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Pharmaceutical Nanotechnology

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ISSN (Print): 2211-7385
ISSN (Online): 2211-7393

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Research Article

Eudragit L-100 Capsules Aromatize and Quaternerize Chitosan for Insulin Nanoparticle Oral Delivery During Toxic Oxidative Stress in Rat Liver and Kidney

Author(s): Reza Mahjub, Farzane K. Najafabadi, Narges Dehkhodaei, Nejat Kheiripour, Amir N. Ahmadabadi, Sara S. Asl, Masomeh Taheri-Azandariani and Akram Ranjbar*

Volume 8, Issue 3, 2020

Page: [239 - 254] Pages: 16

DOI: 10.2174/2211738508666200628033442

Price: $65

Abstract

Background: Insulin, like most peptides, is classified as a hydrophilic and macromolecular drug that is considered as a low permeable and unstable compound in the gastrointestinal (GI) tract. The acidic condition of the stomach can degrade insulin molecules. Moreover, the presence of proteolytic activities of some enzymes such as trypsin and chymotrypsin can hydrolyze amide-bonds between various amino-acids in the structures of peptides and proteins. However, due to its simplicity and high patient compliance, oral administration is the most preferred route of systemic drug delivery, and for the development of an oral delivery system, some obstacles in oral administration of peptides and proteins including low permeability and low stability of the proteins in GI should be overcome.

Objective: In this study, the effects of orally insulin nanoparticles (INPs) prepared from quaternerized N-aryl derivatives of chitosan on the biochemical factors of the liver in diabetic rats were studied.

Methods: INPs composed of methylated (amino benzyl) chitosan were prepared by the PEC method. Lyophilized INPs were filled in pre-clinical capsules, and the capsules were enteric-coated with Eudragit L100. Twenty Male Wistar rats were randomly divided into four groups: group1: normal control rats, group 2: diabetic rats, group 3: diabetic rats received capsules INPs(30 U/kg/day, orally), group 4: the diabetic rats received regular insulin (5 U/kg/day, subcutaneously). At the end of the treatment, serum, liver and kidney tissues were collected. Biochemical parameters in serum were measured using spectrophotometric methods. Also, oxidative stress was measured in plasma, liver and kidney. Histological studies were performed using H and E staining .

Results: Biochemical parameters, and liver and kidney injury markers in serum of the diabetic rats that received INPs improved significantly compared with the diabetic group. INPs reduced oxidative toxic stress biomarkers in serum, liver and kidney of the diabetic treated group. Furthermore, a histopathological change was developed in the treated groups.

Conclusion: Capsulated INPs can prevent diabetic liver and oxidative kidney damages (similar regular insulin). Therefore oral administration of INPs appears to be safe.

Lay Summary: Although oral route is the most preferred route of administration, but oral delivery of peptides and proteins is still a challenging issue. Diabetes Mellitus may lead to severe complications, which most of them are life-threatening. In this study, we are testing the toxicity of oral insulin nanoparticles in kidney and liver of rats. For this investigation, we will prepare insulin nanoparticles composed of a quaternized derivative of chitosan. The nanoparticles will be administered orally to rats and the level of oxidative stress in their liver and kidney will be determined. The data will be compared to the subcutaneous injection of insulin.

Keywords: Chitosan, diabetes, Eudragit L100, insulin nanoparticles, kidney, liver.

