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 across lipid membranes. Passive diffusion can occur via paracellular transport between the epithelial cells, as shown, for example, for flecainide, sotalol, and metformin (Deneer et al. 2002). Passive diffusion may also occur via transcellular transport through the epithelial cells, as shown, for example, for buspirone and lamotrigine (Birudaraj et al. 2005; Mashru et al. 2005). Drugs such as nicotine are believed transverse both pathways simultaneously (Nielsen and Rassing 2002). Specialized transport mechanisms have also been reported for a few drugs and nutrients, including monocarboxylic acids and glucose. Usually, one route is predominant, depending on the physicochemical properties of the drug. The relevant physicochemical properties of the API that favor epithelial absorption have been described in detail in Chapter 4 (Section 4.3.4).
Mucoadhesive systems are used in the oral cavity to maintain an intimate and prolonged contact of the formulation with the oral mucosa, allowing a longer duration for drug absorption. Mucoadhesion is a complex process and numerous theories have been presented to explain the mechanisms involved. The wettability theory (Ugwoke et al. 2005) is mainly applicable to liquid or low viscosity mucoadhesive systems and is essentially a measure of the spreadability of the DDS across the biological substrate. The electronic theory (Dodou et al. 2005) describes adhesion by means of electron transfer between the mucus and the mucoadhesive system arising through the differences in their electronic structures. The electron transfer between the mucus and the mucoadhesive results in the formation of a double layer of electrical charges at the mucus and mucoadhesive interface. The net result of such a process is the formation of attractive forces within this double layer. According to the fracture theory (Ahagon and Gent 1975), the adhesive bond between systems is related to the force required to separate both surfaces from one another and relates the force for polymer detachment from the mucus to the strength of their adhesive bond. The work of fracture has been found to be greater when the polymer network strands are longer, or if the degree of cross-linking within such a system is reduced. According to the adhesion theory (Jiménez-Castellanos et al. 1993), adhesion is defined as being the result of various surface interactions (primary and secondary bonding) between the adhesive polymer and mucus substrate. Primary bonds due to chemisorption result in adhesion due to ionic, covalent, and metallic bonding, which is generally undesirable due to their permanency. The diffusion-interlocking theory (Lee et al. 2000) proposes the time-dependent diffusion of mucoadhesive polymer chains into the glycoprotein chain network of the mucus layer. This is a two-way diffusion process with the penetration rate being dependent upon the diffusion coefficients of both interacting polymers. In practice however, the mechanism by which mucoadhesion occurs will depend on many factors including the nature of the mucus membrane, the mucoadhesive material(s) used and the type of formulation, so that is difficult to predict or assign a single mechanism (Boddupalli et al. 2010).
Significant research has focused on the development of mucoadhesive delivery systems (including tablets, films, wafers, and patches) that contain different components to extend the residence time of dosage forms at the site of application. The most widely investigated macromolecules are those containing numerous negative groups, including hydroxyl (OH–) and carboxyl (COO–) groups, which permit hydrogen bonding with the cell surface. Although hydrogen bonds are weak, numerous bonds are possible with such macromolecules, ensuring a firm attachment to the buccal epithelium. Examples include hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (SCMC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), and polyacrylic acid (PAA), either alone or in combination. Polycarbophil is a synthetic polymer of polyacrylic acid, lightly cross-linked with divinyl glycol. It is a weak polyacrylic acid (pKa = 4.2) containing multiple negative carboxyl groups (COO–), for bonding to the buccal surface. Other mucoadhesive polymers used in commercially available formulations include xanthan and locust bean gums. Thiolated polymers (thiomers) comprise a new class of mucoadhesives, derived from hydrophilic polymers such as polyacrylates. The thiol groups are capable of forming covalent bonds with cysteine-rich subdomains of the mucus gel layer, leading to increased residence time and improved bioavailability (Albrecht et al. 2006).
8.4 LOCAL/TOPICAL DRUG DELIVERY TO THE ORAL CAVITY
Local/topical delivery to the oral cavity is of use in the treatment of local conditions of the mouth, such as aphthous mouth ulcers, oral inflammatory lesions, fungal infections (e.g., oral candidiasis), viral infections (e.g., herpes simplex virus) and bacterial infections.
