Advanced Drug Delivery Reviews, l l (1993) 253 270

1993 Elsevier Science Publishers B.V. All rights reserved. / 0169-409X/93/$24.00 A D R 00148

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Drug delivery using buccal-adhesive systems

J o h n D. Smart
Drug Delivery Research Unit, The School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
(Received April 28, 1992) (Accepted August 12, 1992)

Key words: Buccal cavity; Route o f drug delivery; Saliva; Mucoadhesive; Mucosal adhesive; Buccal dosage forms

Contents
Summary ................................................................................................................. I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. The oral cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . III. Drug delivery via the oral cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Buccal-adhesive dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Mucosal-adhesive materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Mechanism o f mucosal adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (a) Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Patches, tapes, films . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (c) Semisolid preparations (ointments and gels) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (d) Powders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 254 254 257 259 259 259 261 261 263 265 265 266 266

Summary
The buccal mucosa has been investigated for local drug therapy and the systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass
Correspondence: Dr. J. Smart, Drug Delivery Research Unit, The School of Pharmacy and Biomedical Sciences, University of Portsmouth, Park Building, King Henry I Street, Portsmouth POl 2DZ, UK.

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metabolism or are unstable within the rest of the gastrointestinal tract. The mucosa of the oral cavity presents a formidable barrier to drug penetration, and one method of optimising drug delivery is by the use of adhesive dosage forms. Mucosaladhesive materials are hydrophilic macromolecules containing numerous hydrogenbond-forming groups. They have been called "wet" adhesives in that they require moisture to become adhesive and this may be supplied by the saliva; the latter may also act as the dissolution medium. Various buccal-adhesive formulations have been investigated with a view to delivering drugs locally or systemically. If the buccal route is to be used for the systemic delivery of large macromolecules, then a penetration enhancer incorporated into an adhesive dosage form may be a possible approach. I. Introduction The buccal route has been used for many years to deliver drugs such as certain steroids that are subjected to first-pass metabolism [1]. Further recent interest in this route has been generated with regard to the non-parenteral delivery of new peptide and protein drugs produced as a result of advances in biotechnology. The buccal route has the advantage of allowing excellent accessibility, reasonable patient acceptance and compliance, avoids first-pass metabolism and involves a relatively robust mucosa. In order to optimise drug delivery to, or via, the buccal cavity, the use of adhesive dosage forms has been investigated, and this will be considered in this review. II. The oral cavity The functions of the oral cavity (also referred to as the "buccal cavity") includes the analysis of potential foodstuffs, mechanical processing, lubrication and digestion [2]. The anatomy and physiology of the oral cavity has been well reviewed in other texts (e.g. Refs. [2 6]) and will be considered briefly here. The oral cavity consists of two regions, the outer oral vestibule which is bounded by the cheeks, lips, teeth and gingiva (gums) and the oral cavity proper which extends from the teeth and gums back to the fauces (which lead on to the pharynx) with the roof comprising the hard and soft palates. The tongue projects from the floor of the cavity. The buccal mucosa refers to the membrane lining the inside of the cheek, and the term "buccal drug delivery" refers to drug release which can occur when a dosage form is placed in the outer vestibule between the buccal mucosa and gingiva. The outer surface of the oral cavity is a mucous membrane consisting of an epithelium, basement membrane and lamina propria overlying a submucosa containing blood vessels and nerves. The mucosa can be divided into three types: the masticatory mucosa, found on the gingiva and hard palate; the lining mucosa found on the lips, cheek, floor of the mouth, undersurface of the tongue and the soft palate; and the specialised mucosa found on the upper surface of the tongue and parts of the lips. All consist of a squamous stratified epithelium, many cell layers thick (40-50 for the buccal mucosa) overlying a connective tissue layer, the lamina propria. In the case of the masticatory mucosa the outer layers are keratinised and

