Buccal and Sublingual Drug Delivery |
CONTENTS
8.1.1 Overview of the Structure of the Oral Mucosa
8.2 Physiological Barriers to Drug Delivery across the Oral Mucosa
8.3 Oral Transmucosal Drug Delivery Considerations
8.3.1 Transport Mechanisms across the Oral Mucosa
8.4 Local/Topical Drug Delivery to the Oral Cavity
8.5 Oral Transmucosal Drug Delivery Systems
8.5.1 Sublingual Drug Delivery
8.5.2.2 Buccal Patches/Films/Wafers
8.5.3 Other Oral Transmucosal Drug Delivery Systems
8.5.3.1 Pediatric Transmucosal Formulations
8.6 In Vitro and In Vivo Assessment of Oral Transmucosal Systems
Topical delivery to the oral cavity is used to treat localized conditions of the mouth, such as aphthous ulcers, fungal infections, and periodontal disease. However, the oral cavity can also be used to achieve the systemic delivery of a drug, i.e., oral transmucosal delivery. As described in Chapter 7, the peroral (i.e., via the gastrointestinal [GI] tract) route remains the preferred route for the administration of therapeutic agents because of its low cost, ease of administration and high level of patient compliance. However, this route of administration also has disadvantages, such as hepatic first-pass metabolism and acidic and enzymatic degradation within the GI tract, which often prohibits its use for certain drug classes, including peptides and proteins. Consequently, other absorptive mucosa (i.e., the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity) are often considered as an alternative site for drug administration. One such alternative route is oral transmucosal drug delivery, which offers many distinct advantages over peroral administration for systemic drug delivery, including the avoidance of the hepatic first-pass effect and presystemic elimination within the GI tract.
Oral transmucosal delivery is further subdivided into the following:
1. Sublingual delivery: the systemic delivery of drugs through the mucosal membranes lining the floor of the mouth. This route is typically used when a rapid onset of action is required.
2. Buccal delivery: drug administration through the mucosal membranes lining the inner cheeks (buccal mucosa). Buccal delivery can additionally be used to prolong drug retention in the oral cavity, which is advantageous for both systemic and local drug delivery.
A further type of drug delivery to the oral cavity involves orally disintegrating tablets (ODTs), also known as “fast melts,” e.g., Zydis® ODT fast-dissolve formulation. These dosage forms are designed to dissolve rapidly (i.e., less than 30 seconds) in the mouth, in contrast to conventional tablets that must be swallowed whole. ODTs can be used as an alternative for patients who experience dysphagia (difficulty in swallowing), such as in pediatric and geriatric populations, or where compliance is an issue. However, in this case, drug absorption actually takes place in the GI tract after swallowing the dissolved active pharmaceutical ingredient (API), rather than from the oral cavity. As such, ODTs involve GI absorption rather than absorption from the oral cavity. Therefore they are not considered further here—they are discussed instead in Chapter 2 (Section 2.2.2).
8.1.1 OVERVIEW OF THE STRUCTURE OF THE ORAL MUCOSA
The oral cavity comprises the lips, cheek, tongue, hard palate, soft palate, and floor of the mouth (Figure 8.1).
The lining of the oral cavity, referred to as the oral mucosa, includes the buccal, sublingual, gingival, palatal, and labial mucosa. The oral mucosa is a stratified squamous epithelium, comprising many cell layers (see Chapter 4, Figure 4.7). The epithelium sits on an underlying connective tissue layer (the lamina propria), which contains a rich blood supply. An API is absorbed through the blood capillaries in the lamina propria and gains access to the systemic circulation (Squier and Wertz 1996).
FIGURE 8.1 The oral cavity. (Modified from Alexilusmedical/Shutterstock.com.)
The oral mucosa varies depending on its location in the oral cavity, so that three distinct types are described (see also Chapter 4, Section 4.5.2):
1. The lining mucosa: found in the outer oral vestibule (the buccal mucosa) and the sublingual region (floor of the mouth). It comprises approximately 60% of the total surface area of the oral mucosal lining in an adult human.
2. The specialized gustatory (taste) mucosa: found on the dorsal surface of tongue, specifically in the regions of the taste buds on the lingual papillae, located on the dorsal surface of the tongue. These regions contain nerve endings for general sensory reception and taste perception. This specialized mucosa comprises approximately 15% of the total surface area.
