Next Article in Journal
Hybrid Films Prepared from a Combination of Electrospinning and Casting for Offering a Dual-Phase Drug Release
Next Article in Special Issue
Chitosan Microparticles Loaded with New Non-Cytotoxic Isoniazid Derivatives for the Treatment of Tuberculosis: In Vitro and In Vivo Studies
Previous Article in Journal
Poly-ε-Caprolactone-Hydroxyapatite-Alumina (PCL-HA-α-Al2O3) Electrospun Nanofibers in Wistar Rats
Previous Article in Special Issue
Effect of Polymers and Permeation Enhancers in the Release of Quetiapine Fumarate Transdermal Patch through the Dialysis Membrane
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Polymers
Volume 14
Issue 11
10.3390/polym14112131
polymers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Surveying the Oral Drug Delivery Avenues of Novel Chitosan Derivatives

by
Iyyakkannu Sivanesan
1,
Shadma Tasneem
2,
Nazim Hasan
2,
Juhyun Shin
3,
Manikandan Muthu
4,
Judy Gopal
4 and
Jae-Wook Oh
3,*
1
Department of Bioresources and Food Science, Konkuk University, Seoul 143-701, Korea
2
Department of Chemistry, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia
3
Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 143-701, Korea
4
Department of Research and Innovation, Department of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences (SIMATS), Thandalam, Chennai 602105, Tamil Nadu, India
*
Author to whom correspondence should be addressed.
Polymers 2022, 14(11), 2131; https://0-doi-org.brum.beds.ac.uk/10.3390/polym14112131
Submission received: 6 April 2022 / Revised: 5 May 2022 / Accepted: 16 May 2022 / Published: 24 May 2022
(This article belongs to the Special Issue Biomedical Applications of Polymeric Materials)
Browse Figures
Review Reports Versions Notes

Abstract

:
Chitosan has come a long way in biomedical applications: drug delivery is one of its core areas of imminent application. Chitosan derivatives are the new generation variants of chitosan. These modified chitosans have overcome limitations and progressed in the area of drug delivery. This review briefly surveys the current chitosan derivatives available for biomedical applications. The biomedical applications of chitosan derivatives are revisited and their key inputs for oral drug delivery have been discussed. The limited use of the vast chitosan resources for oral drug delivery applications, speculated to be probably due to the interdisciplinary nature of this research, is pointed out in the discussion. Chitosan-derivative synthesis and practical implementation for oral drug delivery require distinct expertise from chemists and pharmacists. The lack of enthusiasm could be related to the inadequacy in the smooth transfer of the synthesized derivatives to the actual implementers. With thiolated chitosan derivatives predominating the oral delivery of drugs, the need for representation from the vast array of ready-to-use chitosan derivatives is emphasized. There is plenty to explore in this direction.

1. Introduction

Chitosan, made up of β-(1,4)-N-acetyl-glucosamine [1,2,3], is obtained following the deacetylation of chitin. Chitin is found extensively in the exoskeletons of crustaceans and insects and in the cell walls of bacteria and fungi [4]. The quality of chitosan is influenced by the source of chitin, separation method and the degree of deacetylation [5]. The major advantages of chitosan are that it is nontoxic, mucoadhesive, hemocompatible, biodegradable and able to exhibit antioxidant, antitumor, antimicrobial properties. These properties render chitosan a highly attractive biomaterial option. The iconic characteristic of chitosan is that it does not provoke intense inflammation nor induce the body’s immunity. Researchers have confirmed that chitosan with different molecular weights and degrees of deacetylation exhibit low toxicity [6,7,8,9]. The catatonic nature of chitosan gives it its bactericidal and bacteriological properties [10,11]. However, chitosan is not soluble in aqueous solutions, a major disadvantage that limits its widespread application in living systems [12].
Chitosan’s surface adherence comes in handy when delivering useful molecules across mucosal pathways and adsorbs molecules that do not have any affinity for mucus [13]. Chitosan, through its permeation-related attributes, is able to open the tight epithelial junctions [14]. Chitosan also plays a role in coagulation. It accelerates the rate of wound healing by enabling interactions between amino and platelet groups [15]. These hemostatic properties are used with respect to wound healing applications. As a material for wound dressing, chitosan possesses chemoattraction, macrophage and neutrophil activation, analgesic properties, acceleration of granulation tissue/re-epithelization, limited scar formation and contraction, hemostasis and antibacterial properties [16]. The antitumor properties of chitosan and its derivatives have been well demonstrated in both in vitro and in vivo models [17]. The beneficial effects of antioxidants are well known [18], chitosan and its derivatives are able to scavenge free radicals in vitro [19,20]. The biodegradability of chitosan is yet another unique feature in biological organisms. Within the system, chitosan interacts with bioenzymes to depolymerize. The degradation breakdown products, N-acetyl glucose and glucosamine, are nontoxic to the human body. These degraded intermediates do not stay in the body and have no immunogenicity.
This review focusses on surveying the various novel chitosan derivatives that are available for use as drug delivery options. The milestones achieved based on the use of chitosan derivatives in the area of oral drug delivery has been comprehensively reviewed. The lack of implementing the various chitosan derivatives for oral drug delivery has been highlighted. The plausible reasons for this gap in the application of the various chitosan derivatives for oral drug delivery has been discussed. The possible accomplishments that could be achieved through utilization of the available resources has been addressed under future perspectives.