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may be said to be similar (but not identical) to skin. The total surface area of the oral mucosa is about 100 cm 2 and the buccal mucosa makes up about a third of this. Generally, the non-keratinised mucosae tend to be thicker than the keratinised mucosae. The buccal mucosa is approximately 0.5 mm thick while other mucosae are thinner, i.e. about 0.25 mm. The cells, particularly those in the non-keratinised epithelium, are turned over very rapidly (i.e. within 3-8 days). The biochemistry of the oral mucosa has been considered by Gerson and Harris [7]. All the layers of the oral mucosa contain a large amount of protein in the form of tonafilaments, consisting of at least seven proteins called "keratins" with molecular sizes of 40 70 KDa. The difference between keratinised and non-keratinised epithelia is merely the difference in the molecular size of these keratins. Cells of nonkeratinised epithelia contain lower-molecular-weight proteins while those in keratinised epithelia contain mainly higher-molecular-weight keratins. The lipid content of the cells varies between tissues. The non-keratinised buccal and sublingual mucosae contain polar lipids while the keratinised gingival and palatal mucosae contain non-polar lipids [5]. Squier [8] and Squier and Lesch [9] proposed that the intercellular material between the superficial epithelial layers is extruded by a unique organelle called a "membrane-coating granule". It has been shown in rat keratinised epithelium that the lamella contents of the membrane-coating granules mix with existing material and form broad sheets in the intercellular spaces [10]. These sheets are orientated parallel to the cell membrane and therefore may act as a barrier to permeability. The surface of the oral cavity is constantly bathed with a stream of saliva (approximately 1 litre per day) produced by the salivary glands. The major salivary glands, producing up to 90% of the saliva, are the pairs of parotid, submaxillary (submandibular) and sublingual glands. The parotid glands are situated some way from, but drain into, the oral cavity via long ducts that open onto the inner surface of the cheek. The submaxillary glands lie below the lower jaw and release saliva through ducts on each side of the floor of the mouth. The sublingual glands are located below the tongue with several ducts emptying onto the floor of the mouth. Minor salivary glands, i.e. the buccal glands exist in or below the oral mucosa. The function and constituents of saliva have been the subject of several reviews (e.g. Refs. [11-13]) and the physiological functions listed in Table I have been identified. The importance of saliva is illustrated in a condition called "xerostomia" (dry mouth) where patients complain of a variety of symptoms including sore mouth, oral infections, difficulty in talking, adhesion of the tongue to the side or roof of the mouth, and dental caries [12].
TABLE I P H Y S I O L O G I C A L F U N C T I O N S O F SALIVA Modulation of the oral flora Remineralisation of the teeth with calcium phosphate salts Neutralisation of acid in the oral cavity and oesophagus Lubrication and cleansing of the oral, pharyngeal and oesophageal mucosae Assistance in bolus formation Stimulation of epithelial proliferation Initiation of fat and starch digestion

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Chemically, saliva consists of 99.5% water with 0.5% solutes. The solutes include ions (sodium, potassium, calcium, magnesium, phosphate, bicarbonate and chloride), dissolved gases, urea, uric acid, serum albumin, globulin, mucin, and enzymes (lysozyme and amylase (ptyalin)). The nature of the secretions varies from gland to gland; the parotid glands produce predominantly an amylase-containing watery secretion while the buccal and sublingual glands produce mainly a viscous saliva containing mucin with little enzymic activity. The submaxillary glands have an intermediate secretion containing both amylase and mucin. Ordinarily just enough saliva is secreted to keep the oral mucosa moist, 70% of which originates from the submaxillary gland. When food is ingested, secretion increases so that the saliva can lubricate, dissolve and bring about the chemical breakdown of food. Saliva can be produced at a rate of up to 7 ml m i n - 1, 50% coming from the parotid gland. Thus the nature of the salivary secretion may alter from viscous to watery (and the enzyme content is also variable). The salivary pH will also vary from 6.2 to 7.4 (from low to high flow rates) although bacteria around the teeth may produce a lower localised pH. The glycoproteins in saliva can be divided into two groups: those of mucous cell origin which have a high molecular weight and are heavily glycosylated and those of serous cell origin which have a lower molecular weight and contain less than 50% carbohydrate [14]. The salivary mucin glycoprotein MG1 has been the subject of most studies (e.g. Refs. [15,16]). It consists of several disulphide-linked subunits containing a protein core with 4-16 oligosaccharide side-chain units. Its molecular size is over 1000 kDa, and it contains approximately 15% protein, 78% carbohydrate with about 5-10% covalently bound fatty acids [16]. A smaller mucin glycoprotein (MG2) has been identified from submaxillary and sublingual saliva [17]. This contains 30% protein and 68% carbohydrate and has a molecular weight of 200-250 kDa. It consists of a single peptide chain with 2-7 oligosaccharide side-chain units. Another important glycoprotein found in human parotid saliva is proline-rich glycoprotein (PRG). This contains 60% protein and 30% carbohydrate and is 38.9 kDa in size [18]. It also consists of a single peptide chain with 14 oligosaccharide side-chain units. Components of saliva are adsorbed onto the surface of the oral mucosa to form a salivary pellicle 0.1-0.7 mm thick [19]. This pellicle coats all surfaces in the mouth and is a multilayered structure. Initially, salivary macromolecules are selectively adsorbed onto the mucosal surface, then these molecules complex with other molecules in the ambient saliva. It has been proposed that these salivary components may be covalently crosslinked to the epithelial cell surface and to each other by the actions of transglutaminases [20]. It has been speculated that MG1 functions at the hard and soft tissue interfaces to provide a permeability barrier for protection against environmental insult and desiccation [21]. The nature of the salivary pellicle (i.e. its effectiveness in increasing the wettability of a surface) has been seen to change throughout the day [22]. It has been suggested that the lubricating properties of biological fluids depends on the ability of glycoproteins to form a boundary layer on opposing surfaces, thus reducing friction, and it was found, using a modified lubometer, that on a molar basis MG1 is a better lubricant than MG2, with PRG being the least effective [14]. The oral cavity contains large numbers of microorganisms and the salivary pellicle has been shown to be a determinant in bacterial

