Biocompatible non-covalent complexes of chitosan and different polymers: characteristics and application in drug delivery
The formulation of biocompatible drug carriers based on cationic biopolymer chitosan and natural or synthetic polymers represents an important research interest. Therefore, this review aims to perceive their potential in drug delivery. The most investigated chitosan-based polymer blends are polyelectrolyte complexes (PECs) obtained by establishing ionic interactions with biocompatible polyanions as alginates, pectin, xanthan gum, carrageenan, carboxymethylcellulose, and collagen. Depending on the preparation conditions, PECs could be prepared in versatile forms including membranes/films, hydrogel beads, nanoparticles, and microparticles, to achieve controlled (e.g., extended, delayed, colon-specific and pH-dependent) drug delivery. PECs can encapsulate hydrophilic and lipophilic drug substances with different molecular weights. Drug encapsulation allows the preservation of their structure, activity, improvement in absorption efficiency, reduction in adverse effects and long-term stability in vitro and in vivo. The biocompatible structures as non-covalent chitosan-based complexes could be formed also by establishing hydrogen bonds, for example with poly(vinyl alcohol). The swelling of these complexes is not pH-dependent and encapsulated drug substances are often released by already known types of diffusion. Moreover, grafted chitosan derivatives (e.g., carboxymethyl chitosan, trimethyl chitosan, acrylated chitosan) are synthesized to improve water solubility at a wide pH range and enhance the encapsulation capacity of promising PEC-based drug carriers.
Berger J, Reist M, Mayer JM, Felt O, Gurny R. Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications. Eur J Pharm Biopharm. 2004;57(1):35–52.
Muxika A, Etxabide A, Uranga J, Guerrero P, de la Caba K. Chitosan as a bioactive polymer: Processing, properties and applications. Int J Biol Macromol. 2017;105:1358–68.
Ali A, Ahmed S. A review on chitosan and its nanocomposites in drug delivery. Int J Biol Macromol. 2018;109:273–86.
Shariatinia Z. Pharmaceutical applications of chitosan. Adv Colloid Interface Sci. 2019;263:131–94.
Hamman JH. Chitosan based polyelectrolyte complexes as potential carrier materials in drug delivery systems. Mar Drugs. 2010;8(4):1305–22.
Bhattarai N, Gunn J, Zhang M. Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev. 2010;62(1):83–99.
Luo Y, Wang Q. Recent development of chitosan-based polyelectrolyte complexes with natural polysaccharides for drug delivery. Int J Biol Macromol. 2014;64:353–67.
De Robertis S, Bonferoni MC, Elviri L, Sandri G, Caramella C, Bettini R. Advances in oral controlled drug delivery: The role of drug-polymer and interpolymer non-covalent interactions. Expert Opin Drug Deliv. 2015;12(3):441–53.
Chen Y, Yan X, Zhao J, Feng H, Li P, Tong Z, et al. Preparation of the chitosan/poly(glutamic acid)/alginate polyelectrolyte complexing hydrogel and study on its drug releasing property. Carbohydr Polym. 2018;191:8–16.
Martínez-Ruvalcaba A, Chornet E, Rodrigue D. Viscoelastic properties of dispersed chitosan/xanthan hydrogels. Carbohydr Polym. 2007;67(4):586–95.
Argin-Soysal S, Kofinas P, Lo YM. Effect of complexation conditions on xanthan-chitosan polyelectrolyte complex gels. Food Hydrocoll. 2009;23(1):202–9.
Ćirić A, Medarević Đ, Čalija B, Dobričić V, Mitrić M, Djekic L. Study of chitosan/xanthan gum polyelectrolyte complexes formation, solid state and influence on ibuprofen release kinetics. Int J Biol Macromol. 2020;148:942–55.
Khong TT, Aarstad OA, Skjåk-Bræk G, Draget KI, Vårum KM. Gelling concept combining chitosan and alginate - Proof of principle. Biomacromolecules. 2013;14(8):2765–71.
