Background

Chitosan is a linear polysaccharide obtained by the deacetylation of chitin, which, after cellulose, is the second biopolymer most abundant in nature. It’s a major component of the exoskeleton of crustaceans and insects. Chitosan has attracted great interest in the scientific community due to its features and benefits as a flexible and widely available biopolymer. These include:

  • Biocompatibility
  • Biodegradability
  • Non-toxicity
  • Mucosal adhesion and permeation-enhancing activities
  • Simplicity of chemical modifications

Chitosan also demonstrates diverse biological properties which include, but are not limited to;

With all this, it can be used to form films, hydrogels, and micro- and nanoparticles. Moreover, its cationic (positively charged) characteristic, makes it unique among biopolymers. This is responsible for chitosan’s ability of chitosan to interact with many different types of molecules (including cells and tissue) and for its intrinsic antimicrobial, anti-inflammatory, and hemostatic activities. However, its pH-dependent solubility represents one of its major drawbacks. Presently, chitosan and its derivatives are widely investigated for a great variety of medical applications, particularly in drug delivery. Among the alternative routes to overcome the problems related to the classic oral drug administration, the mucosal route has become a promising non-invasive delivery pathway.1-3  This brief summary aims to provide an overview of the key properties of chitosan in mucosal drug delivery, namely;

  • Muco-Adhesiveness
  • Biocompatibility, Biodegradability, and Pharmacokinetics
  • Permeation Enhancer Ability
  • In Situ Gelling Properties 

Introduction

Considerable research has recently gone into investigating novel and more effective forms of drug delivery compared to traditional oral and parenteral forms of systemic drug delivery.   A significant focus continues to be the mucosal approach as a promising pathway for systemic and local drug delivery, and other therapeutics. Mucosal delivery can provide the following benefits:

  • Non-invasive
  • Painless administration
  • Easy accessibility
  • Self-administration
  • Increase bioavailability
  • Rapid onset of action
  • Elimination of the hepatic first-pass effect
  • Improved patient compliance, and
  • Low cost

All this represents a promising alternative to the parenteral route. Moreover, mucosal delivery offers different absorptive surfaces, i.e., buccal, nasal, ocular, vaginal, and rectal mucosa, thus providing opportunities not only for systemic but also for local administration of a variety of compounds.  It enables the targeting of specific tissue, high “in situ” drug concentrations and reduced systemic side-effects with local treatment of diseases3,4. Mucosal drug delivery can be also obtained by the oral administration of suitable mucoadhesive delivery systems, exploiting the mucosa lining of the gastrointestinal tract5.

Parallel to the growing interest in mucosal delivery, the mucoadhesive polymer, chitosan became an increasingly attractive and dominant platform for the development of mucosal delivery systems 6–9,10–12.  Chitosan is a linear polysaccharide of natural origin. It’s obtained by deacetylation of chitin, which is the second most abundant biopolymer in nature after cellulose and is found in the exoskeleton of marine organisms (such as crabs and shrimps) and insects. 13,14.  It’s a copolymer composed of randomly distributed β-1,4-linked D-glucosamine and N-acetyl-D-glucosamine units (Figure 1).

structure of partially N-acetylated chitosan.
Figure 1. Structure of N-acetylated chitosan

Chitosan is insoluble in water but is soluble in acidic solutions where its amino groups become protonated. Its cationic character (positive charge), which renders it unique among biodegradable polymers, is responsible for many of the properties of chitosan, including its ability to significantly interact with many different types of molecules, such as the anionic components of the mucosal surface10–12,15, as well as to form polyelectrolyte complexes (PECs) with a variety of negatively charged polyanionic materials16–18.

Chitosan is considered one of the most versatile natural polymers, being endowed with many favorable biological, biomedical, biopharmaceutical, and technological features, along with an absence of toxicity19–21. On one hand, it exhibits several biological properties and activities22, as previously mentioned.  On the other hand, its wide availability, low cost, non-toxic, biocompatible, biodegradable, ease of chemical modifications, mucoadhesion, and permeation enhancer power. All this including the capability to form films, hydrogels, and micro- and nanoparticles, makes chitosan a promising biomaterial for the development of not only a variety of delivery systems 37,38 but also in gene delivery 39, tissue engineering 40, and food technology 41, etc. Moreover, in order to improve its physicochemical properties and stability and further extend its applications, several derivatives of chitosan can be obtained by both chemical modifications 12,42–44 or by polyelectrolyte complexes (PECs) formation16–18,45,46.

Even though the use of chitosan was proposed for a very wide range of drug delivery systems, one of the major interests in chitosan-based systems is mucosal drug delivery, due to both the increasing importance of the mucosal route as an effective alternative method of administration, and the unique biological properties of chitosan. A considerable amount of research has now proved the importance and potential of chitosan and its derivatives in improving mucosal delivery 10–12,46,47.