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adhesion [14]. The salivary pellicle also concentrates protective molecules (e.g. IgA) at the mucosal surface and may act as a selective barrier to macromolecules [23].

III. Drug delivery via the oral cavity

The oral cavity can be used for local and systemic therapy. Examples of local therapy would be the treatment of oral infections, dental caries, mouth ulcers, and stomatitis. The buccal route is of particular interest with regard to the systemic delivery of small molecules that are subjected to first-pass metabolism, or for the administration of proteins and peptides. The multilayered structure and mainly protective role of the mucosa within the oral cavity would imply that it would not be as good a site for drug absorption as other single cell layer mucosae, e.g. those found in the small and large intestines. Of the non-keratinised mucosae, the buccal mucosa, being comparatively thicker, is a poorer site for drug absorption than other, thinner mucous membranes, e.g. the sublingual mucosa [6]. It has been suggested that these physiological features explain the comparatively few reports to date (relative to other non-parenteral routes) of peptide absorption across the buccal mucosa [24,25]. For absorption to occur the drug has to be in solution, therefore in the case of a dry dosage form the drug will have to dissolve in the saliva. It is therefore possible that much of the drug may be "washed out" from the oral cavity and swallowed. One other important factor to consider is the organoleptic property of the drug, and it may be necessary to chemically modify or microencapsulate the drug to reduce any unpleasant taste [26]. The experimental procedures by which drug absorption from the oral cavity has been investigated have been reviewed by Rathbone and Hadgraft [27], and include buccal absorption tests [28], disc methods [29] and perfusion cells [30]. The buccal mucosa has been said to behave predominantly as a lipoidal barrier to the passage of drugs, as is the case with many other mucosae, and (within limits) the more lipophilic (or less ionised) the drug molecule, the more readily it is absorbed [28,31,32]. It has been concluded that passive diffusion in accordance with the pHpartition theory of drug absorption is the major route of drug absorption for most drugs [27]. However, it has been reported that certain molecules, e.g. some sugars and vitamins, may be transported by a specialised transport system capable of saturation [33,34]. In keratinised oral mucosal tissue as with skin, the keratinised upper layer is the major barrier to drug absorption [35,36]. In non-keratinised tissue it has been proposed that the upper epithelial layer acts as a lipoidal barrier while the basal lamina presents a major transport barrier to large hydrophilic molecules [37,38]. The lamina propria is believed to offer little resistance to drug permeation. Regional variations in oral mucosal drug absorption have also been reported [36], which is consistent with the differences in the thickness and composition of the mucosa within the oral cavity. As with the skin, it has also been proposed that the intercellular route, rather than the transcellular route, is the predominant route for drug absorption [9]. Large hydrophilic molecules in particular are believed to be transported by the intercellular route and the presence of the contents of membranecoating granules in the intercellular space may inhibit penetration in both keratinised and non-keratinised mucosae [38].