Liquid dosage forms are not readily retained in the oral cavity, cannot easily achieve drug targeting within the mouth and deliver relatively uncontrolled amounts of drug. For these reasons, liquid formulations for topical delivery tend to be confined to antibacterial mouthwashes, such as chlorhexidine gluconate mouth rinse (Periogard®), benzydamine hydrochloride mouthwash (Oroeze®), and antiseptic essential oil mouth rinse (Listerine®).
Semisolid dosage forms (SSDFs) for topical delivery include gels, creams, paste and ointments. These typically contain a hydrophilic polymer and drug, plus any required excipient dissolved or suspended as a fine powder, in an aqueous or nonaqueous base. Semisolid formulations can be applied using the finger (or syringe) to a target region and tend to be more acceptable in terms of “mouth feel” to patients, relative to a solid dosage form (SDF). However, they may deliver variable amounts of active ingredients. They are further limited by their short contact time with the oral mucosa and the need for multiple doses each day.
In order to improve contact time, more advanced technologies for local therapy typically incorporate a mucoadhesive polymer into the formulation. Kenalog® in Orabase® dental paste contains the steroidal drug triamcinolone acetonide, for the temporary relief of symptoms associated with oral inflammatory lesions and ulcerative lesions resulting from trauma. This paste formulation contains hydrophilic polymers such as gelatin, pectin, and SCMC, in Plastibase®: a plasticized hydrocarbon gel. Upon application, the paste forms a thin film covering the lesions; it is recommended for use at bedtime to ensure intimate contact between the formulation and mucosal site.
Similarly, Gelclair® contains PVP and sodium hyaluronate in a liquid gel, which, in contact with the oral mucosa, forms a protective film that adheres to the mucosa, offering rapid and effective pain management of lesions of the oral mucosa. PVP hydrate acts as a bioadhesive polymer and retains the formulation at the site of action for a prolonged period of time.
Lauriad™ technology utilizes hypromellose and a proprietary milk protein concentrate, in order to achieve mucoadhesion. The technology is used for the buccal delivery of the antifungal drug miconazole (Loramyc® in Europe, Oravig® in the United Kingdom). The buccal tablet provides sustained local release of miconazole over several hours, with just one daily application. Lauriad™ technology is also used in Sitavig® buccal tablets, for the prolonged local delivery of the antiviral drug acyclovir, in the treatment of oral herpes.
8.5 ORAL TRANSMUCOSAL DRUG DELIVERY SYSTEMS
Continuous research into the improvement of oral transmucosal drug delivery has resulted in the development of several conventional and novel dosage forms like solutions, tablets/lozenges, chewing gums, sprays, patches and films, hydrogels and microspheres. These dosage forms can be broadly classified into liquid, semisolid, solid or spray formulations. An overview of the different types of dosage forms currently available and in development is provided in the following text.
8.5.1 SUBLINGUAL DRUG DELIVERY
As described earlier, the sublingual mucosa is more permeable and thinner than the buccal mucosa and, because of the considerable surface area and high blood flow, it is a favorable site when a rapid onset is desired. The sublingual route is thus generally used for drug delivery in the treatment of acute conditions, such as in pain relief, antimigraine treatment or relief from an angina attack. Limitations of the route include that its surface is constantly washed by saliva; the short residence time at the site of absorption may result in incomplete absorption. Also tongue activity makes it difficult to keep a dosage form in contact with the mucosa for an extended period of time.
Glyceryl trinitrate (GTN) provides an excellent example of an API that benefits from the avoidance of first-pass metabolism when administered via the sublingual route. It was one of the first drugs successfully developed for oral transmucosal delivery, with a sublingual form introduced as early as 1847. GTN sublingual tablet (Nitrostat®) is delivered rapidly via the sublingual route, providing rapid relief/prophylaxis in angina. Other commercial examples of sublingual tablets include pain relief formulations such as buprenorphine hydrochloride (Temgesic®), buprenorphine hydrochloride in combination with naloxone (Suboxone®), and fentanyl citrate (Abstral®). Further sublingual tablets include zolpidem (Edluar®), lorazepam (Ativan®), nicotine (Nicorette Microtab®), and asenapine maleate (Sycrest®).
