Abstract
The absorption-enhancing effects of glycol chitosan modified by 5β-cholanic acid nanoparticles (5β-CHA/GC-NPs) on a drug with poor absorption in the intestine were studied by the method of in situ closed loop. We chose fluorescein isothiocyanate-labeled dextrans (FDs) and insulin as the model drugs. 5β-CHA/GC-NPs loaded to different drugs were prepared by the dialysis method, and the physicochemical characteristics and in vitro release profiles of nanoparticles were also estimated. The results showed that 5β-CHA/GC-NPs markedly increased the absorption of insulin and FDs in the jejunum, ileum, and colon. The ratios of absorption for all the drugs in the jejunum were higher than those in the ileum and colon. In addition, the enhancing effect of 5β-CHA/GC-NPs for the absorption of FDs from the jejunum was decreased with increasing molecular weights. In the toxicity test, 5β-CHA/GC-NPs did not significantly increase the release of protein and the activities of LDH, indicating that the nanoparticles did not cause any membrane damage to the intestine. These findings suggested that 5β-CHA/GC-NPs were safe and useful carriers for enhancing the absorption of the drug with poor absorption by intestinal membranes.
Similar content being viewed by others
References
Niu Z, Conejos-Sánchez I, Griffin BT, O’Driscoll CM, Alonso MJ. Lipid-based nanocarriers for oral peptide delivery. Adv Drug Deliv Rev. 2016;106(PtB):337–54.
Yin T, Zhang Y, Liu Y, Chen Q, Fu Y, Liang J, et al. The efficiency and mechanism of N-octyl-O, N-carboxymethyl chitosan-based micelles to enhance the oral absorption of silybin. Int J Pharm. 2017;536(1):231–40.
Arafat M, Kirchhoefer C, Mikov M, Sarfraz M, Löbenberg R. Nanosized liposomes containing bile salt: a vesicular nanocarrier for enhancing oral bioavailability of BCS class III drug. J Pharm Pharm Sci. 2017;20:305–18.
Pooja D, Kulhari H, Kuncha M, Rachamalla SS, Adams DJ, Bansal V, et al. Improving efficacy, oral bioavailability, and delivery of paclitaxel using protein-grafted solid lipid nanoparticles. Mol Pharm. 2016;13(11):3903–12.
Mooranian A, Negrulj R, Mathavan S, Martinez J, Sciarretta J, Chen-Tan N, et al. An advanced microencapsulated system: a platform for optimized oral delivery of antidiabetic drug-bile acid formulations. Pharm Dev Technol. 2015;20(6):702–9.
Janes KA, Calvo P, Alonso MJ. Polysaccharide colloidal particles as delivery systems for macromolecules. Adv Drug Deliv Rev. 2001;47:83–97.
Lehr CM, Bouwstra JA, Schacht E, Junginger HE. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm. 1992;78:43–8.
Aspden TJ, Mason JD, Jones NS. Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J Pharm Sci. 1997;86:509–13.
Barbari GR, Dorkoosh FA, Amini M, Sharifzadeh M, Atyabi F, Balalaie S, et al. A novel nanoemulsion-based method to produce ultrasmall, water-dispersible nanoparticles from chitosan, surface modified with cell-penetrating peptide for oral delivery of proteins and peptides. Int J Nanomedicine. 2017;12:3471–83.
Hecq J, Siepmann F, Siepmann J, Amighi K, Goole J. Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration. Drug Dev Ind Pharm. 2015;41(12):2037–44.
Sonaje K, Chuang EY, Lin KJ, Yen TC, Su FY, Tseng MT, et al. Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations. Mol Pharm. 2012;9(5):1271–9.
Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, et al. Chitosan-DNA nanoparticles as gene carriers: synthesis, characterization and transfection efficiency. J Control Release. 2001;70:399–421.
Yinbo P, Chenlu S, Chuanfeng Y, Qige G, Min Y. Low molecular weight chitosan-coated silver nanoparticles are effective for the treatmentof MRSA-infected wounds. Int J Nanomedicine. 2017;12:295–304.
Zeng L, Qin C, Wang W, Chi W, Li W. Absorption and distribution of chitosan in mice after oral administration. Carbohydr Polym. 2008;71:435–40.
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.
Yhee JY, Son S, Kim SH, Park K, Choi K, Kwon IC. Self-assembled glycol chitosan nanoparticles for disease-specific theranostics. J Control Release. 2014;193:202–13.
Lee SJ, Koo H, Jeong H, Huh MS, Choi Y, Jeong SY, et al. Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy. J Control Release. 2011;152:21–9.