2. Comprehensive List of Novel Chitosan Derivatives

This section deals with a brief overview of the various chitosan derivatives that have been synthesized and are available for biomedical applications. The synthesis and their characterization and their applications have been elaborately reviewed by various authors [21,22,23]; here, we are restricted to a snapshot of their names. Figure 1 gives an overview of the various modification processes involved in the making of various chitosan derivatives.
N-(Aminoalkyl) Chitosan is a broad category of chitosan derivatives, which house many other forms. The encapsulation of calcium alginate beads with poly(L-lysine) (PLL), is the most accomplished encapsulation system for sustained delivery of bioactive agents. However, due to its high cost, large scale usage of this system for oral vaccination of animals is not possible. This is why a more economic and reliable microencapsulation chitosan and alginate system was sought after. Succinyl, Quateraminated, and Octanoyl Chitosan Porous chitosan microspheres for the delivery of antigens have been reported by Mi et al. [24]. The porous chitosan microspheres were chemically modified incorporating carboxyl, hydrophobic acyl, and quaternary ammonium groups.
Mitomycin C Conjugated N-succinyl Chitosan is the other class of chitosan derivatives. N-succinyl-chitosan, due to its carboxyl groups, has low toxicity, excellent biocompatibility and is retained in the body as a drug carrier for prolonged periods. This the reason why highly succinylated succinyl-chitosan (degree of succinylation: [25,26] can be dissolved in alkaline aqueous media, whereas chitosan cannot [27]. Succinyl-chitosan can react easily owing to the –NH2 and –COOH groups.
The N-Alkyl and Acylated Chitosan derivatives, which greatly benefit from the introduction of an alkyl or acyl chain, contribute greatly to chitosan’s molecular design. This modification of chitosan with hydrophobic branches, improved its solubility properties [28,29]. The introduction of an alkyl chain to water soluble modified chitosan (N-methylene phosphonic chitosan) enabled the co-existence of hydrophobic and hydrophilic branches [30]. The alkyl groups in N-lauryl-N-methylene phosphonic chitosan weaken its hydrogen bonds and provide good solubility in solvents. Holding amphiphilic properties, which are typical for surfactants, this derivative has prospective demands in pharmaceutical and cosmetic fields.
Chitosan hydrochloride derivatives have been demonstrated for their effective in vitro release of ofloxacin from mucoadhesive erodible ocular inserts and ocular pharmacokinetics [31].Thiolated chitosans are obtained by the modification of chitosan with 2-iminothiolane [32], in order to improve the properties of chitosan as excipients in drug delivery systems. Chitosan-2-iminothiolane was obtained by grafting 2-iminothiolane onto the chitosan backbone. This exhibits excellent in situ gelling properties and improved mucoadhesive and drug releasing properties due to the thiol groups on chitosan. Phosphorylated chitosan, which is prepared by reacting chitosan with orthophosphoric acid and urea in DMF [33] or phosphorous pentoxide in methanesulphonic acid, is a water-soluble derivative of chitosan with huge potential for drug delivery.
MCC and SNOCC chitosan derivatives are a biomedically significant class. Mono-N-Carboxymethyl Chitosan (MCC), is a polyampholytic chitosan derivative, soluble at both neutral and alkaline pH [34], synthesized using glyoxolic acid in chitosan [34]. These derivatives are highly soluble and applicable for the administration of polyanionic drugs. It has also been demonstrated by the same group that MCC can improve low molecular weight heparin (LMWH) transport through Caco-2 cells.
Anionic chitosan derivatives were also attempted. N-sulfonato-N,O-carboxymethylchitosan (SNOCC) was produced [35], which retains around 50% of its nitrogen centers on the glucose subunits as free amino groups [36], which contribute to its unique biomedical characteristics.
PEGylated Chitosans are a prominent group of derivatives. Chitosan-PEG for oral peptide delivery was attempted by Prego et al. [37]. PEGylation of chitosan is apt for oral peptide/protein delivery, because generally PEGylation improves biocompatibility [38] and improves stability in GI fluid [37]. PEGylated chitosan showed enhanced solubility of hydrophobics.

3. Oral Drug Delivery by Chitosan Derivatives

Although drug delivery is a broad terminology, which is backed up by enumerable reviews when it comes to chitosan and drug delivery and good number of reviews when it comes to chitosan derivatives, this review chooses to specifically delve into oral drug delivery applications. The sections below consolidate what has been achieved in the area of oral drug delivery based on chitosan derivatives and micro/nano particulate chitosan.

3.1. Chitosan/Chitosan Derivatives

When drugs are administered orally, they must be able to survive various ranges of pH and gastrointestinal tract (GIT) secretions. The very process of oral drug absorption rests on transport (via passive diffusion, carrier-mediated transport, or pinocytosis) across the GIT membrane. This is impacted by various GIT physiological. The oral mucosa has a thin epithelium and rich vascularity, which is makes it ideally fit for buccal and sublingual administration [39]. The release of drugs from chitosan and its derivatives follows the conventional protocol that holds good for chitosan. Drug release is influenced by the hydrophilicity of chitosan and pH of the swelling solution. The chitosan-drug release mechanism involves swelling, diffusion of drugs through the polymeric matrix and polymer erosion [40] (Figure 2).
Figure 3 lists the limitations that chitosan and its derivatives have broken, when it can to oral drug delivery. Drug delivery via the oral route is the easiest and e most convenient for patients. Chitosan because of its mucoadhesive nature, is able to protect labile drugs from GIT enzymatic degradation. Additionally, it is able to enhance absorption of administered therapeutic agent without affecting the biological system. This makes chitosan a valuable candidate as an oral delivery agent. Not only chitosan, but also chitosan micro-/nanoparticles have been demonstrated for oral drug delivery. Intestinal disinfection, suppression of Helicobacter pylori and dealing with ulcerative colitis, have been accomplished following treatment with antibiotic loaded chitosan particles. Amoxicillin and clarithromycin loaded into chitosan particles inhibited H. pylori [41,42]. The mucoadhesive properties of chitosan enabled prolonged delivery and oral bioavailability of acyclovir, an antiviral agent. This was because acyclovir chitosan microspheres could enhance drug retention in the upper GIT [43]. Protection against GIT degradation, improvement of oral bioavailability of insulin and enhancement of bioadhesion, have been reported as a result of its encapsulation into chitosan microspheres [44].
Chitosan-based delivery systems have been applied for the protection of insulin from degradation in the upper GIT. Furthermore, it has been used to carry out the release of insulin at the colon (through degradation of the chitosan glycosidic linkage by colon microflora) [45]. Chitosan microspheres coated with cellulose acetate butyrate, loaded with 5-aminosalicylic acid (5-ASA) to treat ulcerative colitis is reported. Here, the bioadhesive nature of chitosan microspheres comes handy [46]. Another study reported localization of 5-ASA in the colon and low drug systemic bioavailability following oral administration of 5-ASA-loaded chitosan-Ca-alginate microparticles to Wistar male rats [47]. The fact that chitosan is highly soluble in the acidic medium, leading to drug burst in the stomach, has been mitigated using pH-sensitive polymer coatings [48,49,50].
Chitosan derivatives have also been reported for oral delivery of therapeutic peptides and proteins. Unmodified native chitosan itself has been proven for its oral peptide and protein delivery (e.g., capability to open tight junctions, mucoadhesive properties), with this being the case, how much more so with the use of chitosan derivatives. Recently, the potential of certain modified chitosans including TMC [51], thiolated chitosan [52,53] and chitosan-enzyme inhibitor conjugates [54,55,56] for noninvasive gene delivery has been widely reported. In addition, thiolated chitosan is able to inhibit efflux pumps, in particular P-glycoprotein (P-gp). In this way, thiolated chitosan comes handy when it comes to oral delivery of P-gp substrates [57,58,59]. The potential of chitosan, TMC and MCC for oral delivery of vaccine have been previously reviewed [60]. We touch on the highlights of these [61,62] reviews here.
The effect of two different trimethyl chitosans (TMC) on the oral absorption of buserelin, a peptide drug, after intraduodenal administration in rats is reported [63] Both formulations significantly enhanced buserelin plasma levels. Enhanced absorption in the presence of TMC60 (60% trimethylation) is because of the inherent ability of TMC60 to open tight junctions. The impact of TMC solutions on octreotide in vitro permeation and in vivo absorption in rats was also investigated [63]. The intrajejunally administered TMC solution led to a fivefold increase in the absorption of octreotide compared to octreotide standalone. The effect of various liquid formulations on the oral bioavailability of octreotide was studied in pigs [64]. Studies with MCC and SNOCC towards oral delivery of LMWH [34,35], confirmed that chitosan derivatives in a concentration of 3% improved the oral bioavailability of LMWH.
In vivo studies using thiolated chitosan tablets were applied using peptide drugs as well as efflux pump substrates. Enteric coated chitosan–TBA conjugated with salmon calcitonin for the oral administration to rats were tested. Besides chitosan–TBA, the tablets contained two different chitosan–enzyme inhibitor conjugates, (chitosan–BBI conjugate and chitosan–elastatinal) [65]. Oral administration of this chitosan conjugate showed decreased plasma calcium levels for several hours [66]. Another study, where stomach targeted delivery system for salmon calcitonin was investigated using tablets containing chitosan–TBA as well as chitosan–pepstatin [67]. The efficacy of chitosan–TBA/GSH for oral peptide delivery was studied using the peptide drug antide. Antide was not absorbed after oral administration; however, absorption of the drug was reported following oral administration of chitosan TBA/GSH tablets [26]. Besides peptides and proteins, oral bioavailability of efflux pump substrates was improved using thiolated chitosan tablets were used. Oral bioavailability of the P-gp substrate Rhodamine 123 (Rho-123) was reported [59]. Guggi et al., used optimized tablets comprising of chitosan-TBA with lower molecular mass (75–150 kDa instead of 400 kDa) and demonstrated a 5.5-fold increase in Rho-123 AUC in comparison to the Rho-123 buffer solution. Guggi et al. investigated the effect of various calcitonin containing tablets on the blood calcium level of rats after oral administration. Compared to tablets containing calcitonin and chitosan only, marginal reduction of the calcium level was observed after administration of chitosan–pepstatin conjugate tablets [67]. Oral insulin delivery using insulin and chitosan–aprotinin conjugate, showed reduced blood glucose level, 8 h after oral administration [68].