Čalija B, Cekić N, Savić S, Daniels R, Marković B, Milić J. PH-sensitive microparticles for oral drug delivery based on alginate/oligochitosan/Eudragit® L100-55 "sandwich" polyelectrolyte complex. Colloids Surfaces B Biointerfaces. 2013;110:395–402.
Unagolla JM, Jayasuriya AC. Drug transport mechanisms and in vitro release kinetics of vancomycin encapsulated chitosan-alginate polyelectrolyte microparticles as a controlled drug delivery system. Eur J Pharm Sci. 2018;114:199–209.
Lefnaoui S, Moulai-Mostefa N, Yahoum MM, Gasmi SN. Design of antihistaminic transdermal films based on alginate–chitosan polyelectrolyte complexes: characterization and permeation studies. Drug Dev Ind Pharm. 2018;44(3):432–43.
Wasupalli GK, Verma D. Molecular interactions in self-assembled nano-structures of chitosan-sodium alginate based polyelectrolyte complexes. Int J Biol Macromol. 2018;114:10–7.
Gallardo-Rivera R, de los Ángeles Aguilar-Santamaría M, Silva-Bermúdez P, García-López J, Tecante A, Velasquillo C, et al. Polyelectrolyte complex of Aloe vera, chitosan, and alginate produced fibroblast and lymphocyte viabilities and migration. Carbohydr Polym. 2018;192:84–94.
Bigucci F, Luppi B, Cerchiara T, Sorrenti M, Bettinetti G, Rodriguez L, et al. Chitosan/pectin polyelectrolyte complexes: Selection of suitable preparative conditions for colon-specific delivery of vancomycin. Eur J Pharm Sci. 2008;35:435–41.
Maciel VB V., Yoshida CMP, Franco TT. Chitosan/pectin polyelectrolyte complex as a pH indicator. Carbohydr Polym. 2015;132:537–45.
Da Costa MPM, De Mello Ferreira IL, De Macedo Cruz MT. New polyelectrolyte complex from pectin/chitosan and montmorillonite clay. Carbohydr Polym. 2016;146:123–30.
Neufeld L, Bianco-Peled H. Pectin–chitosan physical hydrogels as potential drug delivery vehicles. Int J Biol Macromol. 2017;101:852–61.
Andishmand H, Tabibiazar M, Mohammadifar MA, Hamishehkar H. Pectin-zinc-chitosan-polyethylene glycol colloidal nano-suspension as a food grade carrier for colon targeted delivery of resveratrol. Int J Biol Macromol. 2017;97:16–22.
Kulkarni N, Wakte P, Naik J. Development of floating chitosan-xanthan beads for oral controlled release of glipizide. Int J Pharm Investig. 2015;5(2):73–80.
Horn MM, Martins VCA, de Guzzi Plepis AM. Influence of collagen addition on the thermal and morphological properties of chitosan/xanthan hydrogels. Int J Biol Macromol. 2015;80:225–30.
Kim J, Hwang J, Seo Y, Jo Y, Son J, Choi J. Engineered chitosan–xanthan gum biopolymers effectively adhere to cells and readily release incorporated antiseptic molecules in a sustained manner. J Ind Eng Chem. 2017;46:68–79.
Shu G, He Y, Chen L, Song Y, Meng J, Chen H. Microencapsulation of Lactobacillus Acidophilus by xanthan-chitosan and its stability in yoghurt. Polymers. 2017;9(12):1–11.
Maciel DJ, Ferreira IL de M. Properties evaluation of polyelectrolyte complex based on iota carrageenan and chitosan in acidic and basic media. Mater Lett. 2018;229:142–7.
Volod’ko A V., Davydova VN, Nedashkovskaya OI, Terentieva NA, Chusovitin EA, Galkin NG, et al. Morphology, electrokinetic characteristics and the effect on biofilm formation of carrageenan:chitosan polyelectrolyte complexes. Int J Biol Macromol. 2018;117:1118–24.
Mahdavinia GR, Karimi MH, Soltaniniya M, Massoumi B. In vitro evaluation of sustained ciprofloxacin release from κ-carrageenan-crosslinked chitosan/hydroxyapatite hydrogel nanocomposites. Int J Biol Macromol. 2019;126:443–53.
