10 kDa, but
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since the late 1970s in advance of recent progress on can range from 2 10 to 15 10 kDa. Most mucus
nanotechnologies [1–4]. glycoproteins carry a net negative charge due to the
presence of sialic acids and ester sulfates at the termi-
1. Particulate design and functions nus of some sugar units. The brash border membrane
is composed of epithelial monolayer of absorptive ente-
Principal functions required for nanoparticles as a rocytes that are conjugational through tight junctions.
carrier of oral peptide delivery are summarized in Fig. In addition, solitary lymphoid nodules are widespread
6.1. Two major functions for the successful oral pep- along the entire intestine as oval aggregates in the
tide delivery are discussed below. antimesometrial gut wall, the so-called Peyer’s patches
[3]. The epithelial part of Peyer’s patches is composed
(1) Drug loading of highly specialized enterocytes, the membranous
Loading of peptide drugs into carriers should be car- microfold (M) cells, having a function to collect vari-
ried out so as to make the loading efficiency and the ous antigens from the gastrointestinal surface.
content high enough to ensure the therapeutic efficacy In order to overcome these physiological and mor-
while it should not affect the chemical stability of phological barriers against peptide delivery, two pos-
peptide drugs (Fig. 6.1). The loading procedures can sible approaches have been considered. One is to
be classified into two categories, i.e., peptides can be provide muco-penetrative and/or muco-adhesive
loaded during (in situ loading) or after the preparation properties to drug carriers for prolonging their resi-
of carriers (pro-loading). The in situ loading often dence time at the absorption site. The particles with
provides high drug content, while attention must be smaller size are likely to be diffusive in the mucus
paid to a possible denaturation of peptide drugs if layer much higher, provided that diffusion of the par-
preparation conditions of the carriers require the use ticles in the mucus layer obeys the Stokes–Einstein
of organic solvents (or even aqueous solvents with equation. Compared with the microparticles, there-
large alteration of pH), high temperatures and/or high fore, the nanoparticles can penetrate into the deeper
share forces. In contrast, the pro-loading is usually zone of the mucus layer [10–12]. This is one of major
accomplished by simple soaking of the carrier into an reasons why nanoparticulate drug carriers have been
aqueous peptide solution, so that it may have an abil- attracted much attention for the purpose of oral pep-
ity to stably load the drug under a relatively mild con- tide delivery. Modification of nanoparticle surface
dition. Nevertheless, the loading efficiency and/or the with muco-adhesive components may lead to further
drug content may be limited to a certain extent if sim- prolongation of the residence time at the absorption
ple equilibrium partitioning without specific interac- site. Drug release from the nanoparticles at the epithe-
tion between the drug and the carrier takes place. lial cell lining followed by penetration of the nanopar-
ticles into the depths of the mucus layer can give rise
(2) Behaviors of nanoparticles in the gastrointestinal tract to high drug concentration gradient across the intes-
Orally administered nanoparticulate carriers should tinal membrane, possibly leading to the increased
have an ability to protect the loaded peptides from the drug absorption by passive diffusion. Alternative
digestive enzymes, such as pepsin, in the stomach approach is to directly traverse the nanoparticles
with acidic conditions while they do not release the themselves to the blood stream through the intestinal
loaded peptides (Fig. 6.1). Followed by passing membrane. This approach makes it possible to protect
through the stomach, the nanocarriers reach the small peptide drugs from proteolytic degradation by diges-
intestine that is a major absorption site for peptide tive enzymes such as trypsin and chemotripsin exist-
drugs. Here, two major biological barriers for the ing in the intestinal mucus layer. The nanoparticulate
drug absorption exist, i.e., the brush border mem- carriers used for this purpose must be constructed
brane and mucus layer. Mucus is a fully hydrated vis- with biocompatible and/or biodegradable materials
coelastic gel (water occupies almost 95% of the since they are absorbed into the body. As transport
contents under nonpathological conditions) overlying pathways through the intestinal membrane, three pos-
epithelial cell surfaces as a continuous gel blanket sible routes have been suggested: (1) uptake by the
[5–7]. Its neo-genesis continuously takes place with Peyer’s patches, (2) gap between epithelial absorptive
relatively rapid turnover rate [8]. The thickness of enterocytes (paracellular route), (3) uptake by absorp-
human mucus varies depending on the anatomical tive enterocytes (transcellular route) [3]. There are

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