3.2. Micro- and Nanoparticulate Oral Drug Delivery Systems Based on Chitosan Derivatives

3.2.1. Microparticulate Chitosan Derivatives Oral Drug Delivery Systems

Authors reported the preparation of liposome microspheres were coated with TMC and chitosan–EDTA. In vivo studies on oral absorption of insulin, confirmed that chitosan EDTA coated liposomes decreased blood glucose [69]. Microspheres based on chitosan–succinate proved their potential for oral delivery of insulin [25]. The delivery system was tested in vivo in diabetic rats, with chitosan–succinate microspheres, the relative pharmacological efficacy showed fourfold improvement [25]. Intragastric administration of calcitonin containing liposomes coated with dodecylated chitosan was confirmed in rats. Similar results were obtained in case of chitosan–phthalate microspheres too. PEGylated chitosan was tested for oral delivery of salmon calcitonin. Alginate–chitosan microspheres with narrow size distribution were prepared by membrane emulsification technique in combination with ion (Ca2+) and polymer (chitosan) solidification. The blood glucose level of diabetic rats was effectively reduced. It was made available for as long as 60 h after oral administration of the insulin-loaded alginate–chitosan microspheres. Therefore, the alginate–chitosan microspheres were found to be promising vectors showing a good efficiency in oral administration of protein or peptide drugs [70]. Chitosan microparticles prepared using the precipitation/coacervation method to obtain biodegradable chitosan microparticles. The entrapped ovalbumin was released after intracellular digestion into the Peyer’s patches. The proved that the labeled chitosan microparticles could be taken up by the epithelium of the murine Peyer’s patches. Since uptake by Peyer’s patches is an essential step in oral vaccination, these results confirmed that the chitosan microparticles are useful when it comes to vaccine delivery system [71]. Chitosan and chondroitin sulphate microspheres were prepared and reported for controlled release of metoclopramide hydrochloride in oral administration [72]. Microparticles prepared by ionic crosslinking between tripolyphosphate (TPP) and chitosan (Cs) were applied to enable the oral bioavailability of curcumin. The developed microparticles are reported to successfully enhance the dissolution of the poorly water-soluble drug Cur, and eventually, improve its oral bioavailability effectively [73].

3.2.2. Nanoparticulate Chitosan Derivatives Oral Drug Delivery Systems

TMC-based insulin-loaded nanoparticles were investigated, it was reported that insulin-TMC polyelectrolyte complexes exhibited higher colloidal stability in simulated intestinal fluid and protected insulin from trypsinic degradation [74]. TMC nanoparticles has also been demonstrated for its oral vaccine delivery. Intragastrical (IG) administration of TMC-nanoparticles containing the model vaccine urease could result in higher IgG and IgA levels [75]. Another study reported the efficiency of TMC as vector for in vitro and in vivo gene delivery [76]. Three different TMC-based nanoparticles encapsulated pDNA encoding green fluorescent protein (GFP) were demonstrated for their successful delivery attributes. Nanoparticles based on chitosan–TGA and pDNA for oral delivery are also reported [53]. Acrylic nanoparticles with chitosan–TBA are also reported. In vivo studies with thiolated chitosan nanoparticles for oral delivery are still lacking, however, oral insulin delivery using thiolatedpoly(acrylic acid) nanoparticles [77] and intranasal gene delivery using chitosan-TGA nanoparticles have been demonstrated [52]. Fucoidan (FD) has hypoglycemic effects, TMC and FD were loaded with insulin. TMC/FD NPs are pH sensitive and defend insulin from degradation in the GIT. Moreover, they enhance the cellular transport of insulin across the intestinal barrier [78]. The delivery of insulin via glycerol monocaprylate-modified chitosan nanoparticles has also been demonstrated using TMC/FD NPs [79]. A nanoemulsion was coated with two different PEGylated chitosans. In vivo studies in rats showed, that the oral uptake of salmon calcitonin when administered in carriers coated with PEGylated chitosan was higher than the nanoemulsion alone [37]. Table 1 gives the consolidated list of chitosan derivatives that have been employed for oral drug delivery applications.