A major limitation of sublingual tablets is that dissolution can vary considerably, depending on the type, size, and shape of the tablet. Thus, sublingual dosage forms generally have a high inter- and intraindividual variation in absorption and bioavailability. Also, such types of systems are not able to provide unidirectional drug release. A sublingual aerosol spray is an alternative to sublingual tablets, which can deliver the API more rapidly and uniformly into the salivary fluid, or onto the mucosal surface, where it is readily available for absorption. Nitroglycerin (Nitrolingual® pump spray, Nitromist®, and Glytin®), zolpidem (Zolpimist®), nicotine (Nicorette Quickmist®), and flurbiprofen (Benactiv®), are the currently marketed, spraytype formulations.
The buccal mucosa can be used for both local and systemic therapies. As outlined earlier, the buccal mucosa is relatively permeable, robust and, in comparison with other mucosal tissues, more tolerant to potential allergens and has a reduced tendency to irreversible irritation or damage. When rapid buccal delivery is required, the drug may be delivered as buccal tablets that have a relatively rapid in-mouth disintegration time (15 minutes or less). Sprays, films, wafers, lozenges, and lollipop-like systems may also be used for this purpose. The buccal mucosa, in contrast to the sublingual mucosa, also offers a smooth and relatively immobile surface: this facilitates the placement of a retentive DDS for prolonged exposure, such as a buccal tablet, film or wafer. In this case, the drug is released slowly, for continuous absorption throughout the oral mucosa. In some cases, some of the dose may be swallowed, with subsequent absorption occurring from the GI tract.
Buccal tablets can be formulated so that the drug is dispersed within a bioadhesive matrix. This type of system facilitates multidirectional release. Unidirectional release may be achieved via the incorporation of a second impermeable backing layer, typically an insoluble polymer layer, which covers the underlying drug/adhesive layer. In addition to ensuring unidirectional flow across the buccal mucosa, the outer impermeable layer may prevent overwetting of the tablet and subsequent formation of slippery mucilage, which can limit bioadhesive retention. In some cases, the outer layer can be a slowly dissolving layer, so that after drug absorption has taken place, the DDS dissolves and does not have to be physically removed.
Disadvantages of buccal tablets can include poor patient acceptability (due to uncomfortable mouth feel, taste, irritation, and discomfort) and the nonubiquitous distribution of drug within saliva for local therapy. There is also the risk that the dosage form could separate from the oral mucosa, be swallowed, and then adhere to the wall of the esophagus.
Some commercially available buccal tablets are described here. Buccastem® tablets are a long-established buccal delivery system for the antiemetic prochlorperazine, which contains PVP, xanthan gum, and locust bean gum, to achieve bonding with the buccal mucosa. On application, the tablet softens and adheres to the gum where it forms a gel, from which the prochlorperazine is released and absorbed. One 3 mg buccal tablet twice a day results in steady-state plasma levels bioequivalent to those achieved by the standard oral dosage of one 5 mg tablet taken three times a day.
Suscard® buccal tablets are prolonged release mucoadhesive buccal tablets for the delivery of GTN. The Suscard tablet is placed high up between the upper lip and gum to either side of the front teeth; hypromellose in the formulation ensures mucoadhesion. Once in place, the duration of action of the tablet correlates with its dissolution time and is normally 3–5 hours. However, the first few doses may dissolve more rapidly until the patient is used to the presence of the tablet. During the dissolution time, the tablet softens and adheres to the gums; in practice the presence of the tablet is not noticeable to the patient after a short time.
Striant® SR tablets contain testosterone in a mucoadhesive system comprising a combination of carbopol, polycarbophil, and hypromellose designed to adhere to the gum or inner cheek. It provides a controlled and sustained release of testosterone through the buccal mucosa as the buccal system gradually hydrates. Application of Striant® twice a day, in the morning and in the evening, provides continuous systemic delivery of testosterone.
