Novel approach of Buccal Drug Delivery System: An Overview

About Authors:
Ranabir Chanda, Saumya Samanta*, Dilip De, Jyotishman Bhattacharya, Anurup Mandal
Bengal School of Technology, Hooghly, West Bengal, India

Buccoadhesives have long been employed to improve the bioavailability of drugs undergoing significant hepatic first pass metabolism. Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable. It is the objective of this article to review buccal drug delivery by discussing the structure and environment of the oral mucosa, mechanism of buccoadhesion,  factors affecting buccoadhesion,  polymers used ,types of buccal dosage form and the experimental methods used in assessing buccal drug permeation/absorption.


Amongst the various routes of drug delivery, oral route is the most preferred to the patient. However, disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract limits its use for certain drugs. Different absorptive mucosas are considered as potential site for drug administration eg, nasal, rectal, vaginal, ocular and oral cavity [1].

Bioadhesion may be defined as the state in which two materials, at least one of which is of biological nature, are held together for extended periods of time by interfacial forces [2]. For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specific biological location. The biological surface can be epithelial tissue or the mucous coat on the surface of a tissue. If adhesive attachment is to a mucous coat, the phenomenon is referred to as mucoadhesion. Mucous coat includes the mucosal linings of the nasal, rectal, esophageal, vaginal, ocular, and oral cavity [3].

The idea of bioadhesive drug delivery systems was introduced as a new concept to the pharmaceutical sciences by the pioneering work of several research groups in the United States, Japan and Europe in the mid-1980s [4-7].

Since then, the idea to “stick” dosage forms to the site of application and/or drug absorption, respectively, has stimulated researchers all over the world. Originally, the advantages of bioadhesive drug delivery systems were seen in their potential (i) to prolong the residence time at the site of drug absorption (e.g., to reduce the dosing frequency for bioadhesive controlled release formulations) and (ii) to intensify contact with the underlying mucosal epithelial barrier (e.g., to enhance the epithelial transport of usually poorly absorbed drugs, such as peptides and proteins).  The tight and close contact of drug delivery system (DDS) with the absorptive mucosa should generate a steeper concentration gradient, thus increasing the absorption rate [8].This principle, in particular, supported hopes of increased bioavailability of peptide drugs.

Later, it was discovered that some mucoadhesive polymers can also modulate the permeability of epithelial tissues by loosening the tight intercellular junctions [9-10]. and that some mucoadhesive polymers can also act as inhibitors of proteolytic enzymes [11-12].

These drug delivery system utilize property of bioadhesion of certain water soluble polymers which become adhesive on hydration and hence can be used for targeting particular site. Buccal delivery is the administration of the drug via buccal mucosa (lining of the cheek) to the systemic circulation [13].

1.      Overview of the Oral Mucosa

The oral mucosa is composed of an outermost layer of stratified squamous epithelium (Figure 1). Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium [14].

The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers.

The turnover time for the buccal epithelium has been estimated at 5-6 days, and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 µm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure at about 100-200 µm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosa of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosa of the soft palate, the sublingual, and the buccal regions, however, are not keratinized [15]. The keratinized epithelia contain neutral lipids like ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide [16-18].

Figure 1

The oral mucosa in general is somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin [19].

As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa. In general, the permeabilities of the oral mucosa decrease in the order of sublingual greater than buccal, and buccal greater than palatal. This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness and keratinized. [20]

It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the so-called ‘membrane coating granules’ (MCG) [21]. When cells go through differentiation, MCGs start forming and at the apical cell surfaces they fuse with the plasma membrane and their contents are discharged into the intercellular spaces at the upper one third of the epithelium. This barrier exists in the outermost 200µm of the superficial layer. Permeation studies have been performed using a number of very large molecular weight tracers, such as horseradish peroxidase. When applied to the outer surface of the epithelium, these tracers penetrate only through outermost layer or two of cells. When applied to the submucosal surface, they permeate up to, but not into, the outermost cell layers of the epithelium. According to these results, it seems apparent that flattened surface cell layers present the main barrier to permeation, while the more isodiametric cell layers are relatively permeable. In both keratinized and non-keratinized epithelia, the limit of penetration coincided with the level where the MCGs could be seen adjacent to the superficial plasma membranes of the epithelial cells. Since the same result was obtained in both keratinized and non-keratinized epithelia, keratinization by itself is not expected to play a significant role in the barrier function [22].

The cells of the oral epithelia are surrounded by an intercellular ground substance, mucus, the principle components of which are complexes made up of proteins and carbohydrates. These complexes may be free of association or some maybe attached to certain regions on the cell surfaces. This matrix may actually play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another [23]. Along the same lines, the mucus is also believed to play a role in bioadhesion of mucoadhesive drug delivery systems [6]. In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells like the goblet cells, however in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva. Up to 70% of the total mucin found in saliva is contributed by the minor salivary glands [24].

At physiological pH the mucus network carries a negative charge (due to the sialic acid and sulphate residues) which may play a role in mucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer [14].

Another feature of the environment of the oral cavity is the presence of saliva produced by the salivary glands. Saliva is the protective fluid for all tissues of the oral cavity. It protects the soft tissues from abrasion by rough materials and from chemicals. It allows for the continuous mineralisation of the tooth enamel after eruption and helps in remineralisation of the enamel in the early stages of dental caries [25].

Saliva is an aqueous fluid with 1% organic and inorganic materials. The major determinant of the salivary composition is the flow rate which in turn depends upon three factors: the time of day, the type of stimulus, and the degree of stimulation. The salivary pH ranges from 5.5 to 7 depending on the flow rate. At high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH. The daily salivary volume is between 0.5 to 2 liters and it is this amount of fluid that is available to hydrate oral mucosal dosage forms. A main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity [23].

2.      Mechanisms of Mucoadhesion
The mechanism of mucoadhesion is generally divided into two steps: the contact stage and the consolidation stage (Figure 2). The first stage is characterized by the contact between the mucoadhesive and the mucus membrane, with spreading and swelling of the formulation, initiating its deep contact with the mucus layer.

In the consolidation stage (Figure 2), the mucoadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive molecules to break free and to link up by weak van der Waals and hydrogen bonds [26].

Figure 2



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