Chitosan and its derivatives as intestinal absorption enhancers

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Abstract

Chitosan is a non-toxic, biocompatible polymer that has found a number of applications in drug delivery including that of absorption enhancer of hydrophilic macromolecular drugs. Chitosan, when protonated (pH<6.5), is able to increase the paracellular permeability of peptide drugs across mucosal epithelia. Chitosan derivatives have been evaluated to overcome chitosan’s limited solubility and effectiveness as absorption enhancer at neutral pH values such as those found in the intestinal tract. Trimethyl chitosan chloride (TMC) has been synthesized at different degrees of quaternization. This quaternized polymer forms complexes with anionic macromolecules and gels or solutions with cationic or neutral compounds in aqueous environments and neutral pH values. TMC has been shown to considerably increase the permeation of neutral and cationic peptide analogs across Caco-2 intestinal epithelia. The mechanism by which TMC is enhancing the intestinal permeability is similar to that of protonated chitosan. It reversibly interacts with components of the tight junctions, leading to widening of the paracellular routes. This chitosan derivative does not provoke damage of the cell membrane, and does not alter the viability of intestinal epithelial cells. Co-administrations of TMC with peptide drugs were found to substantially increase the bioavailability of the peptide in both rats and juvenile pigs compared with administrations without the polymer.

Introduction

Macromolecular drugs are poorly absorbed across mucosal membranes due to their hydrophilic nature and molecular mass. These compounds represent a class of valuable therapeutics that is administered via the parenteral route. One of the greatest challenges to drug delivery scientists is to deliver macromolecules orally [1]. These poorly-bioavailable drugs are inefficient when administered per os, because a limited portion of the dose reaches the plasma to exert its pharmacological effect. Low oral bioavailability leads to low plasma levels and increased inter- and intrasubject variability [2]. Therefore, there is a practical need for improving the bioavailability of such compounds when applied at mucosal absorptive surfaces. A final aim should be the design of pharmaceutical dosage forms of macromolecular drugs for peroral administration and absorption to therapeutic levels. Such dosage forms may comprise of excipients that should (a) provide the drug intact to the specific site of absorption, (b) preferentially prolong its residence time, and (c) reversibly increase the permeability of the mucosal epithelium to allow for unhampered transport of the macromolecular drug to the blood circulation and/or the lymph system. Additionally, a safety requirement should be that these excipients should not show adverse systemic effects, damage or exfoliate the epithelium.

Therapeutic compounds that are characterized by poor permeability across mucosal membranes commonly possess one or more of the following physicochemical characteristics: low octanol/water partitioning, presence of charged or hydrogen-bonding functional groups, and high polar surface area. Such drugs are peptides, peptide analogs, proteins or polysaccharides like heparins (unfractionated and low molecular weight) [3].

In order to increase the absorption of poorly permeable drugs, excipients such as absorption enhancers have been evaluated [4], [5]. These enhancers facilitate the absorption of hydrophilic macromolecules by increasing their transcellular, and/or paracellular transport across mucosal epithelia [6]. During the last decade a number of structurally different compounds with absorption enhancing properties have been investigated and part of them has been rejected due to serious damaging of the mucosal epithelium [7], [8], whereas another part found application in therapeutic practice [9]. The identification and evaluation of compounds that selectively and reversibly open the tight junctions namely the ‘paracellular permeability enhancers’ (PPE) has been keenly followed in the pharmaceutical field [8].

A large number of absorption enhancers has been evaluated. These enhancers do not differ only structurally, but also mechanistically. From a biopharmaceutical viewpoint we can roughly distinguish two main classes: enhancers that have characteristics that favour per se absorption (i.e. small molecular weight compounds) across the epithelium and those whose physicochemical characteristics do not favour their absorption (i.e. high molecular weight polymers).

To the latter class of enhancers belong chitosans. Chitosan [(1→4)-2-amino-2-deoxy-β-d-glucan] is the deacetylated chitin that has become of great interest as a functional material of high potential in various fields such as the biomedical one. Chitosans have found application as biomaterials in tissue engineering and in controlled drug release systems for various routes of delivery [9], [10], [11], [12], [13]. However, it was Illum et al. who first reported that chitosan is able to promote the transmucosal absorption of small polar molecules as well as peptide and protein drugs from nasal epithelia [14]. Immediately afterwards Artursson et al. reported that chitosan can increase the paracellular permeability of [14C]mannitol (a marker for paracellular routes) across Caco-2 intestinal epithelia [15]. These findings attributed to chitosan polymers the property of transmucosal absorption enhancement.

In this review the major classes of absorption enhancers as well as their mechanisms and safety aspects will be addressed. Special attention will be given to chitosan and its derivatives and their ability to increase the intestinal absorption of hydrophilic macromolecules.

Section snippets

Mucosal absorption enhancers: mechanisms and safety

Absorption enhancers that have been evaluated in recent years represent a group of compounds that differ concerning their chemical, mechanistic and toxic profiles [8]. Various non-ionic, anionic and cationic surfactants have been investigated as absorption enhancers. Anderberg et al. [16] studied a series of surfactants registered in solid oral drug products. The effects of anionic sodium dodecyl sulfate (SDS) and non-ionic (polysorbate 80 and polyoxyl 40 hydrogenated castor oil) surfactants as

Chitosans as absorption enhancers of hydrophilic macromolecular drugs: mechanism and safety

Chitosan is a polysaccharide, comprising copolymers of glucosamine and N-acetylglucosamine. Nowadays chitosan is available in different molecular weights (polymers 50 000 Da–oligomers 2000 Da), viscosity grades, and degrees of deacetylation (40–98%). Chitosan is insoluble at neutral and alkaline pH values, whereas it forms salts with inorganic and organic acids such as glutamic acid, hydrochloric acid, lactic acid and acetic acid. Chitosan is generally regarded as a biocompatible, slowly

Chitosan derivatives in peroral macromolecular drug delivery

Chitosan and chitosan salts lack the advantage of good solubility at neutral pH values. Chitosan aggregates in solutions at pH values above 6.5, and only protonated chitosan (i.e. in its uncoiled configuration) can trigger the opening of the tight junctions, thereby facilitating the paracellular transport of hydrophilic compounds. This property implies that chitosan can be effective as an absorption enhancer only in a limited area of the intestinal lumen where the pH values are close to its pKa

Conclusions

Chitosan is a biocompatible polymer that, when in solution (protonated), is able to interact with the tight junctions and to provoke their opening allowing for paracellular permeation of hydrophilic macromolecular drugs. Chitosan’s effects on the integrity of the epithelium or the cell membranes are minimal when compared to the effects of known absorption enhancers. The problem of chitosan’s ineffectiveness at neutral pH values can be tackled by derivatization at the amine group that renders

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    This article is an update of the article that has been submitted to ADDR for publication (Feb. 2001) in the ADDR issue with the subject, Chitosan.

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