4. Future Endeavors

This review briefly surveyed the current scenario of oral drug delivery using chitosan derivatives. Drug delivery is a very appropriate subject area, which chitosan have enormously impacted. We ran a pubmed search, using keywords, chitosan and drug delivery, chitosan derivatives and oral drug delivery, chitosan derivatives and drug delivery. Backed up by a total of 10,000 odd publications as per our pubmed search from 1981–2022, chitosan has indeed generously contributed to drug delivery. Novel chitosan derivatives, which are the second-generation innovations emerging from chitosan, have a 2635 publication record when it comes to drug delivery applications.
Chitosan derivatives are well reported for their use in delivery of poorly soluble drugs, for colon-targeted drug delivery, for mucosal drug delivery, ocular drug delivery and topical delivery [81,82,83,84].
Chopra et al. [85] have extensively reviewed the advances and potential applications of chitosan derivatives as mucoadhesive biomaterials in modern drug delivery. When it comes to drug delivery, the drawbacks of chitosan have been overcome through derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan and Tan et al. have reviewed the applications of quaternized chitosan as antimicrobial agents, including their antimicrobial activity, mechanism of action and biomedical applications in orthopedics [86]. These have become an appropriate platform for sustained release at a controlled rate, prolonged residence time, improved patient compliance through reduced dosing frequency, enhanced bioavailability leading to significant improvement in therapeutic efficacy.
Currently, chitosan derivative nanoparticles are mainly used for sustained release, preparation of targeted drugs and as vectors for gene therapy. As delivery carriers, chitosan and its derivatives are usually available as microspheres, nanoparticles, micelles, and gels in delivery carriers [87,88]. Besides these options, chitosan derivative nanoparticles are also used for the delivery of polypeptides. Chitosan derivative nanoparticles interact with peptides through strong hydrogen bonds and static electricity, obtaining peptide-loaded nanoparticles. Fatty-acid-modified quaternary ammonium chitosan nanoparticles loaded with insulin have been shown to be beneficial [89]. Chitosan derivative nanoparticles have also been applied for gene delivery. Gene therapy is a promising strategy for challenging diseases. A key step in gene therapy is the successful delivery of genes [90,91]. Chitosan derivative nanoparticles, as non-viral vectors, have excellent solubility, biodegradability, biocompatibility, non-toxicity and a higher transfection rate than chitosan nanoparticles [92]. Methoxy polyethylene glycol-modified trimethyl chitosan (mPEG-TMC) has been covalently linked to doxorubicin (DOX) and cis-itaconic anhydride (CA), for better anti-tumor activities [93,94]. O-carboxymethyl chitosan inhibited tumor cell migration in vitro [95]. The poly-β-amino ester nanoparticle loading gene, after the addition of thiolated O-carboxymethyl chitosan, showed a higher cell transfection rate [96]. These are a notable few brief mention of the drug delivery potentials of chitosan derivatives, which have been dealt in detail by earlier reviews.
Chitosan derivatives upgraded to break many of the limitations that chitosan was facing, and with that reputation, it was believed that higher research curiosity and much more research interest would be evident. This expectation is well below the actual trend. As for oral drug delivery, chitosan derivatives are within the 500-article mark, which is one fifth lesser than the interest on chitosan derivatives and drug delivery. Figure 4 summarizes this trend. However, as this review points out, there is definitely a high potential contribution from chitosan derivatives in biomedical applications and drug delivery, which we stress has not been fully tapped into in terms of oral drug delivery applications. This review hopes to provoke some though and awareness towards this area of research.
Non-invasive oral drug delivery is the crown of drug delivery approaches, chitosan derivatives are the latest generation upgrades, a fusion of both these should break numerous boundaries and limitations. The fact that this is truly an interdisciplinary area, where synthetic chemists and pharmacologist need to collaborate to access the full potential of either expertise, may be the retardant. The reason for the low enthusiasm could be the interdisciplinary nature of this area of research. There is no dearth for chitosan derivatives, as pointed out by the review, diverse chitosan derivatives are in the market. Yet, as pointed out in this review, only thiolated chitosans have been predominantly applied, and few other scattered versions too. There are a whole lot of options to consider and avenues that they would open up which are yet to be looked into. This review hopes to enthuse the researchers in this direction.
Combining nanoaspects of chitosan with synthesis of chitosan derivatives is definitive progress in this area. Nanoforms have always pushed limitations of various applications, and there is surely a lot more to derive from nanostucturization of the chitosan derivatives. Oral drug delivery has benefitted greatly from the use of nanochitosan forms; combining chitosan derivatives with nano aspects could prove highly beneficial.

5. Conclusions

The objective of this review was to showcase the wealth of available chitosan derivatives and to evaluate their achievements in the area of oral drug delivery. Numerous reviews exist in the area of chitosan and drug delivery, chitosan derivatives and drug delivery applications are also well reported. We reviewed the comparatively less-reported chitosan derivative application into oral drug delivery. During the review process, it became clear that there is no doubt as to the advantages of employing the use of chitosan derivatives for oral drug delivery purposes. However, as pointed out in the review, there is a huge gap between the available knowledge and the synthesized chitosan derivations and their oral drug delivery applications. There are so many derivatives synthesized, yet only few have been used for oral drug delivery applications. The reasons for this gap and the various reasons that could have led to this have been speculated. The need to bridge these ends have been emphasized. There is definitely much to harness and more to achieve, through proper inclusion of chitosan derivatives that have so far not been attempted for oral drug delivery applications.

Author Contributions

I.S., Revisions and funding support; M.M., S.T. and J.G., preparation of original draft; N.H. and J.S., review and revisions; J.-W.O., participated in review and revisions and funding support. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