An interesting formulation approach is used in the OraVescent® tablet, which exploits a localized, transient pH change that occurs over the course of tablet disintegration and dissolution, in order to facilitate drug dissolution and buccal absorption. As the tablet disintegrates in the oral cavity, a CO2-generating reaction produces a modest initial decrease in the pH of the tablet microenvironment. For weakly basic drugs, this lower pH (below its pKa) favors the ionized form of the drug, thereby accelerating drug dissolution. A pH-modifying substance present in the tablet (e.g., sodium carbonate) then begins to dissolve, so that the pH microenvironment subsequently increases with time, causing ionized drugs to convert predominantly to the unionized form, thereby increasing transmembrane permeability. This technology is used for the buccal delivery of the opioid analgesic, fentanyl (Fentora®), to treat “breakthrough” cancer pain. Following buccal administration of Fentora®, fentanyl is readily absorbed with an absolute bioavailability of 65%. The absorption profile of Fentora® is largely the result of an initial absorption from the buccal mucosa, with peak plasma concentrations generally attained within an hour after buccal administration. Approximately, 50% of the total dose administered is absorbed transmucosally and becomes systemically available. The remaining half of the total dose is swallowed and undergoes more prolonged absorption from the GI tract (Darwish et al. 2007).
8.5.2.2 Buccal Patches/Films/Wafers
Buccal patches/films/wafers are emerging as alternative formulation choices to buccal tablets. Their thinness and flexibility means that they are less obtrusive and therefore more acceptable to the patient. Similar to buccal tablets, they can provide multidirectional or unidirectional drug release. They are usually prepared by casting a solution of the polymer, drug, and any excipients (such as a plasticizer) on to a surface and allowing it to dry. They can be up to 10–15 cm2 in size, but are more usually 1–3 cm2, often with an ellipsoid shape to fit comfortably into the center of the buccal mucosa. The relative thinness of the films, however, means that they are more susceptible to overhydration and loss of the adhesive properties. Such formulations may also suffer from low drug loading.
FIGURE 8.2 Buccal delivery using a BioErodible MucoAdhesive Film showing unidirectional drug delivery. (Courtesy of BioDelivery Sciences International, Inc.)
BioErodible MucoAdhesive Film (BEMA™) features a bilayered buccal film technology, in which the active drug is dissolved within a mucoadhesive layer; a backing layer then facilitates unidirectional flow of drug. On application, saliva moistens the mucoadhesive layer, ensuring adhesion of the film to the buccal mucosa within seconds; rapid systemic drug absorption then follows (Figure 8.2). The film is bioerodible and dissolves completely within 15–30 minutes of application.
Onsolis® (fentanyl buccal soluble film) uses the BEMA™ bilayer delivery technology for the buccal delivery of the potent opioid analgesic, fentanyl citrate. The API is incorporated into a bioadhesive layer comprising carboxymethyl cellulose and HPC. An insoluble backing layer of HEC promotes unidirectional drug release and drug absorption across the oral mucosa. The amount of fentanyl delivered transmucosally is proportional to the film surface area. The absorption pharmacokinetics of fentanyl from Onsolis® is a combination of an initial rapid absorption from the buccal mucosa (about 50% of the dose) and a more prolonged absorption of swallowed fentanyl from the GI tract. Of the swallowed fentanyl, about 20% of the total dose escapes hepatic and intestinal first-pass elimination and becomes systemically available. The BEMA™ platform is also used for the buccal delivery of buprenorphine with naloxone (Bunavail®) and is under study for a variety of other drugs.
Buccal sprays offer the advantage of a rapid onset of action: a spray delivers the dose in fine particulates or droplets; thus, the lag time for the API to be available at the site of absorption is reduced. For example, a pharmacokinetic study of buccal insulin spray in patients with Type I diabetes revealed no statistical difference in glucose, insulin, and C-peptide plasma levels, compared to insulin administered subcutaneously (s.c.) (Pozzilli et al. 2005).
Oral-lyn™ is an oral spray for the systemic delivery of insulin, for the treatment of Type I and II diabetes, based on the RapidMist™ technology platform. Regular recombinant human insulin is delivered to the membranes of the oral cavity by a simple asthma-like inhaler device, and Orallyn™ is offered as a pain-free alternative to s.c. injections of prandial insulin. It is on the market in some regions and is preparing for FDA approval.
