Insulin systems for peroral peptide drug delivery [24,

Insulin Delivery

Several alternative routes of insulin
administration have been developed, such as pulmonary, nasal, buccal, oral,
rectal, ocular, transdermal, vaginal, and intrauterine 16. Oral insulin delivery has been expected to
be more expedient and to enhance patient adherence. More importantly, oral
insulin absorption closely imitates insulin secretion under physiological
conditions. Thus, it may exercise direct effects on hepatic glucose production
and reduce the risk of hypoglycemia associated with peripheral insulin
injection 17. Oral insulin delivery remains challenging,
however, and numerous attempts have failed to improve outcomes, including
liposomes, microcapsules, beads, hydrogels, and chemical modifications of the
molecule 18. Nonetheless, augmented research efforts in
the past decades evidently demonstrate the possibility of developing polymeric
strategies for oral insulin therapy. Even though some of these methods have
shown low bioavailability of insulin and exhibit several negative effects such
as irritation of the intestinal mucosal membrane and damage of the membrane
barrier, yet few strategies including copolymeric hydrogel microparticle of
poly(methacrylic acid) joined with poly(ethylene glycol) P(MAAg- EG) have
demonstrated 19-22 enhancement of oral insulin absorption in
animal experiments up to 4.2% bioavailability in addition to their ability to
protect insulin from the enzymes as well as adhesive features on the mucus
membrane. In a recent study by Sonaje et al. 23 the highest achievement of insulin
bioavailability was demonstrated in animal diabetic models. They was prepared a
pH-sensitive nanoparticle (NP) system composed of poly(g-glutamic acid) and
chitosan as a potential approach for the oral delivery of insulin 8. Dorkoosh
et al. 24 have prepared a novel delivery systems based
on superporous hydrogel (SPH) and SPH composite (SPHC) polymers were used to
improve the intestinal absorption of insulin in healthy pigs. These results
indicate that the absorption of insulin was slightly increased using
SPH/SPHC-based delivery systems. Furthermore, a large variability was observed,
probably due to physiological and metabolic changes during the experiments. In
conclusion, SPH/SPHC-based delivery systems are able to enhance the intestinal
absorption of insulin and are, therefore, considered as promising systems for
peroral peptide drug delivery 24, 25. A sustained injectable insulin delivery
system of poly (?-amino ester)-poly (?-caprolactone)-poly (ethylene
glycol)-poly (?-caprolactone)-poly (?-amino ester) (PAE-PCL-PEG-PCL-PAE)
pentablock copolymer as a pH -temperature-sensitive hydrogel was assessed by
Huynh et al. The obtained results showed that hydrogel complex could be
suggested the therapeutic potential for diabetic patients 26. In the same study, the novel pH-, ionic
strength and temperature- sensitive hydrogel was used for insulin delivery 27. The pH/thermosensitive polymeric beads based
polymers of N-isopropylacrylamide (NIPAm), butyl methacrylate (BMA), and
acrylic acid (AA) applied to release of insulin. The molecular weight (MW) of
the polymers was affected upon the release rate of drug 28. In another study, James et al. have prepared
smart polymeric as “intelligent” delivery systems able to sustained release of
therapeutic macromolecules29. Amongst nanocarriers, polymeric
nanoparticles (NPs) have showed significant advantages for protein and peptide
drug delivery following oral, nasal, pulmonary, parenteral, transdermal, and
ocular performances 30. PCL– PEG–PCL, chitosan (CS), and PLA NPs was
achieved higher insulin loading and employed to improve bioavailability and
hypoglycemic activity of insulin via oral route 31, 32. The chitosan-N-acetyl-L-cysteine (CS-NAC)
NPs, and Hybrid poly-oligosaccharide NPs comprising of CS and cyclodextrins
were applied as nanocarriers for nosal insulin delivery 33, 34. Nanocarriers such as CS NPs has been
suggested as an excellent formulation for local and systemic delivery of
insulin following pulmonary route 30, 35. The polymeric nanocarriers to insulin
delivery have been using to increase the properties as solubility,
bioavailability, and prolonged circulation times. 36. Insulin-loaded acrylic hydrogels containing
absorption enhancers applied to rectal insulin delivery: in vitro and in vivo
study 37.