This article was supported by the KU Research Professor Program of Konkuk University.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kato, Y.; Onishi, H.; Machida, Y. Application of chitin and chitosan derivatives in the pharmaceutical field. Curr. Pharm. Biotechnol. 2003, 4, 303–309. [Google Scholar] [CrossRef] [PubMed]
  2. Singla, A.K.; Chawla, M. Chitosan: Some pharmaceutical and biological aspects—An update. J. Pharm. Pharmacol. 2001, 53, 1047–1067. [Google Scholar] [CrossRef] [PubMed]
  3. Kas, H.S. Chitosan: Properties, preparations and application to microparticulate systems. J. Microencapsul. 1997, 14, 689–711. [Google Scholar] [CrossRef] [PubMed]
  4. Varshosaz, J. The promise of chitosan microspheres in drug delivery systems. Expert Opin. Drug Deliv. 2007, 4, 263–273. [Google Scholar] [CrossRef]
  5. Galed, G.; Miralles, B.; Panos, I.; Santiago, A.; Heras, A. N-Deacetylation and depolymerization reactions of chitin/chitosan: Influence of the source of chitin. Carbohydr. Polym. 2005, 62, 316–320. [Google Scholar] [CrossRef]
  6. Yan, C.Y.; Gu, J.W.; Hou, D.P.; Jing, H.Y.; Wang, J.; Guo, Y.Z.; Katsumi, H.; Sakane, T.; Yamamoto, A. Synthesis of Tat tagged and folate modified N-succinyl-chitosan self-assembly nanoparticles as a novel gene vector. Int. J. Biol. Macromol. 2015, 72, 751–756. [Google Scholar] [CrossRef]
  7. Zhu, A.P.; Chen, T.; Yuan, L.H.; Wu, H.; Lu, P. Synthesis and characterization of N-succinyl-chitosan and its self-assembly of nanospheres. Carbohydr. Polym. 2006, 66, 274–279. [Google Scholar] [CrossRef]
  8. Chien, R.C.; Yen, M.T.; Mau, J.L. Antimicrobial and antitumor activities of chitosan from shiitake stipes, compared to commercial chitosan from crab shells. Carbohydr. Polym. 2016, 138, 259–264. [Google Scholar] [CrossRef]
  9. Huang, M.; Khor, E.; Lim, L.Y. Uptake and cytotoxicity of chitosan molecules and nanoparticles: Effects of molecular weight and degree of deacetylation. Pharm. Res. 2004, 21, 344–353. [Google Scholar] [CrossRef]
  10. Kong, M.; Chen, X.G.; Xing, K.; Park, H.J. Antimicrobial properties of chitosan and mode of action: A state of the art review. Int. J. Food Microbiol. 2010, 144, 51–63. [Google Scholar] [CrossRef]
  11. Goy, R.C.; de Britto, D.; Assis, O.B.G. A Review of the Antimicrobial Activity of Chitosan. Polimeros 2009, 19, 241–247. [Google Scholar] [CrossRef]
  12. Ngo, D.H.; Vo, T.S.; Ngo, D.N.; Kang, K.H.; Je, G.Y.; Pham, H.N.; Byun, H.G.; Kim, S.K. Biological effects of chitosan and its derivatives. Food Hydrocoll. 2015, 51, 200–216. [Google Scholar] [CrossRef]
  13. Bugnicourt, L.; Ladaviere, C. Interests of chitosan nanoparticles conically cross-linked with tripolyphosphate for biomedical applications. Prog. Polym. Sci. 2016, 60, 1–17. [Google Scholar] [CrossRef]
  14. Yamamoto, H.; Kuno, Y.; Sugimoto, S.; Takeuchi, H.; Kawashima, Y. Surface-modified PLGA nanosphere with chitosan improved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellular tight junctions. J. Control. Release 2005, 102, 373–381. [Google Scholar] [CrossRef] [PubMed]
  15. Okamoto, Y.; Yano, R.; Miyatake, K.; Tomohiro, I.; Shigemasa, Y.; Minami, S. Effects of chitin and chitosan on blood coagulation. Carbohydr. Polym. 2003, 53, 337–342. [Google Scholar] [CrossRef]
  16. Busilacchi, A.; Gigante, A.; Mattioli-Belmonte, M.; Manzotti, S.; Muzzarelli, R.A.A. Chitosan stabilizes platelet growth factors and modulates stem cell differentiation toward tissue regeneration. Carbohydr. Polym. 2013, 98, 665–676. [Google Scholar] [CrossRef]
  17. Tokoro, A.; Tatewaki, N.; Suzuki, K.; Mikami, T.; Suzuki, S.; Suzuki, M. Growth-Inhibitory Effect of Hexa-N-Acetylchitohexaose and Chitohexaose against Meth-a Solid Tumor. Chem. Pharm. Bull. 1988, 36, 784–790. [Google Scholar] [CrossRef] [Green Version]
  18. Ngo, D.H.; Kim, S.K. Antioxidant effects of chitin, chitosan, and their derivatives. Adv. Food Nutr. Res. 2014, 73, 15–31. [Google Scholar] [CrossRef]
  19. Younes, I.; Rinaudo, M. Chitin and chitosan preparation from marine sources. Structure, properties and applications. Mar. Drugs 2015, 13, 1133–1174. [Google Scholar] [CrossRef] [Green Version]
  20. Park, P.J.; Je, J.Y.; Kim, S.K. Free radical scavenging activity of chitooligosaccharides by electron spin resonance spectrometry. J. Agric. Food Chem. 2003, 51, 4624–4627. [Google Scholar] [CrossRef]
  21. Riaz Rajoka, M.S.; Zhao, L.; Mehwish, H.M.; Wu, Y.; Mahmood, S. Chitosan and its derivatives: Synthesis, biotechnological applications, and future challenges. Appl. Microbiol. Biotechnol. 2019, 103, 1557–1571. [Google Scholar] [CrossRef] [PubMed]
  22. Confederat, L.G.; Tuchilus, C.G.; Dragan, M.; Sha’at, M.; Dragostin, O.M. Preparation and Antimicrobial Activity of Chitosan and Its Derivatives: A Concise Review. Molecules 2021, 26, 3694. [Google Scholar] [CrossRef] [PubMed]
  23. Zhao, D.; Yu, S.; Sun, B.; Gao, S.; Guo, S.; Zhao, K. Biomedical Applications of Chitosan and Its Derivative Nanoparticles. Polymers 2018, 10, 462. [Google Scholar] [CrossRef] [Green Version]
  24. Mi, F.L.; Shyu, S.S.; Chen, C.T.; Schoung, J.Y. Porous chitosan microsphere for controlling the antigen release of Newcastle disease vaccine: Preparation of antigen-adsorbed microsphere and in vitro release. Biomaterials 1999, 20, 1603–1612. [Google Scholar] [CrossRef]
  25. Ubaidulla, U.; Khar, R.K.; Ahmad, F.J.; Sultana, Y.; Panda, A.K. Development and characterization of chitosan succinate microspheres for the improved oral bioavailability of insulin. J. Pharm. Sci. 2007, 96, 3010–3023. [Google Scholar] [CrossRef]
  26. Bernkop-Schnurch, A.; Pinter, Y.; Guggi, D.; Kahlbacher, H.; Schoffmann, G.; Schuh, M.; Schmerold, I.; Del Curto, M.D.; D’Antonio, M.; Esposito, P.; et al. The use of thiolated polymers as carrier matrix in oral peptide delivery—Proof of concept. J. Control. Release 2005, 106, 26–33. [Google Scholar] [CrossRef]
  27. Yamaguchi, R.; Arai, Y.; Itoh, T.; Hirano, S. Preparation of Partially N-Succinylated Chitosans and Their Cross-Linked Gels. Carbohydr. Res. 1981, 88, 172–175. [Google Scholar] [CrossRef]
  28. Nishimura, S.I.; Miura, Y.; Ren, L.D.; Sato, M.; Yamagishi, A.; Nishi, N.; Tokura, S.; Kurita, K.; Ishii, S. An Efficient Method for the Syntheses of Novel Amphiphilic Polysaccharides by Regioselective and Thermoselective Modifications of Chitosan. Chem. Lett. 1993, 22, 1623–1626. [Google Scholar] [CrossRef]