Tieshi L, Lara L, Froilan GM, Timothy JM, Yun Y, Anna S. Use of glycol chitosan modified by 5β-cholanic acid nanoparticles for the sustained release of proteins during murine embryonic limb skeletogenesis. J Control Release. 2010;144(1):101–8.
Hyung GJ, Kyung HM, Tae HN, Seong JN, Jae HP, Seo YJ. Prolonged antidiabetic effect of zinc-crystallized insulin loaded glycol chitosan nanoparticles in type 1 diabetic rats. Arch Pharm Res. 2008;31(7):918–23.
Park JH, Cho YW, Chung H, Kwon IC, Jeong SY. Synthesis and characterization of sugar-bearing chitosan derivatives: aqueous solubility and biodegradability. Biomacromolecules. 2003;4(4):1087–91.
Zheng Y, Wu Y, Yang W, Wang C, Fu S, Shen X. Preparation, characterization, and drug release in vitro of chitosan-glycyrrhetic acid nanoparticles. J Pharm Sci. 2005;95(1):181–91.
Farnaz E, Mohammad HG, Behnaz E, Mohammad RK, Fatemeh A, Rassoul D. PLGA nanoparticles of different surface properties: preparation and evaluation of their body distribution. Int J Pharmaceut. 2008;349(1):249–55.
Fetih G, Habib F, Okada N, Fujita T, Attia M, Yamamoto A. Nitricoxide donors can enhance the intestinal transport and absorption of insulin and [Asu1,7]-eel calcitonin in rats. J Control Release. 2005;106:287–97.
Chengyun Y, Jiwei G, Yuguang L, Weiguo S, Hongying J. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat. Drug Deliv Transl Res. 2017;7:408–15.
Koo H, Min KH, Lee SC, Park JH, Park K, Jeong SY, et al. Enhanced drug-loading and therapeutic efficacy of hydrotropic oligomer-conjugated glycol chitosan nanoparticles for tumor-targeted paclitaxel delivery. J Control Release. 2013;172:823–31.
Lamprecht A, Schafer U, Lehr CM. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm Res. 2001;18:788–93.
Kim JH, Kim YS, Kim S, Park JH, Kim K, Choi K, et al. Hydrophobically modified glycol chitosan nanoparticles as carriers for paclitaxel. J Control Release. 2006;111:228–34.
Kwon S, Park JH, Chung H, Kwon IC, Jeong SY. Physicochemical characteristics of self-assembled nanoparticles based on glycol chitosan bearing 5-cholanic acid. Langmuir. 2003;19(24):10188–93.
Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev. 2001;47:39–55.
Takeuchi H, Matsui Y, Yamamoto H, Kawashima Y. Mucoadhesive liposomes coated with chitosan or carbopol for oral administration of peptide drugs. In: Proceedings of 26th international symposiumon controlled release of bioactive materials; 1999. p. 988–9.
Park JH, Kwon S, Nam JO, Park RW, Chung H, Seo SB, et al. Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery. J Control Release. 2004;95:579–88.
Kim JH, Kim YS, Park K, Kang E, Lee S, Nam HY, et al. Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy. Biomaterials. 2008;29:1920–30.
Yuan Z, Ye Y, Gao F, Yuan H, Lan M, Lou K, et al. Chitosan-graft-β-cyclodextrin nanoparticles as a carrier for controlled drug release. Int J Pharm. 2013;446:191–8.
Park K, Hong HY, Moon HJ, Lee BH, Kim IS, Kwon IC, et al. A new atherosclerotic lesion probe based on hydrophobically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides. J Control Release. 2008;128(3):217–23.
Yamabe K, Kato Y, Onishi H, Machida Y. Potentiality of double liposomes containing salmon calcitonin as an oral dosage form. J Control Release. 2003;20:429–36.
Lee VHL, Yamamoto A, Kompella UB. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit Rev Ther Drug Carrier Syst. 1991;8:91–2.
Funding
We sincerely thank the National Natural Science Foundation of China (No. 31860266) and the Program of GuangXi Provincial Natural Science Foundation of China (No. 2018JJA140093) for the financial support.
Author information
Authors and Affiliations
Corresponding author
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yan, C., Gu, J., Lv, Y. et al. 5β-Cholanic Acid/Glycol Chitosan Self-Assembled Nanoparticles (5β-CHA/GC-NPs) for Enhancing the Absorption of FDs and Insulin by Rat Intestinal Membranes. AAPS PharmSciTech 20, 30 (2019). https://doi.org/10.1208/s12249-018-1242-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12249-018-1242-6