3. The masticatory mucosa: found on the hard palate (the upper roof of the mouth) and the gingiva (gums) and comprises the remaining approximately 25% of the total surface area.
The specialized mucosa is dedicated to taste perception. The masticatory mucosa is located in the regions particularly susceptible to stresses and strains resulting from masticatory activity. The superficial cells of the masticatory mucosa are keratinized, to help withstand the physical stresses of this region. The multilayered barrier of the masticatory mucosa, reinforced with keratin in the surface layers, presents a formidable barrier to drug permeation.
In contrast, the lining mucosa is subject to much lower masticatory stress and consequently has a nonkeratinized epithelium, which sits on a thin and elastic lamina propria, and submucosa. It is this lining epithelium that is the primary focus for drug delivery.
8.2 PHYSIOLOGICAL BARRIERS TO DRUG DELIVERY ACROSS THE ORAL MUCOSA
The environment of the oral cavity presents some significant challenges for systemic drug delivery. Certain physiological aspects of the oral cavity play significant roles in this process, including its pH, fluid volume, enzyme activity, and permeability. Table 8.1 provides a comparison of the physiological characteristics of the oral mucosa in comparison with the mucosa of the GI tract (Patel et al. 2011).
The principal physiological environment of the oral cavity, in terms of pH, fluid volume, and composition, is shaped by the secretion of saliva. Saliva is secreted by three major salivary glands (parotid, submaxillary and sublingual). The parotid and submaxillary glands produce a watery secretion, whereas the sublingual glands produce mainly viscous saliva with limited enzymatic activity. The main functions of saliva are to lubricate the oral cavity, to facilitate swallowing and to prevent demineralization of the teeth. It also contributes to carbohydrate digestion and regulates oral microbial flora by maintaining the oral pH and enzyme activity. The daily total salivary volume is between 0.5 and 2.0 mL. However, the volume of saliva constantly available is around 1.1 mL with a pH of ≈5.5–7.6, thus providing a relatively low fluid volume available for drug release from dosage forms, when compared to the GI tract. Overall, the pH and salivary compositions are dependent on the flow rate of saliva, which in turn depends upon three factors: the time of day, the type of stimulus and the degree of stimulation. For example, at high flow rates, the sodium and bicarbonate concentrations increase, leading to an increase in the pH. Such changes in pH can affect the absorption of ionizable drugs. For example, drugs such as midazolam, buprenorphine, nicotine, fentanyl, and lamotrigine are reported to have pH-dependant drug absorption across the oral mucosa (Mashru et al. 2005; Myers et al. 2013; Nielsen and Rassing 2002; Streisand et al. 1995).
TABLE 8.1
Comparison of Oral and Gastrointestinal Mucosa
Nevertheless saliva provides a water-rich environment of the oral cavity, which can be favorable for drug release from delivery systems, especially those based on hydrophilic polymers. However, saliva flow decides the time span of the released drug at the delivery site. This flow can lead to premature swallowing of the drug before effective absorption occurs through the oral mucosa and is a well-accepted concept known as “saliva washout.”
Drug permeability through the oral cavity mucosa represents another major physiological barrier for oral transmucosal drug delivery. The oral mucosal thickness varies depending on the site, as does the composition of the epithelium. The characteristics of the different regions of interest in the oral cavity are shown in Table 8.2 (Patel et al. 2011).
As outlined earlier, the areas of the mucosa subject to mechanical stress (i.e., the masticatory mucosa of the gingiva and hard palate) are keratinized (similar to the epidermis), which makes drug permeation difficult. They also contain neutral lipids like ceramides and acylceramides, making them relatively impermeable to water. Any formulation adhering to these areas can also present a problem in swallowing. For these reasons, the masticatory mucosa has not been used widely for drug delivery. In contrast, the nonkeratinized epithelia do not contain acylceramides and have only small amounts of ceramides, and also contain polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia are therefore considerably more permeable to water than the keratinized epithelia and are consequently more widely explored for drug delivery.