The RapidMist™ technology is based on the formation of microfine micelles, loaded with insulin. A combination of different proprietary absorption enhancers encapsulates and protects insulin within the micelles. The device produces a high-velocity (100 mph) aerosol, which is claimed impels the insulin-containing micelles across the superficial layers of the buccal mucosa; rapid transmucosal absorption is further facilitated by aerosol particle size and the absorption enhancers in the formulation. Following oral administration, insulin appears in the blood within 5 minutes, peaks at 30 minutes, and is back to baseline at 2 hours. This rapid absorption profile means that even though the formulation contains regular recombinant human insulin, its delivery profile is more akin to that of the synthetic fast-acting insulin analogs (lispro, aspart, and glulisine) administered subcutaneously.
The spray orifice in the actuator of the device is designed for maximum impact with the buccal cavity. It is claimed that the size of the insulin-containing micelles that are formed (85% having mean size >10 μm) ensures that absorption is limited to the mouth, with no entry of product into the lungs, thereby avoiding pulmonary side effects.
The technology is designed so that one spray delivers approximately 10 U of insulin; thus, approximately 1 U of insulin is absorbed systemically. Application of >10 U of insulin (e.g., after a meal) therefore requires more than 10 puffs, which is time-consuming and not very user-friendly. The insulin is claimed to be released from the device as a metered dose, so that the delivered dose should be identical from the first puff to the last. However, effective dosing requires some patient education and training. Notwithstanding, the RapidMist™ technology is in clinical development for the buccal delivery of a variety of other drugs, including fentanyl citrate, morphine, and low-molecular-weight heparin.
8.5.3 OTHER ORAL TRANSMUCOSAL DRUG DELIVERY SYSTEMS
A lozenge-on-a-stick unit offers nonspecific drug delivery to oral mucosa, i.e., drug release from the formulation is not specific to either the sublingual or buccal mucosa and a drug can be absorbed both from these mucosa as well as from the GI tract once swallowed by the patient. An example of this type of delivery device is Actiq®, for the oral transmucosal delivery of the potent opioid analgesic fentanyl citrate. The advantage of this system is that the stick handle allows the Actiq® unit to be easily removed from the mouth if signs of excessive opioid effects appear during administration. Normally, approximately 25% of the total dose of Actiq® is rapidly absorbed from the buccal mucosa and becomes systemically available. The remaining 75% of the total dose is swallowed with the saliva and then is slowly absorbed from the GI tract. About 1/3 of this amount (i.e., 25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available. Thus, the generally observed 50% bioavailability of Actiq® is divided equally between rapid transmucosal, and slower GI, absorption.
Medicated chewing gum is another means of delivering drugs nonspecifically to the oral cavity. The approach is widely used for the delivery of nicotine as an aid in smoking cessation. Nicotine, a small, lipophilic molecule, is readily absorbed from the oral mucosa when administered in chewing gum. Blood levels are obtained within 5–7 minutes and reach a maximum about 30 minutes after the start of chewing. Blood levels are roughly proportional to the amount of nicotine chewed.
Nicotrol® Inhaler (nicotine inhalation system) consists of a mouthpiece and a plastic cartridge delivering 4 mg of nicotine from a porous plug containing 10 mg nicotine. The cartridge is inserted into the mouthpiece prior to use. Most of the nicotine released from the Nicotrol® Inhaler is deposited in the mouth, with only a fraction (less than 5%) of the dose reaching the lower respiratory tract. An intensive inhalation regimen (80 deep inhalations over 20 minutes) releases on average 4 mg of the nicotine content of each cartridge, of which about 2 mg is systemically absorbed. Peak plasma concentrations are typically reached within 15 minutes of the end of inhalation. Absorption of nicotine through the buccal mucosa is relatively slow, so that the rapid peaks and troughs obtained with cigarette smoking are not achieved.