  29. Holme, K.R.; Hall, L.D. Chitosan Derivatives Bearing C-10-Alkyl Glycoside Branches—A Temperature-Induced Gelling Polysaccharide. Macromolecules 1991, 24, 3828–3833. [Google Scholar] [CrossRef]
  30. Ramos, V.M.; Rodriguez, N.M.; Rodriguez, M.S.; Heras, A.; Agullo, E. Modified chitosan carrying phosphonic and alkyl groups. Carbohydr. Polym. 2003, 51, 425–429. [Google Scholar] [CrossRef]
  31. Di Colo, G.; Zambito, Y.; Burgalassi, S.; Serafini, A.; Saettone, M.F. Effect of chitosan on in vitro release and ocular delivery of ofloxacin from erodible inserts based on poly(ethylene oxide). Int. J. Pharm. 2002, 248, 115–122. [Google Scholar] [CrossRef]
  32. Bernkop-Schnurch, A.; Hornof, M.; Zoidl, T. Thiolated polymers-thiomers: Synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates. Int. J. Pharm. 2003, 260, 229–237. [Google Scholar] [CrossRef]
  33. Sakaguchi, T.; Horikoshi, T.; Nakajima, A. Studies on the Accumulation of Heavy-Metal Elements in Biological-Systems. 20. Adsorption of Uranium by Chitin Phosphate and Chitosan Phosphate. Agric. Biol. Chem. Tokyo 1981, 45, 2191–2195. [Google Scholar] [CrossRef] [Green Version]
  34. Thanou, M.; Nihot, M.T.; Jansen, M.; Verhoef, J.C.; Junginger, H.E. Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 2001, 90, 38–46. [Google Scholar] [CrossRef]
  35. Thanou, M.; Henderson, S.; Kydonieus, A.; Elson, C. N-sulfonato-N,O-carboxymethylchitosan: A novel polymeric absorption enhancer for the oral delivery of macromolecules. J. Control. Release 2007, 117, 171–178. [Google Scholar] [CrossRef]
  36. Hayes, E.R. N,O-carboxymethyl Chitosan and Preparative Method Therefor. U.S. Patent US4619995A, 28 October 1986. [Google Scholar]
  37. Prego, C.; Torres, D.; Fernandez-Megia, E.; Novoa-Carballal, R.; Quinoa, E.; Alonso, M.J. Chitosan-PEG nanocapsules as new carriers for oral peptide delivery—Effect of chitosan pegylation degree. J. Control. Release 2006, 111, 299–308. [Google Scholar] [CrossRef]
  38. Zhang, M.; Li, X.H.; Gong, Y.D.; Zhao, N.M.; Zhang, X.F. Properties and biocompatibility of chitosan films modified by blending with PEG. Biomaterials 2002, 23, 2641–2648. [Google Scholar] [CrossRef]
  39. Ashford, M. Biopharmaceutical principles of drug delivery. In Pharmaceutics: The Science of Dosage Form Design, 2nd ed.; Aulton, M.E., Ed.; Churchill Livingstone: New York, NY, USA, 2001; pp. 211–253. [Google Scholar]
  40. Younis, M.K.; Tareq, A.Z.; Kamal, I.M. Optimization Of Swelling, Drug Loading And Release From Natural Polymer Hydrogels. IOP Conf. Ser. Mater. Sci. Eng. 2018, 454, 12–17. [Google Scholar] [CrossRef]
  41. Gisbert, J.P.; Torrado, G.; Torrado, S.; Olivares, D.; Pajares, J.M. Clinical trial evaluating amoxicillin and clarithromycin hydrogels (Chitosan-polyacrylic acid polyionic complex) for H. pylori eradication. J. Clin. Gastroenterol. 2006, 40, 618–622. [Google Scholar] [CrossRef]
  42. Chang, C.H.; Lin, Y.H.; Yeh, C.L.; Chen, Y.C.; Chiou, S.F.; Hsu, Y.M.; Chen, Y.S.; Wang, C.C. Nanoparticles incorporated in pH-sensitive hydrogels as amoxicillin delivery for eradication of Helicobacter pylori. Biomacromolecules 2010, 11, 133–142. [Google Scholar] [CrossRef]
  43. Dhaliwal, S.; Jain, S.; Singh, H.P.; Tiwary, A.K. Mucoadhesive microspheres for gastroretentive delivery of acyclovir: In vitro and in vivo evaluation. AAPS J. 2008, 10, 322–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Wei, W.; Ma, G.H.; Wang, L.Y.; Wu, J.; Su, Z.G. Hollow quaternized chitosan microspheres increase the therapeutic effect of orally administered insulin. Acta Biomater. 2010, 6, 205–209. [Google Scholar] [CrossRef] [PubMed]
  45. Hejazi, R.; Amiji, M. Chitosan-based gastrointestinal delivery systems. J. Control. Release 2003, 89, 151–165. [Google Scholar] [CrossRef]
  46. Varshosaz, J.; Jaffarian Dehkordi, A.; Golafshan, S. Colon-specific delivery of mesalazine chitosan microspheres. J. Microencapsul. 2006, 23, 329–339. [Google Scholar] [CrossRef] [PubMed]
  47. Mladenovska, K.; Raicki, R.S.; Janevik, E.I.; Ristoski, T.; Pavlova, M.J.; Kavrakovski, Z.; Dodov, M.G.; Goracinova, K. Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles. Int. J. Pharm. 2007, 342, 124–136. [Google Scholar] [CrossRef]
  48. Eizatahry, A.A.; Eldin, M.S.M. Preparation and characterization of metronidazole loaded chitosan nanoparticles for drug delivery application. Polym. Adv. Technol. 2008, 19, 1787–1791. [Google Scholar] [CrossRef]
  49. Jain, S.K.; Jain, A.; Gupta, Y.; Ahirwar, M. Design and development of hydrogel beads for targeted drug delivery to the colon. AAPS PharmSciTech 2007, 8, E56. [Google Scholar] [CrossRef] [Green Version]
  50. Oosegi, T.; Onishi, H.; Machida, Y. Novel preparation of enteric-coated chitosan-prednisolone conjugate microspheres and in vitro evaluation of their potential as a colonic delivery system. Eur. J. Pharm. Biopharm. 2008, 68, 260–266. [Google Scholar] [CrossRef]
  51. Li, H.Y.; Birchall, J. Chitosan-modified dry powder formulations for pulmonary gene delivery. Pharm. Res. 2006, 23, 941–950. [Google Scholar] [CrossRef]
  52. Lee, D.; Zhang, W.; Shirley, S.A.; Kong, X.; Hellermann, G.R.; Lockey, R.F.; Mohapatra, S.S. Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene delivery. Pharm. Res. 2007, 24, 157–167. [Google Scholar] [CrossRef]
  53. Martien, R.; Loretz, B.; Thaler, M.; Majzoob, S.; Bernkop-Schnurch, A. Chitosan-thioglycolic acid conjugate: An alternative carrier for oral nonviral gene delivery? J. Biomed. Mater. Res. A 2007, 82, 1–9. [Google Scholar] [CrossRef] [PubMed]
  54. Loretz, B.; Foger, F.; Werle, M.; Bernkop-Schnurch, A. Oral gene delivery: Strategies to improve stability of pDNA towards intestinal digestion. J. Drug Target. 2006, 14, 311–319. [Google Scholar] [CrossRef] [PubMed]
  55. Martien, R.; Loretz, B.; Schnurch, A.B. Oral gene delivery: Design of polymeric carrier systems shielding toward intestinal enzymatic attack. Biopolymers 2006, 83, 327–336. [Google Scholar] [CrossRef] [PubMed]
  56. Loretz, B.; Bernkop-Schnurch, A. In vitro evaluation of chitosan-EDTA conjugate polyplexes as a nanoparticulate gene delivery system. AAPS J 2006, 8, E756–E764. [Google Scholar] [CrossRef] [Green Version]
  57. Foger, F.; Hoyer, H.; Kafedjiiski, K.; Thaurer, M.; Bernkop-Schurch, A. In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein. Biomaterials 2006, 27, 5855–5860. [Google Scholar] [CrossRef]