Bigucci F, Abruzzo A, Vitali B, Saladini B, Cerchiara T, Gallucci MC, et al. Vaginal inserts based on chitosan and carboxymethylcellulose complexes for local delivery of chlorhexidine: Preparation, characterization and antimicrobial activity. Int J Pharm. 2015;478(2):456–63.
Cerchiara T, Abruzzo A, Parolin C, Vitali B, Bigucci F, Gallucci MC, et al. Microparticles based on chitosan/carboxymethylcellulose polyelectrolyte complexes for colon delivery of vancomycin. Carbohydr Polym. 2016;143:124–30.
Cho AR, Chun YG, Kim BK, Park DJ. Preparation of Chitosan-TPP Microspheres as Resveratrol Carriers. J Food Sci. 2014;79(4):568–76.
Bernabé P, Peniche C, Argüelles-Monal W. Swelling behavior of chitosan/pectin polyelectrolyte complex membranes. Effect of thermal cross-linking. Polym Bull. 2005;55(5):367–75.
Čalija B, Savic S, Krajišnik D, Daniels R, Vučen S, Markovic B, et al. PH-sensitive polyelectrolyte films derived from submicron chitosan/Eudragit® L 100-55 complexes: Physicochemical characterization and in vitro drug release. J Appl Polym Sci. 2015;132(39):1–9.
Wu Y, Ying Y, Liu Y, Zhang H, Huang J. Preparation of chitosan/poly vinyl alcohol films and their inhibition of biofilm formation against Pseudomonas aeruginosa PAO1. Int J Biol Macromol. 2018;118:2131–7.
Shu XZ, Zhu KJ. The release behavior of brilliant blue from calcium-alginate gel beads coated by chitosan: The preparation method effect. Eur J Pharm Biopharm. 2002;53(2):193–201.
Pasparakis G, Bouropoulos N. Swelling studies and in vitro release of verapamil from calcium alginate and calcium alginate-chitosan beads. Int J Pharm. 2006;323(1–2):34–42.
Rodrigues S, Costa AMR Da, Grenha A. Chitosan/carrageenan nanoparticles: Effect of cross-linking with tripolyphosphate and charge ratios. Carbohydr Polym. 2012;89(1):282–9.
Čalija B, Milić J, Cekić N, Krajišnik D, Daniels R, Savić S. Chitosan oligosaccharide as prospective cross-linking agent for naproxen-loaded Ca-alginate microparticles with improved pH sensitivity. Drug Dev Ind Pharm. 2013;39(1):77–88.
Varga N, Benko M, Sebok D, Dékány I. BSA/polyelectrolyte core-shell nanoparticles for controlled release of encapsulated ibuprofen. Colloids Surfaces B Biointerfaces. 2014;123:616–22.
Lai WF, Shum HC. Hypromellose-graft-chitosan and its polyelectrolyte complex as novel systems for sustained drug delivery. ACS Appl Mater Interfaces. 2015;7(19):10501–10.
Lv X, Zhang W, Liu Y, Zhao Y, Zhang J, Hou M. Hygroscopicity modulation of hydrogels based on carboxymethyl chitosan/Alginate polyelectrolyte complexes and its application as pH-sensitive delivery system. Carbohydr Polym. 2018;198:86–93.
Du J, Zhang S, Sun R, Zhang LF, Xiong CD, Peng YX. Novel polyelectrolyte carboxymethyl konjac glucomannan-chitosan nanoparticles for drug delivery. II. Release of albumin in vitro. J Biomed Mater Res (Part B Appl Biomater). 2005;72(2):299–304.
Du J, Dai J, Liu JL, Dankovich T. Novel pH-sensitive polyelectrolyte carboxymethyl Konjac glucomannan-chitosan beads as drug carriers. React Funct Polym. 2006;66(10):1055–61.
Naidu VGM, Madhusudhana K, Sashidhar RB, Ramakrishna S, Khar RK, Ahmed FJ, et al. Polyelectrolyte complexes of gum kondagogu and chitosan, as diclofenac carriers. Carbohydr Polym. 2009;76(3):464–71.