Chitosan for Mucosal Drug Delivery

CS is a very promising biomaterial in mucosal drug delivery, not only by virtue of its several favorable biological features, the most important of which are commented on in more detail below but also due to its inherent biological activities, such as, in particular, its wound healing, anti-inflammatory and antimicrobial properties [26,27,36].

1.1 Muco-Adhesiveness

Mucoadhesion is a complex phenomenon mainly involving interactions with mucin, a complex mixture of glycoproteins representing an essential component of the mucus, the protective barrier lining all mucosal surfaces of the human body.

Mucoadhesive ability, i.e., the capacity to adhere to mucous membranes, is an important requisite for the development of an effective mucosal drug delivery system, since it can allow intimate contact and prolonged residence time of the dosage form at the targeted sites, and then a gradual release and absorption of the active ingredients. The main expected advantages of mucoadhesive drug delivery systems are site-specific drug delivery; sustained/controlled release; improved drug bioavailability (by virtue of the extended contact time with the mucosal surface) and consequent reduction of drug dose and dose-related side effects.

Many studies reported on the potent mucoadhesive properties of CS and on its beneficial effects on drug absorption improvement, as shown in a recent review 48, even though the detailed mechanisms behind these properties as well as the role of the peculiar structural features of the polymer remain not completely understood. Both the intrinsic properties of the interacting species, chitosan and mucin, as well as the environmental conditions, are involved in the complex phenomenon 49. Chitosan–mucin interactions appeared to be mainly caused by electrostatic attraction forces between the cationic polymer and the negatively-charged glycoproteins of mucin, complemented by other forces, such as hydrogen bonding, as well as hydrophobic interactions 50,51. Chitosan mucoadhesion power seems to be directly related to its deacetylation degree (DD), which affects both the number of free amino groups and the overall polymer conformation and chain flexibility 11,51. Extrinsic factors which can affect chitosan–mucin interactions are the polymer concentration and the ionic strength and pH of the medium 49. In particular, chitosan concentration should be below its critical concentration, beyond which its chains tend to overlap, forming a complex network, and then they are no longer free to interact with the mucin glycoprotein chains 52. On the other hand, high salt concentrations could have an adverse effect, since they could screen electrostatic forces on the surface of the macromolecule, thus nullifying the contribution of electrostatic interactions between chitosan and mucin 52. Finally, the pH of the medium is a critical factor to be considered, since CS mucoadhesiveness, being strongly related to its cationic nature, may occur only at acidic pH (pH < 6) 53. This could be a drawback, giving rise to possible limits in its uses, particularly in gene or protein/peptide delivery, as well as to problems of chitosan precipitation when its acidic solutions will encounter neutral to basic pH environments once they are topically or systemically administered, with consequent variations in the carrier system performance. To overcome these issues and further improve its mucoadhesive properties, taking advantage of the ease of its chemical modification, chitosan derivatization was widely investigated to develop several modified versions of the polymer, endowed with customized physicochemical features 12. Trimethylated-Chitosan 54 (Figure 2) and thiolated-Chitosan 55,56 (Figure 3) are among the more extensively utilized and favored mucoadhesive chitosan derivatives.

trimethyl chitosan chemical structure
Figure 2. Trimethyl chitosan chemical structure
Figure 3. Examples of chemical structures of thiolated chitosan and derivatives.

1.2 Biocompatibility, Biodegradability and Pharmacokinetics

The term “biocompatibility” substantially denotes the property of a particular material that renders it compatible with living tissue, that is, does not generate a toxic or immunological response when exposed to the body or bodily fluids. It also denotes that the material efficiently and positively interacts with the biological environment of the human body. In other words, to be considered biocompatible, a biomaterial should carry out its functions giving rise to the desired effect without evoking any adverse reaction. The lack of any local irritant or harmful effect of the drug delivery system on the applied mucosal surface is a key requirement for allowing its safe, effective, and repeated use.

One of the main favorable features of chitosan is that it performs its beneficial functions without inducing any immune response or inflammation or any other significant adverse effect on the biological system. Biocompatibility and the absence of cytotoxicity of chitosan carriers are reported in several reviews 20,57,58.  The exceptional biocompatibility and non-toxicity of chitosan are mainly attributed to the analogy between its chemical structure to that of glycosaminoglycans, which are one of the principal components of the human extracellular matrix 11.

This same favorable similarity also contributes to chitosan’s biodegradability. In fact, due to its structural similarity to the physiological glycosaminoglycans, chitosan is easily degraded in vivo by the hydrolytic action of lysozyme, a non-specific enzyme largely present in the mucus, and of chitinases and N-acetyl-D-glucosaminidases, enzymes produced by the colon-residing bacteria. The susceptibility to enzymatic depolymerization is an exclusive characteristic of CS with respect to other polysaccharides. Its final degradation products are D-glucosamine, N-acetyl-glucosamine and N-acetyl-glucose, which are all nontoxic to the human body; moreover, its degradation intermediates do not give rise to problems of accumulation in the body and do not have immunogenic power 59. This allows the safe administration and degradation of topically applied chitosan-based mucosal delivery systems. Chitosan biodegradation rate mainly depends on its polymer molecular weight (MW), deacetylation degree (DD) and the pattern of N-acetyl-glucosamine residues; moreover, it is also inversely related to the polymer crystallinity, which is maximum for fully deacetylated polymer and has the lowest values for intermediate DD values, around 60% 60. In addition, chemical modifications of CS can clearly significantly affect its biodegradation rate.

