Development of Acid-Resistant Alginate/Trimethyl Chitosan Nanoparticles Containing Cationic β-Cyclodextrin Polymers for Insulin Oral Delivery

Abstract

Abstract. In this study, the use of trimethylchitosan (TMC), by higher solubility in comparison with chitosan, in alginate/chitosan nanoparticles containing cationic β-cyclodextrin polymers (CPβCDs) has been studied, with the aim of increasing insulin uptake by nanoparticles. Firstly, TMCs were synthesized by iodomethane, and CPβCDs were synthesized within a one-step polycondensation reaction using choline chloride (CC) and epichlorohydrine (EP). Insulin-CβCDPs complex was prepared by mixing 1:1 portion of insulin and CPβCDs solutions. Then, nanoparticles prepared in a three-step procedure based on the iono-tropic pregelation method. Nanoparticles screened using experimental design and Placket Burman methodology to obtain minimum size and polydispercity index (pdI) and the highest entrapment efficiency (EE). CPβCDs and TMC solution concentration and pH and alginate and calcium chloride solution concentrations are found as the significant parameters on size, PdI, and EE. The nanoparticles with proper physicochemical properties were obtained; the size, PdI, and EE% of optimized nanoparticles were reported as 150.82±21 nm, 0.362±0.036, and 93.2%±4.1, respectively. The cumulative insulin release in intestinal condition achieved was 50.2% during 6 h. By SEM imaging, separate, spherical, and nonaggregated nanoparticles were found. In the cytotoxicity studies on Caco-2 cell culture, no significant cytotoxicity was observed in 5 h of incubation, but after 24 h of incubation, viability was decreased to 50% in 0.5 mμ of TMC concentration. Permeability studies across Caco-2 cells had been carried out, and permeability achieved in 240 min was 8.41±0.39%, which shows noticeable increase in comparison with chitosan nanoparticles. Thus, according to the results, the optimized nanoparticles can be used as a new insulin oral delivery system.

Overviews on the cellular uptake mechanism of polysaccharide colloidal nanoparticles

“…Not only the synthetic polymers such as poly(lactide‐co‐glycolide) , polyacrylates , polycaprolactones and polyethylenimine but also natural polymers such as proteins , nucleic acids and polysaccharides have been used to prepare nanoparticulate drug/gene carriers. Over the years, it has been highlighted that nanoparticles frequently exhibit improved properties for easier translocation across biological barriers as they have the advantages of high surface area/volume ratio and increased mobility, and hence a great interactive potential with the biological surfaces . Nanoparticles also offer the potential to protect the encapsulated molecules from both extracellular and intracellular degradation, resulting in improved intracellular bioavailability .…”

A natural lipopeptide of surfactin for oral delivery of insulin

“…To develop oral INS, different types of drug carriers have been employed to protect INS from the harsh environment of the GI tract and deliver it to the target side in the body (Mansourpour et al, 2015). For example, chemical modification, absorption enhancers, mucoadhesive polymers, protease inhibitors and permeation enhancers as well as encapsulation in drug delivery systems, or even a combination of the aforementioned strategies have been adopted for improving the BA of oral INS (Li et al, 2014;Jain & Jain, 2015).…”

Enteric-coated insulin microparticles delivered by lipopeptides of iturin and surfactin

“…Simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were used for in vitro release studies of the enteric-coated iMSs-ITU and iMSs-ITU-SFN, respectively (Mansourpour et al., 2015 ). Twenty milligram of enteric-coated iMSs-ITU or iMSs-ITU-SFN was suspended in 20 ml of SGF (pH 1.2) or SIF (pH 6.8), then kept in a shaker (50 rpm) at 37 °C.…”