Bhatia M, Ahuja M. Psyllium arabinoxylan: Carboxymethylation, characterization and evaluation for nanoparticulate drug delivery. Int J Biol Macromol. 2015;72:495–501.
Dash M, Samal SK, Morelli A, Bartoli C, Declercq HA, Douglas TEL, et al. Ulvan-chitosan polyelectrolyte complexes as matrices for enzyme induced biomimetic mineralization. Carbohydr Polym. 2018;182:254–64.
Minkal, Ahuja M, Bhatt DC. Polyelectrolyte complex of carboxymethyl gum katira-chitosan: Preparation and characterization. Int J Biol Macromol. 2018;106:1184–91.
Yan JK, Wang YY, Qiu WY, Wu JY. Construction and characterization of nanosized curdlan sulfate/chitosan polyelectrolyte complex toward drug release of zidovudine. Carbohydr Polym. 2017;174:209–16.
Yan JK, Qiu WY, Wang YY, Wu LX, Cheung PCK. Formation and characterization of polyelectrolyte complex synthesized by chitosan and carboxylic curdlan for 5-fluorouracil delivery. Int J Biol Macromol. 2018;107:397–405.
Leonida M, Ispas-Szabo P, Mateescu MA. Self-stabilized chitosan and its complexes with carboxymethyl starch as excipients in drug delivery. Bioact Mater. 2018;3(3):334–40.
Jain D, Bar-Shalom D. Alginate drug delivery systems: Application in context of pharmaceutical and biomedical research. Drug Dev Ind Pharm. 2014;40(12):1576–84.
Das RK, Kasoju N, Bora U. Encapsulation of curcumin in alginate-chitosan-pluronic composite nanoparticles for delivery to cancer cells. Nanomedicine Nanotechnology, Biol Med. 2010;6(1):153–60.
Abreu FOMS, Bianchini C, Forte MMC, Kist TBL. Influence of the composition and preparation method on the morphology and swelling behavior of alginate-chitosan hydrogels. Carbohydr Polym. 2008;74(2):283–9.
Cho AR, Chun YG, Kim BK, Park DJ. Preparation of alginate-CaCl2 microspheres as resveratrol carriers. J Mater Sci. 2014;49(13):4612–9.
George M, Abraham TE. Polyionic hydrocolloids for the intestinal delivery of protein drugs: Alginate and chitosan - a review. J Control Release. 2006;114:1–14.
Chan LW, Lee HY, Heng PWS. Mechanisms of external and internal gelation and their impact on the functions of alginate as a coat and delivery system. Carbohydr Polym. 2006;63(2):176–87.
Ribeiro AJ, Silva C, Ferreira D, Veiga F. Chitosan-reinforced alginate microspheres obtained through the emulsification/internal gelation technique. Eur J Pharm Sci. 2005;25(1):31–40.
Sæther HV, Holme HK, Maurstad G, Smidsrød O, Stokke BT. Polyelectrolyte complex formation using alginate and chitosan. Carbohydr Polym. 2008;74(4):813–21.
Wong TW, Chan LW, Kho S Bin, Sia Heng PW. Design of controlled-release solid dosage forms of alginate and chitosan using microwave. J Control Release. 2002;84(3):99–114.
Tavakol M, Vasheghani-Farahani E, Dolatabadi-Farahani T, Hashemi-Najafabadi S. Sulfasalazine release from alginate-N,O-carboxymethyl chitosan gel beads coated by chitosan. Carbohydr Polym. 2009;77(2):326–30.
Zhang Y, Wei W, Lv P, Wang L, Ma G. Preparation and evaluation of alginate-chitosan microspheres for oral delivery of insulin. Eur J Pharm Biopharm. 2011;77(1):11–9.
Elzatahry AA, Eldin MSM, Soliman EA, Hassan EA. Evaluation of alginate-chitosan bioadhesive beads as a drug delivery system for the controlled release of theophylline. J Appl Polym Sci. 2009;111(5):2452–9.
Wittaya-Areekul S, Kruenate J, Prahsarn C. Preparation and in vitro evaluation of mucoadhesive properties of alginate/chitosan microparticles containing prednisolone. Int J Pharm. 2006;312(1–2):113–8.
