Chitosan is a natural polymer obtained by the hydrolysis of chitin, a native polymer present in shellfish. Together with chitin, chitosan is considered the second most abundant polysaccharide after cellulose. However, unlike cellulose, the use of chitosan as an excipient in pharmaceutical formulations is a relatively new development. This article provides a brief overview on the utility of chitosan as a pharmaceutical excipient for oral drug delivery applications. Chitosan (poly[-(1,4)-2-amino-2-deoxy-D-glucopiranose]) differs from chitin in that a majority of the N-acetyl groups in chitosan are hydrolyzed. The degree of hydrolysis (deacetylation) has a significant effect on the solubility and rheological properties of the polymer. The amine group on the polymer has a pKa in the range of 5.5 to 6.5, depending on the source of the polymer. At low pH, the polymer is soluble, with the sol-gel transition occurring at approximate pH 7. The pH sensitivity, coupled with the reactivity of the primary amine groups, make chitosan a unique polymer for oral drug delivery applications.
Chitosan in conventional solid dosage forms
Chitosan's film forming abilities lend itself well as a coating agent for conventional solid dosage forms such as tablets. Furthermore its gel- and matrix-forming abilities makes it useful for solid dosage forms, such as granules, microparticles, etc. Sakkinen and coworkers studied microcrystalline chitosan as a gel-forming excipient for matrix-type drug granules. Crystallinity, molecular weight, and degree of deacetylation were seen to be factors that affected the release rates from the chitosan-based granules. Combination of positively charged chitosan with negatively charged biomolecules, such as gelatin, alginic acid, and hyalouronic acid, has been tested to yield novel matrices with unique characteristics for controlled release of drugs.
Site-specific targeting
Tozaki and coworkers utilized chitosan capsules for colon-specific delivery to treat ulcerative colitis. A 5-amino salicylic acid was encapsulated into chitosan capsules and delivered in vivo to Male Wistar rats after induction of colitis. It was observed that chitosan capsules disintegrated specifically in the large intestines as compared to the control formulation (in absence of chitosan), which demonstrated absorption of the drug in small intestines. This data is a representative example of utility of chitosan for colon- specific delivery. While the mechanism of chitosan disintegration is speculative at this point in time, the excipient has promise for site-specific delivery.
Permeation enhancer
It has been reported that chitosan, due to its cationic nature is capable of opening tight junctions in a cell membrane. This property has led to a number of studies to investigate the use of chitosan as a permeation enhancer for hydrophilic drugs that may otherwise have poor oral bioavailability, such as peptides. Because the absorption enhancement is caused by interactions between the cell membrane and positive charges on the polymer, the phenomenon is pH and concentration dependant. Furthermore increasing the charge density on the polymer would lead to higher permeability. This has been studied by quaternizing the amine functionality on chitosan. Further details are discussed in the chitosan derivatives section.
Mucoadhesive excipient
Bioadhesivity is often used as an approach to enhance the residence time of a drug in the GI tract, thereby increasing the oral bioavailability. A comparison between chitosan and other commonly used polymeric excipients indicates that the cationic polymer has higher bioadhesivity compared to other natural polymers, such as cellulose, Xantham gum, and starch.
Derivitatives of chitosan
While chitosan provides a number of excellent properties, further derivatization of the amine functionalities can be carried out to obtain polymers with a range of properties. A number of approaches, both chemical and enzymatic, have been tried to exploit the reactivity of the amine functional groups.
N-Trimethylene Chloride Chitosan (TMC)
A number of studies demonstrated that the charge on chitosan has a role in providing intestinal permeability. Hence, a quaternary derivatized chitosan (N-trimethylene chloride chitosan) was shown to demonstrate higher intestinal permeability than chitosan alone. The TMC derivative was used as a permeation enhancer for large molecules, such as octreotide, a cyclic peptide. Hamman and coworkers showed that the degree of quaternization of TMC influences its drug absorption-enhancing properties. Polymers with higher degrees of quaternization (> 22%) were able to reduce the transepithelial electrical resistance and thereby epithelial transport (in vitro) in a neutral environment (pH 7.4). The maximum reduction in transepithelial resistance was reached with TMC with a degree of quaternization of 48 per cent. This degree of quaternization was also seen to be optimum for in vitro transport of model drugs across a Caco-2 monolayer.
Chitosan esters
Chitosan esters, such as chitosan succinate and chitosan phthalate have been used successfully as potential matrices for the colon-specific oral delivery of sodium diclofenac. By converting the polymer from an amine to a succinate form, the solubility profile is changed significantly. The modified polymers were insoluble under acidic conditions and provided sustained release of the encapsulated agent under basic conditions. The same researchers also synthesized an iron cross-linked derivative of hydroxamated chitosan succinate, as a matrix for oral theophylline beads. A similar colon-targeting application was suggested for this polymer as well.
Chitosan conjugates
Reactivity of the amine functionality can be exploited to covalently conjugate functional excipients to the polymer backbone. For example, Guggi and Bernkop attached an enzyme inhibitor to chitosan. The resulting polymer retained the mucoadhesivity of chitosan and further prevented drug degradation by inhibiting enzymes, such as trypsin and chymotrypsin. This conjugated chitosan demonstrated promise for delivery of sensitive peptide drugs, such as calcitonin.
Regulatory status of chitosan
In spite of the promise of chitosan, minimal published information is available on the regulatory aspects of this excipient. The polymer has been used in multiple nutritional supplement products due to its ability to bind fat. However, no controlled studies could be found that test the safety and tolerability of the polymer. Chitosan has an ability to bind metal ions - a property that has led to the use of chitosan for wastewater treatment. This property may also cause mineral depletion in the GI tract. In addition, vitamin depletion may be a side effect given the adsorptive ability of chitosan. According to the documents obtained from the National Toxicology Program website, two Type IV Drug Master Files (DMFs) have been submitted for chitosan. Additional documents, if filed, have not been disclosed. The excipient is not listed on the FDA's Inactive Ingredient Database.
Chitosan is a unique polymer that has demonstrated utility in a number of applications for oral drug delivery. The excipient can serve a number of purposes, including as a coating agent, gel former, controlled-release matrix, in addition to inducing desirable properties, such as mucoadhesion and permeation enhancement to improve oral bioavailability of a drug. Additional safety and toxicology studies in accordance with the FDA's guidelines for new excipient development would however be desired to further promote the use of this polymer as a pharmaceutical excipient.
Chitosan is a natural polymer obtained by the hydrolysis of chitin, a native polymer present in shellfish. Together with chitin, chitosan is considered the second most abundant polysaccharide after cellulose. However, unlike cellulose, the use of chitosan as an excipient in pharmaceutical formulations is a relatively new development. This article provides a brief overview on the utility of chitosan as a pharmaceutical excipient for oral drug delivery applications. Chitosan (poly[-(1,4)-2-amino-2-deoxy-D-glucopiranose]) has a structure as shown in Figure 1. The polymer differs from chitin in that a majority of the N-acetyl groups in chitosan are hydrolyzed. The degree of hydrolysis (deacetylation) has a significant effect on the solubility and rheological properties of the polymer. The amine group on the polymer has a pKa in the range of 5.5 to 6.5, depending on the source of the polymer.1 At low pH, the polymer is soluble, with the sol-gel transition occurring at approximate pH 7. The pH sensitivity, coupled with the reactivity of the primary amine groups, make chitosan a unique polymer for oral drug delivery applications.
- (Source: Drug Delivery Today)