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The salivary pellicle may also act as a barrier for drug absorption. It is known that the salivary pellicle protects the mucosa from acids and enzymes, and there is evidence from animal studies that the absence of this layer allows the diffusion of various compounds through the mucosa, including acridine orange [39] and benzpyrine [40]. Comparatively small molecules have been delivered successfully via the buccal mucosa, e.g. glyceryl trinitrate [41], scopolamine [42] and flurbiprofen [43]. The buccal mucosa is however relatively impermeable to peptide and protein drugs which have the disadvantages of being both large and hydrophilic molecules. It has been reported that the buccal absorption of insulin was negligible until a penetration enhancer was included in the formulation [44,45]. However a low-molecular-weight peptide (a lauroyl derivative of a tri-peptide) was reported to show low but significant absorption in vitro and in vivo [46]. The steady-state permeability coefficient for three peptides--thyrotrophinreleasing hormone, DDAVP (1-deamino-8-D-arginine vasopressin) and insulin-have been calculated for the buccal route using data obtained from previous literature studies [47]. The buccal mucosa was less permeable than nasal or intestinal mucosa, and only DDAVP gave calculated steady-state levels in excess of the therapeutic levels, due mainly to its comparatively long half-life. The use of penetration enhancers such as sodium lauryl sulphate, cetylpyridinium chloride [48], azone [49], and capsaicin [50] has been investigated as a suitable method for improving the penetration of non-peptide drugs through the buccal mucosa. With regard to larger molecules, the bioavailability of insulin from a bioadhesive delivery system was increased to only 0.5% in beagle dogs using the most effective penetration enhancer, sodium glycocholate [44]. Aungst and Rogers [51] evaluated a series of penetration enhancers and vehicles with regard to insulin absorption from a solution instilled into the oral cavity of an anaesthetised rat. Laureth-9, sodium lauryl sulphate and steroidal detergents (e.g. sodium glycocholate) were found to be the most effective enhancers at pH 7.4 and their most effective formulations gave insulin levels one-quarter to one-third as effective as an intramuscular injection. Oh and Ritschel [52], using a buccal cell in an anaesthetised rabbit, also investigated the effect of penetration enhancers on the buccal absorption of insulin. An increase in the absorption of insulin, measured in terms of the hypoglycaemic response, was seen for a range of penetration enhancers, with Brij 35 being the most successful, followed by sodium taurocholate, sodium lauryl sulphate, sodium deoxycholate, sodium methoxysalicylate, sodium dextransulphate and EDTA. The maximum bioavailability of insulin from solution was 12%, while from a dry tablet formulation this was only 4.3%. Because all penetration enhancers perturb membrane integrity, it is inevitable that varying extents of insult will occur to the contacting membranes. Bile salts, laureth-9 and acylcarnitines show a direct relationship between the degree of tissue damage and the extent of absorption promotion [53]. In one study, Richardson et al. [54] found that rat vaginal epithelium (also a stratified squamous epithelium) was severely damaged after 24 hours contact with laureth-9, although, more promisingly, epithelia in contact with the phospholipid enhancer, lysophosphatidylglycerol, showed little or no evidence of damage. In general, non-surfactant-like enhancers appear to produce fewer morphological changes than their surfactant counterparts

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[55]. The potential toxicity of the enhancers themselves, and the effect of breaking down a natural barrier possibly leading to the absorption of unwanted materials may also be limiting factors. Long-term evaluation will therefore be necessary before the routine inclusion of these materials into buccal drug delivery systems, although it may be expected that the buccal mucosa would be more robust than other mucosae used for drug delivery. As with other mucosae, the presence of peptidases within the buccal mucosa may also reduce the bioavailability of proteins and peptides delivered by this route [56,57].

