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

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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.

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ACKNOWLEDGMENTS

This study was made possible by financial supports from Deputy of Research, Tehran University of Medical Sciences.

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The authors declare no conflict of interests.

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Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Enghelab Ave., Tehran, Iran

    Maryam Mansourpour, Reza Mahjub, Elnaz Sadat Shamsa, Morteza Rafiee- Tehrani & Farid Abedin Dorkoosh

  2. Department of Pharmaceutics, School of Pharmacy, Hamedan University of Medical Sciences, Hamedan, Iran

    Reza Mahjub

  3. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Amini

  4. Drug Design and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Amini

  5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Naser Ostad

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  1. Maryam Mansourpour
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Correspondence to Farid Abedin Dorkoosh.

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Mansourpour, M., Mahjub, R., Amini, M. et al. Development of Acid-Resistant Alginate/Trimethyl Chitosan Nanoparticles Containing Cationic β-Cyclodextrin Polymers for Insulin Oral Delivery. AAPS PharmSciTech 16, 952–962 (2015). https://doi.org/10.1208/s12249-014-0282-9

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