Finally, as for the chitosan pharmacokinetic behavior, the data that emerged from inherent pharmacokinetic studies indicate that its intestinal absorption is affected by the polymer MW (increasing with MW decreasing), and that, following both oral or other routes of administration, CS is rapidly eliminated in the urine, without causing significant accumulation in the body, as reported in a recent review 61. Therefore, pharmacokinetics’ data, together with its non-toxicity, confirm the safe use of chitosan as a pharmaceutical excipient.

1.3 Chitosan Permeation Enhancing Activity

Chitosan is considered one of the most effective available polymers endowed with permeation enhancer activity, being at the same time non-toxic, non-irritant, biocompatible, and biodegradable.  The chitosan permeation enhancing properties were mainly attributed to the positive charges of the polymer, which allow its interaction with the cells membranes, resulting in a structural reorganization of the tight-junction proteins, with a consequent reversible opening of the junctions, which favors drug permeation without negatively affecting cell viability or provoking any membrane injury 62,63. The chitosan enhancement effect is clearly powered by the prolonged residence time of the drug at the mucosal surface, provided by the polymer mucoadhesive effect.

The structural features of chitosan, such as, in particular, its deacetylation degree and molecular weight, can significantly affect its permeation enhancer ability. In fact, an increase in the chitosan permeation enhancing effect was observed with an increase in both its deacetylation degree and molecular mass 11,62.

The chitosan permeation-enhancing effect can be further improved by its suitable chemical modification. In particular, thiolated- chitosan derivatives (see Figure 3) not only exhibited improved mucosal adhesion, by virtue of possible additional interactions with the mucosal surface, due to the formation of disulfides with cysteine residues of mucins 55,56, but also showed a higher permeation enhancer effect than unmodified chitosan. This last effect was attributed to the powered ability in tight junctions’ opening by the interactions of thiolated chitosan with the thiol groups of cysteine molecules, largely present on membrane receptors and enzymes 55.

1.4 In Situ Gelling Properties

The ability of chitosan to form hydrogels, by physical or chemical crosslinking, is well known, and it was widely exploited for the development of a variety of drug delivery devices able to provide a local and sustained drug release 38,64. Chemical hydrogels were obtained, for example, by chitosan crosslinking via covalent bonds with other polymers, such as hyaluronic acid 65, polyvinyl alcohol 66 or by UV irradiation 67. On the other hand, physical “reversible” hydrogels can be obtained by the formation of polyelectrolyte complexes (PECs) based on the spontaneous establishment of electrostatic interactions between the protonated ammonium groups of chitosan and a variety of oppositely charged polymers, particularly from a natural origin, such as gums, alginates, pectins, carrageenans, etc. (Figure 4) 46.

Figure 4. Chitosan-based polyelectrolyte complexes (PECs).

Physical hydrogels are generally preferred, since they allow the preservation of all of the favorable properties of chitosan, including biocompatibility. Moreover, PECs’ formation can also be useful to enhance chitosan stability and suitably tune the polymer hydrolytic degradation rate.  Among these different types of chemical or physical chitosan hydrogels, stimuli-responsive “in situ” gelling systems can be obtained, resulting in free-flowing liquid formulations able to undergo a rapid transition into a gel phase on the site of interest, triggered by factors such as pH or temperature changes at the physiological conditions 68.  In situ gelling mucoadhesive polymers, such as chitosan and its derivatives, can be very useful for improving the effectiveness of mucosal drug delivery. In fact, on the one hand, they allow an easy application of the liquid formulation at the level of the different administration sites; on the other hand, their rapid in situ gelation at the site of interest results in a very strong viscosity increase, that improves the polymer mucoadhesive effect and prolongs the mucosal residence time, minimizing shortcomings such as fast clearance or drainage of the drug from the target mucosa 69,70.

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Paper and Researchers
Multiple Roles of Chitosan in Mucosal Drug Delivery: An Updated Review
Paola Mura *, Francesca Maestrelli , Marzia Cirri  and Natascia Mennini
 Department of Chemistry, University of Florence, Via Schiff 6, Sesto Fiorentino, 50019 Florence, Italy; francesca.maestrelli@unifi.it (F.M.); marzia.cirri@unifi.it (M.C.); natascia.mennini@unifi.it (N.M.)
* Correspondence: paola.mura@unifi.it; Tel.: +39-055-4573672
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