IV. Bueeal-adhesive dosage forms

IV.1. Mucosal-adhesive materials Mucosal-adhesive materials have been investigated and identified in previous work [58 60]. These are generally hydrophilic macromolecules that contain numerous hydrogen-bond-forming groups. The presence of carboxyl groups and a molecular size greater than 100 kDa favour adhesion. In most cases these materials require moisture to become adhesive but may excessively hydrate to form a slippery mucilage, and lose their adhesive properties. Several strategies (i.e. the inclusion of a hydrophobic component or a cross-linking agent) have been used to prevent excess hydration [61]. Some of the most extensively studied mucosal adhesives are the poly(acrylic acids), e.g. Carbopol 934 and polycarbophil. The high concentration of carboxyl groups in a dry tablet of poly(acrylic acid) would be predicted to generate a low surface pH on moistening, and pH values of between 2 and 3 have been detected in our laboratories. A low pH would be expected to damage a contacting mucosal surface, and this has been reported in an in vivo study [62]. Salts and bases have been included in poly(acrylic acid)-containing formulations to raise the pH [63], but the presence of predominantly ionised carboxyl groups would result in a loss of the adhesive properties [64]. Thus the ultimate suitability of poly(acrylic acid) for use as a bioadhesive component in a pharmaceutical formulation may be questioned. Other anionic mucosal-adhesive materials include sodium carboxymethylcellulose, sodium alginate, and maleic anhydride copolymers. Non-ionic polymers on the whole tend to be weaker adhesives, and these include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, poly(ethylene oxide), poly(vinyl alcohol), and starch. Chitosan [65] and diethylaminoethyl-dextran [66] are examples of cationic materials that have been proposed as mucosal-adhesive polymers. IV.2. Mechanism of mucosal adhesion Mucosal-adhesive materials are called "wet" adhesives in that they will adhere to most surfaces on moistening. The various theories of bioadhesion have been the subject of several reviews (e.g. Refs. [60,67-69]), and include the electronic theory, the adsorption theory, the wetting theory, the diffusion theory and the fracture theory. It has been envisaged that for dosage forms to adhere to mucous membranes, they must first interact with the overlying layer of mucus [67,68].

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Mucoadhesion is proposed to occur in three stages. Initially, an intimate contact must form between the mucoadhesive and mucus (i.e. they must "wet" each other), then the mucus/mucoadhesive macromolecules interpenetrate, and finally the molecules interact with each other by secondary non-covalent bonds [69]. It would be predicted that the mucus layer would be the weakest component of the mucoadhesive joint. If interpenetration is an important stage in mucoadhesive bond formation, then including bioadhesive polymers into a mucus gel would be expected to increase its resistance to deformation, thus strengthening the adhesive joint. An increase in the viscosity of mucoadhesive/mucus mixes has been reported by Hassan and Gallo [70] and Allen et al. [71], while Kerr et al. [72] and Mortazavi et al. [73] have reported that the storage modulus (a measure of the resistance to elastic deformation) of mucus glycoprotein (and homogenised mucus) gels increased with the inclusion of poly(acrylic acid). With regard to the buccal cavity, dosage forms can be placed directly in position, and so force can be applied to ensure that the two surfaces come into intimate contact. Pressure will also be applied by the cheek and gums and it has been proposed that very little adhesive force is required to hold a dosage form in place [74]. It is likely that the processes involved in mucosal adhesion will differ depending on the nature of the mucosal surface and the dosage form. For example, the stages and mechanism of mucosat adhesion are likely to differ for fully hydrated dosage forms and partially hydrated dosage forms. Chen and Cyr [58] reported that many materials when fully hydrated lose their adhesive properties. Lehr et al. [65], on testing a range of materials, reported that only polycarbophil and chitosan remained adhesive when fully hydrated, and suggested that these should be called "true" mucoadhesives. With polycarbophil, surface energy thermodynamics, i.e. a matching of the polarity of the two hydrated adhering surfaces, appear to be an important factor in mucosal adhesion [75]. It has been recognised that the ability of materials to displace water from a biological surface is a prerequisite for bioadhesion [76]. A dry mucosal-adhesive tablet of poly(acrylic acid) will rapidly dehydrate a contacting mucus gel, thus markedly altering its physical properties and it was predicted that this alone may produce a strong adhesive joint [77]. The localised dehydration of a mucous membrane has been identified as part of the process of adhesion of tablets to the oesophagus [78] and has also been used to explain the increased penetration of peptides when administered in bioadhesive dextran-starch microspheres [79]. Unlike the mucus layers on many other mucosae, the salivary pellicle is comparatively thin (less than 1 ~tm), and it would be predicted that this would rapidly dehydrate in contact with a dry mucosal-adhesive dosage form. Its main role in the adhesive process may therefore be to provide the moisture necessary for adhesion. Thus the surface of the oral cavity may be considered as a moist membrane to which these "wet" adhesives will attach, by predominantly Secondary interactions. Hydration is required to allow the molecules to attain a degree of flexibility to allow good contact with, and then interaction with, the epithelial cell surface [64,80]. It is worth noting that wet cellophane, Visking tubing and other moist surfaces have been successfully used as a model for the oral mucosa in adhesion studies [58,80-82]. It may be concluded, therefore, that the existing interpenetration theory of

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mucoadhesion may not be appropriate for explaining the adhesion of dry dosage forms within the oral cavity. It may also be more appropriate (as suggested by Lehr et al. [65]) to restrict the term "mucoadhesion" to describing the adhesion of hydrated dosage forms to those mucous membranes having a substantial mucus layer. The terms "bioadhesion" or "mucosal adhesion" may be more suitable to describe adhesion to the mucosae of the oral cavity.