DDS such as micro- and nanoparticles and liposomes are also being investigated for oral transmucosal delivery (Heanden et al. 2012). For example, polymeric microparticles (23–38 μm) of Carbopol®, polycarbophil and chitosan or Gantrez® (copolymers of monoalkyl esters of poly (methyl vinyl ether/maleic acid)) were found to adhere to porcine esophageal mucosa, with particles prepared from the polyacrylic acids exhibiting greater mucoadhesive strength during tensile testing studies. In contrast, in elution studies, particles of chitosan or Gantrez® were seen to persist on mucosal tissue for longer periods of time (Kockisch et al. 2004).
8.5.3.1 Pediatric Transmucosal Formulations
Sublingual and buccal DDS are a particularly attractive choice for children, as this target group typically experiences problems in swallowing SDFs. However, relatively few products have been approved for pediatric indications at the current time. Pediatric gel formulations are typically used for topical oral treatment, e.g., teething and antifungal gels. For systemic delivery, SDFs such as lozenges, tablets, capsules, and films/wafers are preferred to liquid formulations, because of their improved drug stability, ease of manufacture, and less bulky nature, all of which increases pediatric patient compliance and decreases the cost of goods. As such, lozenges and tablets are some of the more common types of dosage forms for the buccal/sublingual route in pediatric patients. However, where prolonged contact with the mucosa is required, semisolid formulations may offer greater pediatric acceptability than SDFs, as the former can be spread evenly and thinly over the mucosa, rather than having to be deliberately retained and thus potentially obstructing swallowing, eating, and drinking.
8.6 IN VITRO AND IN VIVO ASSESSMENT OF ORAL TRANSMUCOSAL SYSTEMS
Despite the intensive research efforts dedicated to developing oral transmucosal DDS, relatively few formulations have made the successful translation to commercial product. This can partly be attributed to the current lack of standardized methodology or guidance available for the evaluation and optimization of such delivery systems in vitro and in vivo, prior to performing much more expensive and time-consuming clinical evaluations. Table 8.3 lists the typical in vitro and in vivo methods available for the assessment of current oral transmucosal dosage forms (Patel et al. 2012).
TABLE 8.3
Types of Oral Transmucosal Dosage Forms and Their Testing Requirements
Drug permeation across the oral mucosa is one of the key determinants of the effectiveness of a DDS. This can be assessed using isolated mucosa in a diffusion cell. Buccal epithelium from pigs, dogs, monkeys, rats, hamsters, rabbits, and primates are the most frequently used in such permeation studies. Of these, pig buccal mucosa is the most common, due to its close resemblance to human mucosal tissue with respect to lipid composition, keratinization and overall thickness. The drawbacks of using tissue models include the difficulty in maintaining tissue viability and integrity, as well as the complexity involved in tissue excision. Increasingly, buccal epithelial cell culture models are being used as an alternative.
In vitro–in vivo correlation (IVIVC) data are often used during pharmaceutical development in order to optimize the formulation, while reducing product development time and costs. A good correlation is a tool for predicting in vivo results based on in vitro data, and it allows dosage form optimization with the fewest possible trials in human, fixes drug release acceptance criteria, and can be used as a surrogate for further bioequivalence studies. Very few attempts have been made so far to obtain IVIVC for oral transmucosal DDS, and significant research effort is needed in this area.
Oral transmucosal drug delivery has attracted significant attention from academic and industrial researchers due to a number of advantages the route offers, such as avoidance of first-pass metabolism, improving medication compliance, rapid drug response, and possibility of controlled release. Many formulation approaches have been explored for buccal and sublingual routes, although the number of commercially available formulations is limited. A commercially available buccal spray for the oral transmucosal delivery of insulin has been developed. Oral transmucosal dosage forms will continue to be an exciting research focus for achieving the systemic absorption of drugs that are unsuitable for delivery via the oral route, especially for the new “biologics,” such as peptides, proteins, and DNA-based medicines.
As regards future directions, problems that need to be addressed include those associated with palatability, as well as irritancy caused by DDS retention at the site of application. Robust and validated in vitro and in vivo methods are essential tools that need to be developed and standardized, in order to assess the performance of oral transmucosal DDS and to predict their in vivo behavior.
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