An aqueous nanoparticulate delivery system containing oppositely charged polymers polyethylenimine (PEI) and DS with zinc
as a stabilizer was developed by Tiyaboonchai et al. (43). The pH of PEI solutions, the weight ratio of the two polymers,
and zinc sulfate concentrations affected the particle size of the nanoparticles. Spherical particles of 250 nm mean diameter
with a zeta potential of approximately +30 mV were produced under optimal conditions. Insulin could be loaded up to 90% in
these nanoparticles. Circular dichroism spectra showed no significant conformational changes compared with free insulin under
optimized formulation conditions. In contrast to rapid release of insulin in vitro, the hypoglycemic activity in streptozotocin-induced diabetic rats was prolonged. This system offered a number of advantages,
including ease of manufacturing under mild preparation conditions, completely aqueous processing conditions, use of biocompatible
polymers, ability to control particle size, a high level of drug entrapment, and an ability to preserve secondary structure
and biological activity of protein.
Simon et al. prepared nanosized insulin-complexes based on amine modified comb-like polyesters (44). Protection of insulin
in nanocomplexes from enzymatic degradation was investigated. The interaction with enterocyte-like Caco-2 cells in terms of
cytotoxicity, transport through and uptake in the cell layers was evaluated by measuring transepithelial electrical resistance
(TEER), release of lactate dehydrogenase (LDH), and insulin transport. The protection capacity of the nanocomplexes and their
interaction with Caco-2 cells varied strongly as a function of lactide-grafting (hydrophobicity). With increasing lactide-grafting
(P(26)P(26)-1(LL)P(26)-2(LL)) Nanocomplexes protected as much as 95% of the insulin against degradation by trypsin.
Colon-targeted delivery systems
Proteolytic enzymes in the stomach degrade insulin, but in intestines peptidase activity is low and drainage into lymph is
maximized. Researchers are exploring colon-specific delivery for insulin. To achieve colon specific delivery of insulin, Hideyuki
et al. prepared azopolymer-coated pellets containing fluorescein isothiocyanate dextran (FD-4) (45). In vitro drug-release experiments were carried out according to Japanese Pharmacopoeia XII (rotating basket method). The release of FD-4 from the pellets in phosphate buffered saline was very small. However, the
release of FD-4 was markedly increased in the presence of rat ceacal contents. The pharmacodynamic studies of the azopolymer-coated
pellets containing these peptides with camostat mesilate (protease inhibitor) were carried out by measuring the hypoglycemic
effects. A slight decrease in plasma-glucose levels was observed following the oral administration of these pellets containing
12.5 IU of insulin compared with the same dose of insulin solution. The authors concluded that azopolymer-coated pellets with
protease inhibitor might be useful carriers for the colon-specific delivery of insulin.
Yakugaku Zasshi developed two types of microcapsular devices containing new acrylate-based nanogels with a specific solute-permeability
for the delayed- or thermosensitive-release of peptide drugs (46). A nanogel-particle of acrylic terpolymer, ethyl acrylate-methyl
methacrylate-2-hydroxy-ethyl methacrylate, was newly synthesized by emulsion polymerization to construct delayed-release microcapsules.
The insulin-loaded lactose particles were spray coated with the acrylic terpolymers. These microcapsules showed a pH-in-dependent
delayed-release profile. Oral administration of the microcapsules with the lag time of 6 h to beagle dogs resulted in significantly
reduced blood glucose concentration, leading to colon-specific insulin delivery with pharmacological availability of 5%. Meanwhile,
poly(N-isopropylcarylamide) (p(NIPAAm)] nanogel-particles with a reversible temperature-dependent swelling property were prepared
by dispersion polymerization to fabricate microcapsular membranes with thermosensitively changeable permeability. The microcapsules
constructed by coating of drug-loaded CaCO3 particles with a blend mixture of the p(NIPAAm) nanogels and ethylcellulose pseudo-latex exhibited an on-off positively thermosensitive
drug-release; the release rate was remarkably enhanced at higher temperatures possibly due to the formation of voids through
the shrinkage of p(NIPAAm) nanogels in the membrane. A possible application of this type of microcapsules can be found in
externally temperature-activated pulsatile peptide delivery.