IV.3. Dosage forms

De Vries et al. [83] gave the following requirements for buccal-adhesive dosage forms: (a) they should be flexible enough to follow the movement of the cheek; (b) they should be adhesive enough to be retained on the buccal mucosa but not so strong that the mucosa is damaged on removal; (c) they should be biocompatible and not cause irritation. Buccal-adhesive dosage forms can deliver the drug either locally to treat conditions within the buccal cavity or systemically via the mucosa. It is often a requirement that buccal-adhesive dosage forms should remain adhesive and allow a controlled delivery of drug for prolonged periods. For systemic therapy, dosage forms can be designed to deliver drugs only to the associated section of adhering mucosa (in the buccal pouch this may be the buccal and gingival mucosa), or to release the drug into the saliva prior to absorption. When in place, the dosage form will need to withstand mechanical abrasion by the surrounding tissue, the effect of continued contact with saliva (although this should be less of a problem in the upper regions of the buccal pouch) and the presence of food and drink at mealtimes. Therefore, for sustained drug delivery, buccal-adhesive formulations must contain elements that remain adhesive for a prolonged period, regulate the rate and direction of drug delivery and, in order to allow both of the afore-mentioned, restrict the rate of water ingress. In several of the formulations described in the following sections, separate components are used to achieve each objective, giving formulations with complex multilayered structures that would be difficult to manufacture. Another major problem with formulating dry dosage forms containing "wet" adhesives is that swelling occurs on hydration, and this may disrupt the integrity of these multilayered formulations. For this reason it has been proposed that monolithic matrices may be the most practical formulation [61]. As mucoadhesive materials hydrate and gel in aqueous environments, the rate of diffusion of the drug out of the formulation is regulated and this modifies drug release. The selection of polymers or formulations with the optimum drug release profile may however be at the expense of ideal bioadhesive properties. Buccal-adhesive dosage forms can be divided into the following types of formulation: tablets; patches, tapes, films; semisolids (ointments and gels); powders.

IV.3(a). Tablets
Tablets are dry dosage forms that may have to be moistened prior to placing in contact with the buccal mucosa. The size of the tablet is restricted to that which can be comfortably retained in place for prolonged periods. There are two buccaladhesive tablet preparations currently commercially available in the United Kingdom: "Buccastem" manufactured by Reckitt and Colman, which contains

262 TABLE II SOME BUCCAL-ADHESIVE MATRIX TABLET FORMULATIONS Formulation components Hydroxypropylcellulose, cetostearyl alcohol and hydroxyethylcellulose Chitosan and sodium hyaluronate Modified maize starch with either poly(acrylic acid) or poly(ethylene oxide) Hydroxypropylcellulose and carboxyvinylpolymer Sodium carboxymethylcellulose and hydroxypropylmethylcellulose Hydroxypropylmethylcellulose and poly(acrylic acid) Active ingredient Several suggested, e.g. morphine Brilliant Blue used as a model drug Fluoride Triamcinolone acetonide Codeine phosphate Fluoride

J.D. SMART

Reference 84 85 62 86 87 88

prochlorperazine maleate in a matrix containing ceratonia and xantham gum; and "Suscard Buccal" manufactured by Pharmax, which contains glyceryl trinitrate in a modified hydroxypropylmethylcellulose matrix [41]. The nature of the matrix was probably decided predominantly by the requirement to produce the desired drugrelease profile, and, as would be predicted from their constituents, these are both weakly mucosal-adhesive [74]. This is however probably an advantage since this precludes mucosal damage on removal from the buccal cavity. Several other matrix tablet formulations have been described in the literature, and are summarised in Table II. A double layered formulation, consisting of an adhesive matrix layer of hydroxypropylcellulose and poly(acrylic acid) with an inner core of cocoa butter containing insulin and a penetration enhancer (sodium glycocholate) has been described by Nagai [89]. This formulation was retained within the buccal cavity for over 6 hours in beagle dogs, although only a low insulin availability (0.5%) was
rer

Peripheral base

/ Core base

Fig. 1. Mucosal-adhesivedosage form for lignocaine [90].

