Review article
Factors and strategies for improving buccal absorption of peptides

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Abstract

Peptides and polypeptides have important pharmacological properties but only a limited number (e.g. insulin, oxytocin, vasopressin) have been exploited as therapeutics because of problems related to their delivery. The buccal mucosa offers an alternative route to conventional, parenteral administration. Peptides are generally not well absorbed through mucosae because of their molecular size, hydrophilicity and the low permeability of the membrane. Peptide transport across buccal mucosa occurs via passive diffusion and is often accompanied by varying degrees of metabolism. This review describes various approaches to improve the buccal absorption of peptides including the use of penetration enhancers to increase membrane permeability and/or the addition of enzyme inhibitors to increase their stability. Other strategies including molecular modification with bioreversible chemical groups or specific formulations such as bioadhesive delivery systems are also discussed.

Introduction

Peptides are currently emerging as a major class of therapeutic drugs. Many are endogenous compounds regulating endocrine and other physiological processes in the body. Oligopeptides with less than ten amino acids are not readily absorbed through the gastrointestinal tract because of their high degradation by proteolytic enzymes or their sensitivity to acidic media. Therefore, they are usually not suitable for oral administration, and are mostly delivered by parenteral administration and due to their short biological half-life, repeated injections are often required. Non-parenteral routes of administration need to be developed in order to minimize side effects produced by constant injection. Nasal, ocular, vaginal, rectal and buccal mucous membranes have all been evaluated as potential alternative routes for peptide absorption. Mucosal delivery was found to be much less efficient than parenteral administration due to a combination of poor membrane permeability and metabolization at the site of absorption [1]. However, the buccal route has the advantage of avoiding the first-pass effect and non-exposure of the drug to the gastro-intestinal tract secretions. Furthermore, there are few proteolytic enzymes as compared to oral administration [2] and in addition, the buccal mucosa is highly vascularized.

To date, a wide variety of polypeptidic drugs have been evaluated for buccal absorption [3]. Some of these include gastrointestinal peptides (secretin, substance P), pancreatic hormones (insulin, glucagon), anterior pituitary polypeptides (adrenocorticotropins, growth hormone), posterior pituitary oligopeptides (oxytocin, vasopressin and their analogues), hypothalamic-releasing-hormones (protirelin, gonadorelin, growth hormone-releasing factor hormone, somatostatin) and their derivatives (e.g. the gonadorelin agonists, buserelin, histrelin and nafarelin), as well as enkephalins, calcitonin and interferons [4], [5], [6]. Peptide absorption is limited because of their instability, low diffusivity (due to their molecular weight and hydrophilicity) and rapid metabolism. Other factors such as immunogenicity, biocompatibility, aggregation and adsorption may also affect transport [7]. Chemical modification can be essential in order to improve stability by minimizing enzymatic cleavage. In addition, small peptides may be derivatized to produce prodrugs which possess favourable physico-chemical properties in comparison to the parent compound by rendering the peptide more lipophilic thus facilitating absorption [8], [9]. Bioreversible derivatization may protect small peptides against degradation by peptidases present at the mucosal absorption barrier. Another promising approach is the use of novel permeation enhancers in order to minimize irritation to the mucosal membranes. However, on account of the buccal mucosa's ability of rapid recovery, the toxicological issue with respect to absorption enhancers may not be as significant a factor as with other mucosal sites [10], [11], [12].

The accessibility of this absorption site over other sites and the high acceptance by the patient also favour the buccal mucosa as a site for systemic drug delivery.

Section snippets

Molecular weight and size

Molecular weight and size influence the diffusivity of the drug through the epithelial layer. As a general rule, very large molecules have lower diffusivities. Indeed, small molecules (<75–100 Da) appear to cross the mucosa barrier rapidly [13]. However, permeability falls off markedly molecular size increases. Several authors have investigated the effects of molecular weight upon mucosal absorption of various hydrophilic compounds [14], [15], [16]. It was found that the apparent permeability

Different classes of promoters used for buccal delivery

Relatively few studies have been carried out on the effect of absorption enhancers on peptide transport across buccal mucosa [88]. Most have only shown limited success (summarized in Table 4). The enhancers belong to various chemical classes including surfactants (anionic and non-ionic), bile salts, chelators, fatty acids, and alcohols.

The degree of enhancement depended on a number of factors, including the characteristics of the permeant, the composition of the delivery vehicle, and whether

Conclusions

Buccal delivery has many advantages, including the avoidance of hepatic first-pass metabolism, the membrane is robust and readily accessible and has high patient compliance and it certainly offer to the pharmacologist and clinicians the opportunity to deliver peptides. However, as the buccal mucosa is an effective permeability barrier, several strategies have been proposed to improve absorption. A number of factors define and limit the absorption of drugs from the buccal mucosa, including the

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