  58. Foger, F.; Kafedjiiski, K.; Hoyer, H.; Loretz, B.; Bernkop-Schnurch, A. Enhanced transport of P-glycoprotein substrate saquinavir in presence of thiolated chitosan. J. Drug Target. 2007, 15, 132–139. [Google Scholar] [CrossRef]
  59. Foger, F.; Schmitz, T.; Bernkop-Schnurch, A. In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan. Biomaterials 2006, 27, 4250–4255. [Google Scholar] [CrossRef]
  60. van der Lubben, I.M.; Verhoef, J.C.; Borchard, G.; Junginger, H.E. Chitosan and its derivatives in mucosal drug and vaccine delivery. Eur. J. Pharm. Sci. 2001, 14, 201–207. [Google Scholar] [CrossRef]
  61. Werle, M.; Takeuchi, H.; Bernkop-Schnurch, A. Modified Chitosans for Oral Drug Delivery. J. Pharm Sci. 2009, 98, 1643–1656. [Google Scholar] [CrossRef]
  62. Werle, M.; Bernkop-Schnurch, A. Thiolated chitosans: Useful excipients for oral drug delivery. J. Pharm. Pharmacol. 2008, 60, 273–281. [Google Scholar] [CrossRef] [PubMed]
  63. Thanou, M.; Florea, B.I.; Langemeyer, M.W.; Verhoef, J.C.; Junginger, H.E. N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats). Pharm. Res. 2000, 17, 27–31. [Google Scholar] [CrossRef]
  64. Thanou, M.; Verhoef, J.C.; Verheijden, J.H.M.; Junginger, H.E. Intestinal absorption of octreotide using trimethyl chitosan chloride: Studies in pigs. Pharm. Res. 2001, 18, 823–828. [Google Scholar] [CrossRef] [PubMed]
  65. Guggi, D.; Bernkop-Schnurch, A. In vitro evaluation of polymeric excipients protecting calcitonin against degradation by intestinal serine proteases. Int. J. Pharm. 2003, 252, 187–196. [Google Scholar] [CrossRef]
  66. Guggi, D.; Kast, C.E.; Bernkop-Schnurch, A. In vivo evaluation of an oral salmon calcitonin-delivery system based on a thiolated chitosan carrier matrix. Pharm. Res. 2003, 20, 1989–1994. [Google Scholar] [CrossRef]
  67. Guggi, D.; Krauland, A.H.; Bernkop-Schnurch, A. Systemic peptide delivery via the stomach: In vivo evaluation of an oral dosage form for salmon calcitonin. J. Control. Release 2003, 92, 125–135. [Google Scholar] [CrossRef]
  68. Werle, M.; Loretz, B.; Entstrasser, D.; Foger, F. Design and evaluation of a chitosan-aprotinin conjugate for the peroral delivery of therapeutic peptides and proteins susceptible to enzymatic degradation. J. Drug Target. 2007, 15, 327–333. [Google Scholar] [CrossRef]
  69. Wu, Z.H.; Ping, Q.N.; Lei, X.M.; Li, J.Y.; Cai, P. Effects of the liposomes coated by chitosan and its derivatives on the gastrointestinal transit of insulin. Yao Xue Xue Bao 2005, 40, 618–622. [Google Scholar] [PubMed]
  70. Zhang, Y.; Wei, W.; Lv, P.; Wang, L.; Guanghui, M. Preparation and evaluation of alginate—Chitosan microspheres for oral deliveryof insulin. Eur. J. Pharm. Biopharm. 2011, 77, 11–19. [Google Scholar] [CrossRef] [PubMed]
  71. van der Lubben, I.M.; Verhoef, J.C.; van Aelst, A.C.; Borchard, G.; Junginger, H.E. Chitosan microparticles for oral vaccination: Preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches. Biomaterials 2001, 22, 687–694. [Google Scholar] [CrossRef]
  72. Ganza-González, A.; Anguiano-Igea, S.; Otero-Espinar, F.J.; Blanco Méndez, J. Chitosan and chondroitin microspheres for oral-administration controlled release of metoclopramide. Eur. J. Pharm. Biopharm. 1999, 48, 149–155. [Google Scholar] [CrossRef]
  73. Wan, S.; Sun, Y.; Sun, L.; Tan, F. Chitosan microparticles for oral bioavailability improvement of the hydrophobic drug curcumin. Pharmazie 2012, 67, 525–528. [Google Scholar] [PubMed]
  74. Jintapattanakit, A.; Junyaprasert, V.B.; Mao, S.; Sitterberg, J.; Bakowsky, U.; Kissel, T. Peroral delivery of insulin using chitosan derivatives: A comparative study of polyelectrolyte nanocomplexes and nanoparticles. Int. J. Pharm. 2007, 342, 240–249. [Google Scholar] [CrossRef] [PubMed]
  75. Chen, F.; Zhang, Z.R.; Yuan, F.; Qin, X.; Wang, M.T.; Huang, Y. In vitro and in vivo study of N-trimethyl chitosan nanoparticles for oral protein delivery. Int. J. Pharm. 2008, 349, 226–233. [Google Scholar] [CrossRef] [PubMed]
  76. Zheng, F.; Shi, X.W.; Yang, G.F.; Gong, L.L.; Yuan, H.Y.; Cui, Y.J.; Wang, Y.; Du, Y.M.; Li, Y. Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: Results of an in vitro and in vivo study. Life Sci. 2007, 80, 388–396. [Google Scholar] [CrossRef] [PubMed]
  77. Deutel, B.; Greindl, M.; Thaurer, M.; Bernkop-Schnuerch, A. Novel insulin thiomer nanoparticles: In vivo evaluation of an oral drug delivery system. Biomacromolecules 2008, 9, 278–285. [Google Scholar] [CrossRef]
  78. Tsai, L.C.; Chen, C.H.; Lin, C.W.; Ho, Y.C.; Mi, F.L. Development of mutlifunctional nanoparticles self-assembled from trimethyl chitosan and fucoidan for enhanced oral delivery of insulin. Int. J. Biol. Macromol. 2019, 126, 141–150. [Google Scholar] [CrossRef]
  79. Gao, M.; Sun, Y.; Kou, Y.; Shen, X.; Huo, Y.; Liu, C.; Sun, Z.; Zhang, X.; Mao, S. Effect of glyceryl monocaprylate-modified chitosan on the intranasal absorption of insulin in rats. J. Pharm. Sci. 2019, 108, 3623–3629. [Google Scholar] [CrossRef]
  80. Thanou, M.; Verhoef, J.C.; Marbach, P.; Junginger, H.E. Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J. Pharm. Sci. 2000, 89, 951–957. [Google Scholar] [CrossRef]
  81. Bansal, V.; Sharma, P.K.; Sharma, N.; Pal, O.P.; Malviya, R. Applications of Chitosan and Chitosan Derivatives in Drug Delivery. Adv. Biol. Res. 2011, 5, 28–37. [Google Scholar]
  82. Lai, W.F.; Lin, M.C.M. Nucleic acid delivery with chitosan and its derivatives. J. Control. Release 2009, 134, 158–168. [Google Scholar] [CrossRef]
  83. Moreira, C.; Oliveira, H.; Pires, L.R.; Simoes, S.; Barbosa, M.A.; Pego, A.P. Improving chitosan-mediated gene transfer by the introduction of intracellular buffering moieties into the chitosan backbone. Acta Biomater. 2009, 5, 2995–3006. [Google Scholar] [CrossRef] [PubMed]
  84. Torchilin, V.P. Nanocarriers. Pharm. Res. 2007, 24, 2333–2334. [Google Scholar] [CrossRef] [PubMed]
  85. Chopra, S.; Mahdi, S.; Kaur, J.; Iqbal, Z.; Talegaonkar, S.; Ahmad, F.J. Advances and potential applications of chitosan derivatives as mucoadhesive biomaterials in modern drug delivery. J. Pharm. Pharmacol. 2006, 58, 1021–1032. [Google Scholar] [CrossRef] [PubMed]
  86. Tan, H.; Ma, R.; Lin, C.; Liu, Z.; Tang, T. Quaternized Chitosan as an Antimicrobial Agent: Antimicrobial Activity, Mechanism of Action and Biomedical Applications in Orthopedics. Int. J. Mol. Sci. 2013, 14, 1854–1869. [Google Scholar] [CrossRef]