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obtained. In the same paper a commercially available product, "Aphtach" (Teijin Ltd), used to treat aphthous stomatitis is described. This consists of a thin doublelayered compressed tablet, with the drug (triamcinolone acetonide) incorporated into a hydroxypropylcellulose and poly(acrylic acid) adhesive matrix lower layer, and a lactose upper layer included to assist application. This lactose layer disintegrates soon after application, while the lower layer hydrates and gels, covering the diseased area and releasing the drug. This formulation was found to perform significantly better than an existing triamcinolone acetonide containing bioadhesive ointment. Another interesting formulation [90], prepared by compression, consists of a core base containing the active drug (lignocaine) mixed with freeze-dried hydroxypropylcellulose and poly(acrylic acid). The core was surrounded by a peripheral base containing hydroxypropylcellulose and poly(acrylic acid), with an upper cap layer of freeze dried hydroxypropylcellulose and poly(acrylic acid) mixed with magnesium stearate (Fig. 1). This formulation adhered to the oral mucosa on application but was protected from adhering to other surfaces by the hydrophobic cap. The drug was mainly delivered to the local mucosa, and was protected from release into the saliva by the peripheral base. This dosage form gave prolonged localised drug delivery for up to 4 hours. Konishi [91] describes a four-layered formulation consisting of a standard compressed tablet drug reservoir sandwiched between a drug-impermeable membrane of a polyacrylate or cellulose derivative and a rate-limiting membrane of Eudragit RS, Eudragit E (or other acrylic polymer) with a suitable plasticiser (Fig. 2). The latter completely covered the outer surfaces with the exception of the base and the dosage form is held in place by an adhesive layer of poly(acrylic acid). A multilayered tablet for the local delivery of cetylpyridinium chloride to the oral cavity, consisting of a bioadhesive layer of hydroxypropylcellulose and poly(acrylic acid), which may be separated from a drug matrix layer by an antiadherant layer of magnesium stearate, has been described [92]. This was found to maintain salivary levels of the antimicrobial agent above the minimum inhibitory concentration for over 3 hours in human volunteers, which represented a substantial improvement over a standard lozenge formulation.

IV.3(b). Patches, tapes, films

Buccal-adhesive patches may be up to 10-15 cm 2 in size, but are more usually 1-3 cm 2 so as to be convenient and comfortable for the patient. They must also be flexible and may be ellipsoid in shape to fit comfortably onto the centre of the buccal
Drug release controlling layer -- Drug reservoir Drug impermeable layer (If required) :Adhesive layer Fig. 2. Bioadhesive sustained dosage form [91].

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mucosa [81]. Laminated patches to deliver drugs (specifically peptides) through the oral mucosa have been described by Anders and Merkle [93]. They developed patches consisting of two-ply laminates, with an aqueous solution of the adhesive polymer being cast onto an impermeable backing sheet which was then cut to the required oval shape. The adhesive polymers used were hydroxypropylmethylcellulose, hydroxyethylcellulose, poly(vinyl alcohol) and poly(vinyl pyrrolidone) and contained in addition a plasticiser and the active drug. These patches adhered to the buccal mucosa in vivo for up to an hour, although this may be considered too short a period with regard to the optimal delivery of peptides. Nagai and Konishi [90] have described an adhesive plaster, consisting of a mucosal-adhesive drug reservoir formulation attached to an inert backing, which achieved a sustained delivery of a prostaglandin to the gingival mucosa of an animal model for over 8 hours without any sign of irritation. A three-layered tape dosage form has been described that consists of a backing layer of ethylcellulose and castor oil, a middle layer of butyl rubber, and an adhesive layer containing karaya gum [94]. This was prepared by casting a solution containing ethylcellulose and castor oil dissolved in butanone onto a glass plate, allowing the solvent to evaporate and then casting the components of the second two layers dissolved in the appropriate solvents on top of this. The active drug (e.g. an antibiotic) is either included in the adhesive layer or deposited onto the tape prior to application. Such tape has been successfully used to treat stomatitis and other oral conditions. A bioadhesive multilayered extruded film (containing hydroxypropylcellulose, poly(ethylene oxide), ethylcellulose (or another water-insoluble polymer), a plasticiser and a drug) has also been investigated with a view to achieving local therapy in the oral cavity [95]. An oral bandage containing polymers of methacrylic acid, acrylic acid or maleic anhydride with a vinyl acetate polymer and including an active drug and optionally a salt or base has been described by Inoue et al. [63]. In addition, the successful use of a lignocaine-containing laminated patch for dental analgesia has been discussed [96]. A promising prototype buccal mucosa delivery system, developed in conjunction with 3M/Riker, consisting of a mucoadhesive basement membrane containing polycarbophil, a rate-limiting centre membrane and an impermeable backing membrane has been described (Fig. 3), but giving minimal details of the components

g Membrane

Rate limiting membrane membr~

Mucoadhesive Fig. 3. Prototype buccal mucoadhesive system [46].

