Wide researches have been done to investigate the oral delivery system of insulin for the diabetes’ treatment. Developments in nanotechnology have brought us ever closer to this purpose. The current review focuses on the various barriers existing in the way of oral insulin delivery and the strategies taken so far to dominate those by restrain nanoparticles as potential carriers of insulin.
Keywords: Insulin; Oral Delivery; Diabetes; Nanoparticles; Nanomedicine
Abbreviations: GI: Gastrointestinal; CS: Chitosan
Nanomedicine performance includes monitoring, controlling, construction, repair, protection, and enhancement of human biological organizations at the molecular levels; using nanodevices and nanostructures that operate at a single-cell scale is to reach the medical benefits. The most important application of nanotechnology in medicine is that it can target selected areas thus it increases the efficiency of drugs and reduces their side effects. Nanotechnology or nanomedicine is being exploited widely in research and development of medicine . Diabetes mellitus explains a metabolic disturbance of several etiology defined by persistent hyperglycemia due to disorders of carbohydrate, lipid and protein metabolism which occur from imperfection of insulin secretion, insulin action, or both. The effects of diabetes mellitus involve long–term destruction, dysfunction and failure of many organs . Diabetes is one of the major suffering diseases of modern society and yet, diabetic patients inject insulin directly into their blood-vessels in order to control their blood-sugar levels. Problems and difficulties of insulin injection have produced many efforts to explore an alternative for insulin therapy, including oral, pulmonary, and nasal delivery of insulin. Stomach acid destroys protein-based drugs such as Insulin and makes oral insulin consumption wasteful. Therefore, the desired results could be achieved by encapsulating insulin molecules in polymeric nanoparticles .
Oral Delivery and Its Problems
Oral delivery of drugs is widely preferred because of its easy usage and the more comfortable condition in which patient takes the drug painless. The success of improved oral insulin is very helpful for the treatment of diabetes mellitus to prevail over the problem of daily subcutaneous injections . Particles in the gastrointestinal (GI) area could be absorbed by several sites and mechanisms. The effective factors in absorption are the particle size, surface charge or hydrophobicity, concentration and any targeting mechanisms on the particle that would press out vicinity to determined sites in the GI tract . The duty of the GI system includes the digestion and absorption of nutrients and being as a defense barrier to pathogenic microorganisms and toxins . So, manifold challenges exist for oral delivery of the drugs. Main barriers to oral delivery of peptide- and protein-based drugs include the chemical degradation (extreme pH conditions, proteolysis enzymes) and the physical barrier (Mucus layer and Intestinal epithelium) in GI tract [6,7]. Thus, insulin should be enveloped in a matrix to keep it safe from gastric enzymes. This is reached by encapsulating the insulin molecules in polymeric nanoparticles. Insulin was loaded in different nanoparticles as oral delivery structure, such as natural polymeric nanoparticles , synthetic polymeric nanoparticles , solid lipid nanoparticles , liposomes , and nano emulsions , as well as the inorganic nanoparticles . These nanoscale delivery structures provide a suitable path for insulin delivery. Compared to other nanoparticles, the natural polymeric nanoparticles presented higher biocompatibility and biodegradability, better storage, greater safety and physiological stability .
Most Important Insulin Carrier
Chitosan Production of pharmaceutically active proteins, such as insulin, has become possible. A major barrier to the absorption of hydrophilic drugs is the intestinal epithelium, as they cannot diffuse across epithelial cells through lipid-bilayer cell membranes to the bloodstream. A versatility of intestinal permeation enhancers including chitosan (CS) have been used in order to absorb the hydrophilic macromolecules. Chitosan is a linear polysaccharide derived from chitin, have desirable physicochemical properties, such as biodegradability, non-toxicity, good muco adhesion, abundant renewable sources and low cost . Chitosan, as the unique cationic polysaccharide, could interact with polyanions leading to the spontaneous formation of nanoparticles, which is generally referred as ionic gelation or polyelectrolyte complexation technique. Most convenient chitosan-based nanoparticles are prepared by letting chitosan and its derivatives to react with various anionic polyelectrolytes include tripolyphosphate (TPP) , alginate , poly (g-glutamic acid)  and lecithin . Five general protocols that show the preparation of chitosan-based nanoparticles for oral insulin delivery, are summarized in Figure 1 .
Alginate extracted from brown seaweed and is a water-soluble anionic polysaccharide, including alternating blocks of (1-4)-linked β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues . Alginate has obtained notable interests in oral delivery of insulin, because of some desirable attributes, such as biodegradability, biocompatibility, low immunogenicity, good mucoadhesion, and non-toxicity. Diverse alginate-based nanoparticles have been synthesized by ionic gelation or polyelectrolyte complexation. Asunder from nanotechnology, other strategies, such as pHresponsive alginate/κ-carrageenan composite hydrogel beads , colloidosomes based on chitosan-coated alginate particles , and hydrogel microparticles , have also been investigated to elevate the oral insulin administration using alginate-based delivery methods.
Nanotechnology has presented a helpful substrate for insulin carriers. As expecting, there have been new researches and explorations of potential NPs to provide insulin orally; these formulations are being modified continually so the future of oral insulin seems promising.
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