TABLE 8.2
Characteristics of Oral Mucosa
Abbreviations: K, keratinized tissue; NK, nonkeratinized tissue.
a In rhesus monkeys (mL/min/100 g tissue).
The apical cells of the oral epithelia are covered by mucus layer; the principal components of which are complexes made up of proteins and carbohydrates; its thickness ranges from 40 to 300 μm. In the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva. Although most of the mucus is water (≈95%–99% by weight), the key macromolecular components are a class of glycoprotein known as mucins (1%–5%). Mucins are large molecules with molecular masses ranging from 0.5 to over 20 MDa, containing large amounts of carbohydrate. They are made up of basic units (≈400–500 kDa) linked together into linear arrays, which are able to join together to form an extended 3D network, which acts as a lubricant and may also contribute to cell–cell adhesion. At physiological pH, the mucus network carries a negative charge due to the sialic acid and sulfate residues and forms a strongly cohesive gel structure that binds to the epithelial cell surface as a gelatinous layer. This gel layer is believed to play a role in mucoadhesion for drug delivery systems (DDS), which work on the principle of adhesion to the mucosal membrane and thus extend the dosage form retention time at the delivery site (described further in Section 8.3.2).
8.3 ORAL TRANSMUCOSAL DRUG DELIVERY CONSIDERATIONS
Despite the physiological challenges, the oral mucosa, due to its unique structural and physiological properties, offers several opportunities for drug delivery. As the mucosa is highly vascularized, any drug diffusing across the oral mucosa membranes has direct access to the systemic circulation via capillaries and venous drainage and will bypass hepatic first-pass metabolism. The rate of blood flow through the oral mucosa is substantial and is generally not considered to be the rate-limiting factor in the absorption of drugs by this route (Table 8.2).
In contrast to the harsh environment of the GI tract, the oral cavity offers relatively consistent and mild physiological conditions for drug delivery that are maintained by the continual secretion of saliva. Compared to secretions of the GI tract, saliva is a relatively mobile fluid with less mucin and has limited enzymatic activity and virtually no proteases, which is especially favorable for protein and peptide delivery. The enzymes that are present in the buccal mucosa are believed to include aminopeptidases, carboxypeptidases, dehydrogenases, and esterases.
Within the oral cavity, the buccal and sublingual routes are the focus for drug delivery because of their higher overall permeability, compared to the other mucosa of the mouth (Table 8.2). The buccal and sublingual mucosa are also approximately 13 and 22 times more permeable to water, respectively, in comparison with the skin. Based on relative thickness and their epithelial composition, the sublingual mucosa has the highest potential drug permeability of the oral mucosa and thus is suitable for systemic drug delivery with rapid onset of action. For rapid oral transmucosal delivery, a drug can be presented as lozenges, films or patches, sprays or compressed tablets having fairly rapid disintegration in the mouth (3 minutes or less). The buccal mucosa has moderate permeability and is suitable for both local and systemic drug delivery. The drug can be presented as a mucoadhesive formulation (patch or tablet) and can be released slowly, either to achieve a sustained release systemic absorption profile or to achieve sustained release effects locally in the oral cavity.
A further possibility for drug delivery to the oral cavity is that of vaccine delivery. The oral mucosa has a number of nonspecific mechanisms to protect against invading pathogens, including (1) salivary secretions, which keep the epithelial surface moist, inhibiting bacterial colonization; (2) a process of continuous shedding of the stratified squamous epithelium from the apical surface layer, therefore minimizing bacterial colonization; and (3) a highly resilient underlying lamina propria, which ensures that tissue integrity is maintained. In addition, the oral mucosa contains various types of specific immune-competent cells, as well as specific immune-competent tissue, particularly in the oropharyngeal region. Thus, the oral cavity could offer a potential route for noninvasive vaccine delivery. Promising data are emerging, in particular with respect to vaccine delivery via the sublingual route; this research is described in Chapter 17 (Section 17.4.4).
8.3.1 TRANSPORT MECHANISMS ACROSS THE ORAL MUCOSA
As described in Chapter 4, drugs can be transported across epithelial membranes by passive diffusion, carrier-mediated transport, or other specialized mechanisms (see Chapter 4, Section 4.3 and Figure 4.4). Most studies of buccal absorption indicate that the predominant mechanism is passive diffusion
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