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and method of manufacture [46]. In dogs and humans this patch remained in place for up to 17 hours regardless of food and drink consumed, and the proposal to use this system for peptide drug delivery seems quite feasible. An oral mucoadhesive film, prepared by a casting procedure, consisting of a co-polymer of methacrylic acid and its methyl ester and containing a plasticiser and the active drug metronidazole, has been developed for local therapy within the oral cavity [97]. This was retained at the site of application on the buccal mucosa for 3-5 hours and also allowed prolonged therapeutic levels of drug in the saliva for 5 hours. A matrix film consisting of poly(ethylene glycol) with poly(vinyl pyrrolidone) or poly(ethylene oxide), prepared by melting and casting the ingredients, was proposed for use with a variety of drugs [98]. A novel mucosal adhesive film called "Zilactin", consisting of an alcoholic solution of hydroxypropylcellulose and three organic acids, forms a film when applied to the oral mucosal surface which can be retained in place for at least 4 hours, even when challenged with fluids [99]. It was proposed to use this to protect and reduce the pain in mucosal ulceration, although the application of a vehicle containing alcohol to inflamed mouth ulcers might be expected to be an extremely painful procedure.

IV.3(c). Semisolid preparations (ointments and gels)

In general, it would be expected that bioadhesive ointments or gels would have less patient acceptability than solid adhesive dosage forms, and most are used only for localised drug therapy within the oral cavity. One of the original oral mucosal-adhesive delivery systems--"Orabase R'' (manufactured by E.R. Squibb and Sons Inc.)---consists of finely ground pectin, gelatin and sodium carboxymethylcellulose ("Orahesive" Powder) dispersed in a poly(ethylene) and a mineral oil gel base, which can be maintained at its site of application for 15-150 min [58]. This has been used for the local application of steroids for the treatment of mucosal ulceration. A similar formulation was described in a more recent patent [100], whilst another "bioadhesive" ointment preparation containing a freeze-dried mixture of the co-polymer poly(methyl vinyl ether/maleic anhydride) and gelatin dispersed in a mineral oil containing poly(ethylene) has been described by Browning [101]. A "novel concept" for a mucosal-adhesive ointment was a formulation containing polymethyl methacrylate in a base containing water, sodium hydroxide, glycerol and the active drug (tretinoin) which was used to treat lichen planus [102]. A high-viscosity "gel ointment" containing Carbopol (12.5%), poly(ethylene glycol) or glycerol and an aqueous solution containing sodium salicylate, sustained drug absorption for 5 hours when applied to a hamster cheek pouch [103]. In other work the same authors have described a Carbopol-containing ointment with a white petrolatum base for the delivery of prednisolone [104].

IV.3(d). Powders
Yamamoto et al. [105] have described a hydroxypropylcellulose- and beclomethasone-diproprionate-containing powder that was sprayed onto the oral mucosa of rats. A significant increase in the residence time relative to an oral solution was seen, and 2.5% of the beclomethasone was retained on the oral mucosa for over 4

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hours. Although an increase in the penetration of beclomethasone into the oral mucosa was found, the potential clinical applications of this type of formulation would appear to be limited.
V. Conclusions

The use of buccal-adhesive dosage forms offers an opportunity for optimising the delivery of drugs both locally and systemically, and many different types of formulation have been developed. The presence of saliva within the oral cavity is important in providing the moisture to allow adhesion to occur, and to allow a medium for drug dissolution prior to absorption. Although the mucosa presents a formidable barrier to the penetration of large molecules, small lipophilic molecules and drugs for local therapy would appear to be suitable for delivery by this route. For the delivery of large molecules, the use of a buccal-adhesive dosage form in conjunction with a suitable safe but effective penetration enhancer would appear to provide the optimum conditions for drug absorption if other routes of drug delivery are found to be inappropriate.
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