Nasti A, Zaki NM, De Leonardis P, Ungphaiboon S, Sansongsak P, Rimoli MG, et al. Chitosan/TPP and chitosan/TPP-hyaluronic acid nanoparticles: Systematic optimisation of the preparative process and preliminary biological evaluation. Pharm Res. 2009;26(8):1918–30.
Contreras-Ruiz L, De La Fuente M, García-Vázquez C, Sáez V, Seijo B, Alonso MJ, et al. Ocular tolerance to a topical formulation of hyaluronic acid and chitosan-based nanoparticles. Cornea. 2010;29(5):550–8.
Wadhwa S, Paliwal R, Paliwal SR, Vyas SP. Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: Development, characterization, and evaluation. J Drug Target. 2010;18(4):292–302.
Kalam MA. Development of chitosan nanoparticles coated with hyaluronic acid for topical ocular delivery of dexamethasone. Int J Biol Macromol. 2016;89:127–36.
Kalam MA. The potential application of hyaluronic acid coated chitosan nanoparticles in ocular delivery of dexamethasone. Int J Biol Macromol. 2016;89:559–68.
Luppi B, Bigucci F, Mercolini L, Musenga A, Sorrenti M, Catenacci L, et al. Novel mucoadhesive nasal inserts based on chitosan/hyaluronate polyelectrolyte complexes for peptide and protein delivery. J Pharm Pharmacol. 2009;61(2):151–7.
Lee SB, Lee YM, Song KW, Park MH. Preparation and Properties of Polyelectrolyte Complex Sponges Composed of Hyaluronic Acid and Chitosan and Their Biological Behaviors. J Appl Polym Sci. 2003;90(4):925–32.
Profire L, Pieptu D, Dumitriu RP, Dragostin O, Vasile C. Sulfadiazine modified CS/HA PEC destined to wound dressing. Rev medico-chirurgicalǎ̌ a Soc Medici ş̧i Nat din Iaş̧i. 2013;117(2):525–31.
Dumitriu RP, Profire L, Nita LE, Dragostin OM, Ghetu N, Pieptu D, et al. Sulfadiazine-chitosan conjugates and their polyelectrolyte complexes with hyaluronate destined to the management of burn wounds. Materials. 2015;8(1):317–38.
Lalevée G, Sudre G, Montembault A, Meadows J, Malaise S, Crépet A, et al. Polyelectrolyte complexes via desalting mixtures of hyaluronic acid and chitosan—Physicochemical study and structural analysis. Carbohydr Polym. 2016;154:86–95.
Nath SD, Abueva C, Kim B, Lee BT. Chitosan-hyaluronic acid polyelectrolyte complex scaffold crosslinked with genipin for immobilization and controlled release of BMP-2. Carbohydr Polym. 2015;115:207–14.
Sriamornsak P. Application of pectin in oral drug delivery. Expert Opin Drug Deliv. 2011;8:1009–23.
Sinha VR, Kumria R. Polysaccharides in colon-specific drug delivery. Int J Pharm. 2001;224:19–38.
Yang L, Chu JS, Fix JA. Colon-specific drug delivery: New approaches and in vitro/in vivo evaluation. Int J Pharm. 2002;235:1–15.
Wong TW, Colombo G, Sonvico F. Pectin matrix as oral drug delivery vehicle for colon cancer treatment. AAPS PharmSciTech. 2011;12:201–14.
Munjeri O, Collett JH, Fell JT. Hydrogel beads based on amidated pectins for colon-specific drug delivery: The role of chitosan in modifying drug release. J Control Release. 1997;46(3):273–8.
Kim TH, Park YH, Kim KJ, Cho CS. Release of albumin from chitosan-coated pectin beads in vitro. Int J Pharm. 2003;250(2):371–83.
Hiorth M, Versland T, Heikkilä J, Tho I, Sande SA. Immersion coating of pellets with calcium pectinate and chitosan. Int J Pharm. 2006;308(1–2):25–32.