  87. Rassu, G.; Gavini, E.; Jonassen, H.; Zambito, Y.; Fogli, S.; Breschi, M.C.; Giunchedi, P. New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration. J. Pharm. Sci. 2009, 98, 4852–4865. [Google Scholar] [CrossRef]
  88. Wang, F.; Zhang, Q.; Li, X.; Huang, K.; Shao, W.; Yao, D.; Huang, C. Redox-responsive blend hydrogel films based on carboxymethyl cellulose/chitosan microspheres as dual delivery carrier. Int. J. Biol. Macromol. 2019, 134, 413–421. [Google Scholar] [CrossRef]
  89. Li, H.; Zhang, Z.; Bao, X.; Xu, G.; Yao, P. Fatty acid and quaternary ammonium modified chitosan nanoparticles for insulin delivery. Colloids Surf. B 2018, 170, 136–143. [Google Scholar] [CrossRef]
  90. Trivedi, A.; Hoffman, J.; Arora, R. Gene therapy for atrial fibrillation—How close to clinical implementation? Int. J. Cardiol. 2019, 296, 177–183. [Google Scholar] [CrossRef]
  91. Gollomp, K.L.; Doshi, B.S.; Arruda, V.R. Gene therapy for hemophilia: Progress to date and challenges moving forward. Transfus. Apher. Sci. 2019, 58, 602–612. [Google Scholar] [CrossRef]
  92. Kean, T.; Roth, S.; Thanou, M. Trimethylated chitosans as non-viral gene delivery vectors: Cytotoxicity and transfection efficiency. J. Control. Release 2005, 103, 643–653. [Google Scholar] [CrossRef]
  93. Mai, Q.; Shen, S.; Liu, Y.; Tang, C.; Yin, C. PEG modified trimethyl chitosan based nanoparticles for the codelivery of doxorubicin and iSur-pDNA. Mater. Lett. 2019, 238, 143–146. [Google Scholar] [CrossRef]
  94. Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 2016, 99, 28–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Ren, L.; Xu, J.; Zhang, Y.; Zhou, J.; Chen, D.; Chang, Z. Preparation and characterization of porous chitosan microspheres and adsorption performance for hexavalent chromium. Int. J. Biol. Macromol. 2019, 135, 898–906. [Google Scholar] [CrossRef]
  96. Tang, Y.; Liu, Y.; Xie, Y.; Chen, J.; Dou, Y. Apoptosis of A549 cells by small interfering RNA targeting survivin delivery using poly-β-amino ester/guanidinylated O-carboxymethyl chitosan nanoparticles. Asian J. Pharm. Sci. 2020, 15, 121–128. [Google Scholar] [CrossRef] [PubMed]
Polymers 14 02131 g001 550
Figure 1. Overview of various chemical modification processes that go into the making of chitosan derivatives.
Figure 1. Overview of various chemical modification processes that go into the making of chitosan derivatives.
Polymers 14 02131 g001
Polymers 14 02131 g002 550
Figure 2. Mechanisms of drug release in chitosan and its derivatives.
Figure 2. Mechanisms of drug release in chitosan and its derivatives.
Polymers 14 02131 g002
Polymers 14 02131 g003 550
Figure 3. Listings of the limitations in oral drug delivery that chitosan and its derivatives have helped overcome.
Figure 3. Listings of the limitations in oral drug delivery that chitosan and its derivatives have helped overcome.
Polymers 14 02131 g003
Polymers 14 02131 g004 550
Figure 4. Comparative bar diagrams of research articles published in the area of (a) chitosans and drug delivery (b) chitosan derivatives and drug delivery (c) chitosan derivatives for oral drug delivery, based on our pubmed search.
Figure 4. Comparative bar diagrams of research articles published in the area of (a) chitosans and drug delivery (b) chitosan derivatives and drug delivery (c) chitosan derivatives for oral drug delivery, based on our pubmed search.
Polymers 14 02131 g004
Table
Table 1. Chitosan derivatives that have been used for oral drug delivery applications.
Table 1. Chitosan derivatives that have been used for oral drug delivery applications.
Chitosan DerivativeOral Drug Delivery ApplicationReferences
TMC, thiolated chitosannoninvasive gene delivery[52,53]
Thiolated chitosanoral delivery of P-glycoprotein (P-gp) substrates[57,58,59]
TMC, MCCoral vaccine delivery[60]
Trimethyl chitosans (TMC) oral absorption of the peptide drug buserelin after intraduodenal administration in rats[63]
TMCoctreotide in vitro permeation and in vivo absorption in rats[80]
TMC oral bioavailability of octreotide in pigs[64]
MCC, SNOCCoral delivery of LMWH[34,35]
Chitosan–TBAoral administration of drug salmon calcitonin to rats[65]
Chitosan–TBA/chitosan–enzyme inhibitor conjugateDelivery of drug salmon calcitonin[66]
Chitosan–TBA, chitosan–pepstatinStomach targeted delivery of salmon calcitonin[67]
Chitosan–TBA/GSHoral peptide delivery of peptide drug antide[26]
Chitosan–TBAOral bioavailability of the P-gp substrate Rhodamine 123[59]
Chitosan–TBA5.5-fold increase in Rho-123 AUC[59]
Chitosan–pepstatin conjugate tabletsReduction of blood calcium level of rats after oral administration[67]
Chitosan–aprotinin conjugateOral insulin delivery[68]
TMC–nanoparticles–Vaccine ureaseOral vaccine delivery–higher IgG and IgA levels[75]
TMC nanoparticlesgene delivery[76]
TMC–based nanoparticles encapsulatde pDNA encoding green fluorescentprotein (GFP)Oral delivery[53]
chitosan-TGA and pDNAOral delivery[53]
thiolatedpoly(acrylic acid) nanoparticlesOral insulin delivery[77]
Chitosan–TGA nanoparticlesintranasal gene delivery[52]
liposomes coated with dodecylated chitosanIntragastric administration of calcitonin[37]
TMC and chitosan–EDTAOral absorption of insulin[78]
chitosan-succinateoral delivery of insulin chitosan-succinate microspheres[25]
Chitosan–succinate microspheresin vivo insulin delivery in diabetic rats[25]
TMC/FD NPsdefend insulin from degradation in the GIT, enhance transport[79,80]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Sivanesan, I.; Tasneem, S.; Hasan, N.; Shin, J.; Muthu, M.; Gopal, J.; Oh, J.-W. Surveying the Oral Drug Delivery Avenues of Novel Chitosan Derivatives. Polymers 2022, 14, 2131. https://0-doi-org.brum.beds.ac.uk/10.3390/polym14112131

AMA Style

Sivanesan I, Tasneem S, Hasan N, Shin J, Muthu M, Gopal J, Oh J-W. Surveying the Oral Drug Delivery Avenues of Novel Chitosan Derivatives. Polymers. 2022; 14(11):2131. https://0-doi-org.brum.beds.ac.uk/10.3390/polym14112131

Chicago/Turabian Style

Sivanesan, Iyyakkannu, Shadma Tasneem, Nazim Hasan, Juhyun Shin, Manikandan Muthu, Judy Gopal, and Jae-Wook Oh. 2022. "Surveying the Oral Drug Delivery Avenues of Novel Chitosan Derivatives" Polymers 14, no. 11: 2131. https://0-doi-org.brum.beds.ac.uk/10.3390/polym14112131

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop