Page 471 - Book Hosokawa Nanoparticle Technology Handbook

6 DESIGN OF NANOPARTICLES FOR ORAL DELIVERY OF PEPTIDE DRUGS APPLICATIONS
surface area. In addition, the pore diameter of these enhance its residence time at the absorption site of the
junctions was reported to be smaller than 10 Å [2]. peptide drugs. For example, surface-coating of lipo-
Therefore, significant paracellular transport of parti- somes with muco-adhesive polymers such as chitosan
cles is an unlikely event. Although certain treatments and poly(acrylic acid) was reported to be effective to
to enhance the opening of the tight junctions are thus increase the intestinal calcitonin absorption due to the
necessary, their relevance for the in vivo situation is enhanced adhesion of liposomes to the intestinal
yet agnostic [2]. The transport mechanism of mucus layer [18]. The use of lectins (proteins that rec-
nanoparticles through the intestinal membrane is still ognize and bind to sugar complexes attached to most
phenomenalistic and factors governing the transport cell surface proteins and many lipids in cell mem-
of nanoparticles are also unclear. Thus further sys- branes) as surface-modifying agents was also shown
tematic studies are necessary to clarify such translo- to promote the oral absorption of insulin because of
cation events. the adhesive interaction between the lectin-modified
liposomes and the intestinal absorptive cells [15].
2. Case studies
(2) Polymeric nanoparticles
Because of its protective ability of peptide drugs from Nanoparticles constituted with polymeric materials
harsh gastrointestinal environments as well as its pos- can be usually fabricated by polymerizing monomeric
sible translocation in the intestinal membrane, the materials as sources of the polymers by a variety of
nanoparticulate carriers for oral peptide delivery are polymerization techniques, or nanoprecipitating the
still being studied extensively. Excellent reviews in established polymers by certain methods followed by
relation to this topic are readily available [1–4]. dissolving them in solvents (Table 6.1).
Historical research trends on typical nanoparticle-
based formulations can be found in these reviews. (a) Polyacrylates
Therefore, the present chapter will mainly survey Alkylcyanoacrylates and alkyl(meth)acrylates have
recent reports published in the last decade (Table 6.1). been often used as monomers to prepare nanoparticles
through ionic polymerization for the former and radi-
(1) Liposomes cal one for the latter. In particular, poly(alkylcyano-
Liposome is an artificial vesicle consisting of an acrylates) have been extensively studied as the
aqueous core enclosed in one or more phospholipids promising candidate materials of nanoparticulate
bilayers. Since its discovery by Bangham, it has been drug carriers since 1980s because they have shown to
one of the most extensively studied classes as DDS have biodegradability. Among a number of researches
carriers for a number of drugs including peptides. regarding poly(alkylcyanoacrylates) nanoparticles,
Because its main component is phospholipids one of the most interesting results can be found in the
(lecithin) similar to biomembrane, the liposome pos- report of Damge’s group [19]. They prepared insulin-
sesses an excellent biocompatibility/biodegradability. containing poly(isobutylcyanoacrylate) nanocapsules
This nature has significant advantage over other types (the mean diameter was 220 nm) by the interfacial
of nanoparticulate drug carriers because toxicological polymerization technique. It is worthwhile to note
issues can be less concerned even if the liposome is that oral administration of this insulin-loaded
transported to the systemic circulation as a conse- nanocapsules to diabetic rats showed surprisingly pro-
quence of its intestinal absorption. Another feature of longed hypoglycemic effect lasted up to 20 days after
the liposome is its relatively large capacity of the the administration [19]. More recently, poly(isobutyl-
inner aqueous phase. Since most of peptide- and pro- cyanoacrylate) nanocapsules double-coated with
tein-based drugs are water-soluble, this structural fea- Tween 80 and PEG20000 was shown to effective for
ture allows us to incorporate and retain these drugs in brain targeting of hexapeptide (dalargin) via oral
the liposomes stably and efficiently. For instance, in administration [20].
the cases of loading of insulin and calcitonin into the While most poly(alkyl(meth)acrylates) are practi-
liposomes, high loading efficiencies around 80% cally non-biodegradable, a variety of (meth)acrylic
were successfully achieved, depending on the liposo- monomers with different chemical properties are
mal formulations and preparation conditions [15]. available and thus the combination of two or more dif-
Instability of the liposomes in the gastrointestinal ferent types of acrylic monomers enables us to freely
tract has been concerned in effective oral peptide design multi-functional nanoparticles. A representa-
delivery, but it depends on the lipid composition. Use tive example can be seen in nanospheres synthesized
of a membrane stabilizing agent (cholesterol) [16] by radical polymerization of methacrylic acid (MAA)
and phospholipids with a high gel–liquid crystalline and poly(ethylene glycol) mono methacrylate
transition temperature, and/or surface modification of (PEGMA) in the presence of a cross-linking agent
liposome with polyethylene glycol [17] were shown to (hereafter abbreviated as p(MAA-g-EG)) [21–27].
be effective to enhance the stability of liposome The p(MAA-g-EG) nanospheres are hydrogel
against gastric juice, bile and digestive enzymes. nanoparticles exhibiting pH-responsive swelling
Surface modification of liposome is also proposed to through the formation of interpolymer complexes as a

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