Das S, Chaudhury A, Ng KY. Preparation and evaluation of zinc-pectin-chitosan composite particles for drug delivery to the colon: Role of chitosan in modifying in vitro and in vivo drug release. Int J Pharm. 2011;406(1–2):11–20.
Li L, Ni R, Shao Y, Mao S. Carrageenan and its applications in drug delivery. Carbohydr Polym. 2014;103(1):1–11.
Grenha A, Gomes ME, Rodrigues M, Santo VE, Mano JF, Neves NM, et al. Development of new chitosan/carrageenan nanoparticles for drug delivery applications. J Biomed Mater Res (Part A). 2010;92(4):1265–72.
Kumar A, Rao KM, Han SS. Application of xanthan gum as polysaccharide in tissue engineering: A review. Carbohydr Polym. 2018;180:128–44.
Popa N, Novac O, Profire L, Lupusoru CE, Popa MI. Hydrogels based on chitosan-xanthan for controlled release of theophylline. J Mater Sci Mater Med. 2010;21(4):1241–8.
de Morais Lima M, Carneiro LC, Bianchini D, Dias ARG, Zavareze E da R, Prentice C, et al. Structural, Thermal, Physical, Mechanical, and Barrier Properties of Chitosan Films with the Addition of Xanthan Gum. J Food Sci. 2017;82(3):698–705.
Gun’ko VM, Savina IN, Mikhalovsky S V. Cryogels: Morphological, structural and adsorption characterisation. Adv Colloid Interface Sci. 2013;(187–188):1–46.
Kumar S, Kaur P, Bernela M, Rani R, Thakur R. Ketoconazole encapsulated in chitosan-gellan gum nanocomplexes exhibits prolonged antifungal activity. Int J Biol Macromol. 2016;93:988–94.
Chen H, Fan M. Novel thermally sensitive pH-dependent chitosan/carboxymethyl cellulose hydrogels. J Bioact Compat Polym. 2008;23(1):38–48.
Lee MH, Chun MK, Choi HK. Preparation of Carbopol/chitosan interpolymer complex as a controlled release tablet matrix; Effect of complex formation medium on drug release characteristics. Arch Pharm Res. 2008;31(7):932–7.
Lu Z, Chen W, Hamman J. Chitosan-Polycarbophil Complexes in Swellable Matrix Systems for Controlled Drug Release. Curr Drug Deliv. 2007;4(4):257–63.
He M, Shi L, Wang G, Cheng Z, Han L, Zhang X, et al. Biocompatible and biodegradable chitosan/sodium polyacrylate polyelectrolyte complex hydrogels with smart responsiveness. Int J Biol Macromol. 2019; doi: 10.1016/j.ijbiomac.2019.11.092
Moustafine RI, Margulis EB, Sibgatullina LF, Kemenova VA, Mooter G Van den. Comparative evaluation of interpolyelectrolyte complexes of chitosan with Eudragit® L100 and Eudragit® L100-55 as potential carriers for oral controlled drug delivery. Eur J Pharm Biopharm. 2008;70(1):215–25.
Sareen R, Jain N, Rajkumari A, Dhar KL. PH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: Characterization and pharmacodynamic evaluation. Drug Deliv. 2016;23(1):55–62.
Koyano T, Koshizaki N, Umehara H, Nagura M, Minoura N. Surface states of PVA/chitosan blended hydrogels. Polymer. 2000;41(12):4461–5.
Sugimoto K, Yoshida M, Yata T, Higaki K, Kimura T. Evaluation of poly(vinyl alcohol)-gel spheres containing chitosan as dosage form to control gastrointestinal transit time of drugs. Biol Pharm Bull. 1998;21(11):1202–6.
Cascone MG, Maltinti S. Hydrogels based on chitosan and dextran as potential drug delivery systems. J Mater Sci Mater Med. 1999;10(5):301–7.
Cheaburu-Yilmaz CN, Yilmaz O, Kose FA, Bibire N. Chitosan-graft-poly(N-isopropylacrylamide)/PVA cryogels as carriers for mucosal delivery of voriconazole. Polymers. 2019;11(9):1–20.