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[1]
Fröde TS, Medeiros YS. Animal models to test drugs with potential antidiabetic activity. J Ethnopharmacol 2008; 115(2): 173-83.
[http://dx.doi.org/10.1016/j.jep.2007.10.038] [PMID: 18068921]
[2]
Fonte P, Araújo F, Reis S, Sarmento B. Oral insulin delivery: how far are we? J Diabetes Sci Technol 2013; 7(2): 520-31.
[http://dx.doi.org/10.1177/193229681300700228] [PMID: 23567010]
[3]
Mahjub R, Radmehr M, Dorkoosh FA, Ostad SN, Rafiee-Tehrani M. Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro, ex vivo and in vivo characterizations. Drug Dev Ind Pharm 2014; 40(12): 1645-59.
[http://dx.doi.org/10.3109/03639045.2013.841187] [PMID: 24093431]
[4]
Cao SJ, Xu S, Wang HM, et al. Nanoparticles: oral delivery for protein and peptide drugs. AAPS PharmSciTech 2019; 20(5): 190.
[http://dx.doi.org/10.1208/s12249-019-1325-z] [PMID: 31111296]
[5]
Prego C, Torres D, Fernandez-Megia E, Novoa-Carballal R, Quiñoá E, Alonso MJ. Chitosan-PEG nanocapsules as new carriers for oral peptide delivery. Effect of chitosan pegylation degree. J Control Release 2006; 111(3): 299-308.
[http://dx.doi.org/10.1016/j.jconrel.2005.12.015] [PMID: 16481062]
[6]
Shateri H, Ranjbar A, Kheiripour N, et al. Tempol improves oxidant/antioxidant parameters in testicular tissues of diabetic rats. Life Sci 2019; 221: 65-71.
[http://dx.doi.org/10.1016/j.lfs.2019.02.016] [PMID: 30738867]
[7]
Ranjbar A, Kheiripour N, Ghasemi H, Seif Rabiei MA, Dadras F, Khoshjou F. Antioxidative effects of tempol on mitochondrial dysfunction in diabetic nephropathy. Iran J Kidney Dis 2018; 12(2): 84-90.
[PMID: 29507270]
[8]
Jamshidi M, Ziamajidi N, Khodadadi I, Dehghan A, Kalantarian G, Abbasalipourkabir R. The effect of insulin-loaded trimethylchitosan nanoparticles on rats with diabetes type I. Biomed Pharmacother 2018; 97: 729-35.
[http://dx.doi.org/10.1016/j.biopha.2017.10.097] [PMID: 29102916]
[9]
Mahjub R, Dorkoosh FA, Amini M, Khoshayand MR, Rafiee-Tehrani M. Preparation, statistical optimization, and in vitro characterization of insulin nanoparticles composed of quaternized aromatic derivatives of chitosan. AAPS PharmSciTech 2011; 12(4): 1407-19.
[http://dx.doi.org/10.1208/s12249-011-9716-9] [PMID: 22033812]
[10]
Keiripour N, et al. The effects of synthetic orally administrated insulin nanoparticles in comparison to injectable insulin on the renal function markers of type 1-diabetic rats. Iran J Basic Med Sci 2020; 23(6): 810-8.
[11]
Mahjub R, Dorkoosh FA, Amini M, et al. In vitro characterization and cell cytotoxicity of insulin nanoparticles composed of quaternized aromatic derivatives of chitosan. J Control Release 2013; 172(1)e112
[http://dx.doi.org/10.1016/j.jconrel.2013.08.270]
[12]
Qinna NA, Badwan AA. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats. Drug Des Devel Ther 2015; 9: 2515-25.
[http://dx.doi.org/10.2147/DDDT.S79885] [PMID: 26005328]
[13]
Benzie IF, Strain JJ. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol 1999; 299: 15-27.
[http://dx.doi.org/10.1016/S0076-6879(99)99005-5] [PMID: 9916193]
[14]
Hu ML. Measurement of protein thiol groups and glutathione in plasma. Methods Enzymol 1994; 233: 380-5.
[http://dx.doi.org/10.1016/S0076-6879(94)33044-1] [PMID: 8015473]
[15]
Gergel’ D, Cederbaum AI. Interaction of nitric oxide with 2-thio-5-nitrobenzoic acid: implications for the determination of free sulfhydryl groups by Ellman’s reagent. Arch Biochem Biophys 1997; 347(2): 282-8.
[http://dx.doi.org/10.1006/abbi.1997.0352] [PMID: 9367537]
[16]
Chen S, Guo F, Deng T, et al. Eudragit S100-Coated Chitosan Nanoparticles Co-loading Tat for Enhanced oral colon absorption of insulin. AAPS PharmSciTech 2017; 18(4): 1277-87.
[http://dx.doi.org/10.1208/s12249-016-0594-z] [PMID: 27480441]
[17]
Reis CP, Ribeiro AJ, Veiga F, Neufeld RJ, Damgé C. Polyelectrolyte biomaterial interactions provide nanoparticulate carrier for oral insulin delivery. Drug Deliv 2008; 15(2): 127-39.
[http://dx.doi.org/10.1080/10717540801905165] [PMID: 18293199]
[18]
Sharma S, Jyoti K, Sinha R, Katyal A, Jain UK, Madan J. Protamine coated proliposomes of recombinant human insulin encased in Eudragit S100 coated capsule offered improved peptide delivery and permeation across Caco-2 cells. Mater Sci Eng C 2016; 67: 378-85.
[http://dx.doi.org/10.1016/j.msec.2016.05.010] [PMID: 27287134]
[19]
Wilcox G. Insulin and insulin resistance. The Clinical biochemist. Reviews 2005; 26(2): 19-39.
[20]
Heidarisasan S, Ziamajidi N, Karimi J, Abbasalipourkabir R. Effects of insulin-loaded chitosan-alginate nanoparticles on RAGE expression and oxidative stress status in the kidney tissue of rats with type 1 diabetes. Iran J Basic Med Sci 2018; 21(10): 1035-42.
[PMID: 30524677]
[21]
Sahu SK. Development and evaluation of insulin incorporated nanoparticles for oral administration. ISRN Nanotechnology 2013; 2013: 1-6.
[22]
Kheiripour N, Karimi J, Khodadadi I, Tavilani H, Taghi Goodarzi M, Hashemnia M. Hepatoprotective effects of silymarin on liver injury via irisin upregulation and oxidative stress reduction in rats with type 2 diabetes. Iran J Med Sci 2019; 44(2): 108-17.
[PMID: 30936597]
[23]
Olya S, et al. Oral delivery of insulin-loaded nanoparticles in diabetic rabbits and in sheep. Czech J Anim Sci 2014; 59: 251-6.
[http://dx.doi.org/10.17221/7495-CJAS]
[24]
Lopes M, Aniceto D, Abrantes M, et al. In vivo biodistribution of antihyperglycemic biopolymer-based nanoparticles for the treatment of type 1 and type 2 diabetes. Eur J Pharm Biopharm 2017; 113: 88-96.
[http://dx.doi.org/10.1016/j.ejpb.2016.11.037] [PMID: 28007370]

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