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Chitosan and its derivatives: potential excipients for peroral peptide delivery systems

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Abstract

In the 1990s chitosan turned out to be a useful excipient in various pharmaceutical formulations. By modifications of the primary amino group at the 2-position of this poly(β1→4 d-glucosamine), the features of chitosan can even be optimised according to a given task in drug delivery systems. For peroral peptide delivery these tasks focus on overcoming the absorption (I) and enzymatic barrier (II) of the gut. On the one hand, even unmodified chitosan proved to display a permeation enhancing effect for peptide drugs. On the other hand, a protective effect for polymer embedded peptides towards degradation by intestinal peptidases can be achieved by the immobilisation of enzyme inhibitors on the polymer. Whereas serine proteases are inhibited by the covalent attachment of competitive inhibitors such as the Bowman–Birk inhibitor, metallo-peptidases are inhibited by chitosan derivatives displaying complexing properties such as chitosan-EDTA conjugates. In addition, because of the mucoadhesive properties of chitosan and most of its derivatives, a presystemic metabolism of peptides on the way between the dosage form and the absorption membrane can be strongly reduced. Based on these unique features, the co-administration of chitosan and its derivatives leads to a strongly improved bioavailability of many perorally given peptide drugs such as insulin, calcitonin and buserelin. These polymers are therefore useful excipients for the peroral administration of peptide drugs.

Introduction

Natural produced polymers such as cellulose, starch, pectine and alginate represent biodegradable and toxicological harmless raw-materials of low costs. They have therefore been used as abundant excipients in various pharmaceutical formulations for many decades. Because of progress in pharmaceutical sciences leading to more and more sophisticated drug delivery systems, however, the features of these polymers became in many cases insufficient, which has intensified the search for new, more specific and suitable polymers. A promising strategy in this direction is the chemical modification of natural produced polymers e.g. the development of cellulose derivatives such as methylcellulose or sodium carboxymethylcellulose. Among these natural produced polymers with properties for chemical modifications, in particular chitin has gained considerable attention. The deacetylation of chitin, which can be isolated from insects, crustacea such as crab and shrimp as well as from fungi such as Aspergillus niger (Felt et al., 1998), leads to poly(β1→4 d-glucosamine) or so called chitosan. Because of its superior characteristics together with a very save toxicity profile (Arai et al., 1968), chitosan is widely used as pharmaceutical excipient (Illum, 1998). Due to the primary amino group at the 2-position of each polymer-subunit further chemical modifications are easy feasible. By these modifications, the features of chitosan can be optimised according to a given task in delivery systems focusing on specific pharmaceutic-technological challenges.

One of such challenges is the peroral administration of peptide drugs where chitosan and its derivatives have gained considerable interest in recent years. As oral formulations for therapeutic peptides promise the greatest ease of application and a high patient compliance, thereby excluding any risks such as infections caused by non-sterile needles or haemolytic effects, pharmaceutical industry as well as practitioners involved in the health-system are very interested in such delivery systems. The efficacy of oral formulations, however, is harmed by different barriers encountered with the GI-tract. In general, they can be divided into the absorption (Zhou, 1994) and the enzymatic barrier (Woodley, 1994) which are mainly responsible for a very low bioavailability of orally given peptides and proteins. Because of their permeation enhancing effect (I), enzyme inhibitory capabilities (II), and mucoadhesive properties (III), chitosan and its derivatives are able to reduce both barriers, which makes these polymers important excipients for peroral peptide delivery systems. An overview of chitosan and modified chitosans used in such formulations should provide a good starting point for further research and development in this direction.

Section snippets

Permeation enhancement

In particular for peptides displaying a molecular size greater than 30 Å, the intestinal membrane becomes an important rate limiting factor for drug absorption (Lee, 1995). In order to reduce this barrier, the use of permeation enhancers seems to be essential for most peroral peptide delivery systems. Generally, such permeation enhancers can be divided into surfactants, fatty acids, salicylates, chelating agents and swellable polymers (Aungst et al., 1996). The latter ones — especially if they

Inhibition of pancreatic serine-proteases

Apart from the absorption barrier, the enzymatic barrier is also responsible for the very poor bioavailability of perorally administered peptide drugs. The pancreatic serine-proteases: trypsin, chymotrypsin and elastase are in many cases responsible for the presystemic metabolism of perorally given (poly)peptide drugs. Ikesue et al. (1993), for instance, demonstrated that insulin is strongly degraded by trypsin, chymotrypsin and elastase, whereas almost no degradation caused by brush border

Inhibition of metallo-peptidases

Besides pancreatic serine proteases, metallo-peptidases represent the second major group of enzymes being responsible for the presystemic metabolism of orally administered therapeutic peptides. Generally, intestinal metallo-peptidases can be divided into the luminally secreted enzymes carboxypeptidase A and B and the brush border membrane bound enzymes as listed in Table 2. Complexing agents are well known to be able to inhibit these peptidases because of the deprivation of the essential

Combination of different inhibitory effects

The inhibition of serine proteases as well as metallo-peptidases makes the combination of competitive enzyme inhibitors and complexing agents necessary. In order to achieve that goal, the competitive inhibitors antipain, chymostatin and elastatinal have been covalently bound to chitosan. In a second step, EDTA was immobilised to the remaining primary amino groups of the chitosan-inhibitor conjugate leading to polymers as shown in Fig. 6. The former cationogenic polymer became thereby an

Mucoadhesion

Although it has so far been impossible to improve the GI-transit time of pharmaceutical formulations due to the use of mucoadhesive polymers in man (Khosla and Davis, 1987), their benefit could already be verified in various animal models. Especially for peroral peptide delivery systems, from which the therapeutic agent is released in the intestine, the mucoadhesive properties of the dosage form seem to have an important influence on bioavailability. If the delivery system is not adhesive, the

Delivery systems based on chitosan and its derivatives

The type of the peroral delivery system for peptide drugs mainly relies on the predominant task of the dosage form. Depending on the structure of the therapeutic peptide either the permeation enhancing effect, the protective effect, or the mucoadhesive properties are prevalent. Whereas the permeation enhancing effect for peptides of a molecular size smaller than 30 Å in diameter seems to be less important, it becomes essential for peptides displaying a molecular size above this presumptive ‘cut

Conclusions

Since chitosan displays mucoadhesive properties as well as strong permeation enhancing capabilities for hydrophilic compounds together with a very safe toxicity profile, it has been widely investigated over the last few years for peroral peptide delivery systems. To date, it could already been shown by various in vivo studies that due to the co-administration of this polymer the bioavailability of many peptide drugs including insulin, calcitonin and buserelin could be strongly improved.

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