J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 1 (1):15-30, 1998
Buccal Mucosa As A Route For Systemic Drug Delivery: A Review
Amir H Shojaei, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8
The nasal cavity as a site for systemic drug delivery has been investigated by many research groups (1-7) and the route has already reached commercial status with several drugs including LHRH (8, 9) and calcitonin (10-12). However, the potential irritation and the irreversible damage to the ciliary action of the nasal cavity from chronic application of nasal dosage forms, as well as the large intra- and inter-subject variability in mucus secretion in the nasal mucosa, could significantly affect drug absorption from this site. Even though the rectal, vaginal, and ocular mucosae all offer certain advantages, the poor patient acceptability associated with these sites renders them reserved for local applications rather than systemic drug administration. The oral cavity, on the other hand, is highly acceptable by patients, the mucosa is relatively permeable with a rich blood supply, it is robust and shows short recovery times after stress or damage (13-15), and the virtual lack of Langerhans cells (16) makes the oral mucosa tolerant to potential allergens. Furthermore, oral transmucosal drug delivery bypasses first pass effect and avoids pre-systemic elimination in the GI tract. These factors make the oral mucosal cavity a very attractive and feasible site for systemic drug delivery.
Within the oral mucosal cavity, delivery of drugs is classified into three categories: (i) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (ii) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (iii) local delivery, which is drug delivery into the oral cavity.II. Overview of the Oral Mucosa A. Structure
The oral mucosa is composed of an outermost layer of stratified squamous epithelium (Figure 1). Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium (17). The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers.
The turnover time for the buccal epithelium has been estimated at 5-6 days (18), and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 µm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure at about 100-200 µm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosae of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosae of the soft palate, the sublingual, and the buccal regions, however, are not keratinized (18). The keratinized epithelia contain neutral lipids like ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide (19-21). They also contain small amounts of neutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia have been found to be considerably more permeable to water than keratinized epithelia (18-20).
The oral mucosae in general is a somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin (22). As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosae. In general, the permeabilities of the oral mucosae decrease in the order of sublingual greater than buccal, and buccal greater than palatal (18). This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized.
It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the so-called membrane coating granules (MCG) (23). When cells go through differentiation, MCGs start forming and at the apical cell surfaces they fuse with the plasma membrane and their contents are discharged into the intercellular spaces at the upper one third of the epithelium. This barrier exists in the outermost 200µm of the superficial layer. Permeation studies have been performed using a number of very large molecular weight tracers, such as horseradish peroxidase (24) and lanthanum nitrate (25). When applied to the outer surface of the epithelium, these tracers penetrate only through outermost layer or two of cells. When applied to the submucosal surface, they permeate up to, but not into, the outermost cell layers of the epithelium. According to these results, it seems apparent that flattened surface cell layers present the main barrier to permeation, while the more isodiametric cell layers are relatively permeable. In both keratinized and non-keratinized epithelia, the limit of penetration coincided with the level where the MCGs could be seen adjacent to the superficial plasma membranes of the epithelial cells. Since the same result was obtained in both keratinized and non-keratinized epithelia, keratinization by itself is not expected to play a significant role in the barrier function (24). The components of the MCGs in keratinized and non-keratinized epithelia are different, however (19). The MCGs of keratinized epithelium are composed of lamellar lipid stacks, whereas the non-keratinized epithelium contains MCGs that are non-lamellar. The MCG lipids of keratinized epithelia include sphingomyelin, glucosylceramides, ceramides, and other nonpolar lipids, however for non-keratinized epithelia, the major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids (19). Aside from the MCGs, the basement membrane may present some resistance to permeation as well, however the outer epithelium is still considered to be the rate limiting step to mucosal penetration. The structure of the basement membrane is not dense enough to exclude even relatively large molecules.
The cells of the oral epithelia are surrounded by an intercellular ground substance, mucus, the principle components of which are complexes made up of proteins and carbohydrates. These complexes may be free of association or some maybe attached to certain regions on the cell surfaces. This matrix may actually play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another (26). Along the same lines, the mucus is also believed to play a role in bioadhesion of mucoadhesive drug delivery systems (27). In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells like the goblet cells, however in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva (26, 28). Up to 70% of the total mucin found in saliva is contributed by the minor salivary glands (26, 28). At physiological pH the mucus network carries a negative charge (due to the sialic acid and sulfate residues) which may play a role in mucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer (17).
Another feature of the environment of the oral cavity is the presence of saliva produced by the salivary glands. Saliva is the protective fluid for all tissues of the oral cavity. It protects the soft tissues from abrasion by rough materials and from chemicals. It allows for the continuous mineralisation of the tooth enamel after eruption and helps in remineralisation of the enamel in the early stages of dental caries (29). Saliva is an aqueous fluid with 1% organic and inorganic materials. The major determinant of the salivary composition is the flow rate which in turn depends upon three factors: the time of day, the type of stimulus, and the degree of stimulation (26, 28). The salivary pH ranges from 5.5 to 7 depending on the flow rate. At high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH. The daily salivary volume is between 0.5 to 2 liters and it is this amount of fluid that is available to hydrate oral mucosal dosage forms. A main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity.III. Buccal Routes of Drug Absorption The are two permeation pathways for passive drug transport across the oral mucosa: paracellular and transcellular routes. Permeants can use these two routes simultaneously, but one route is usually preferred over the other depending on the physicochemical properties of the diffusant. Since the intercellular spaces and cytoplasm are hydrophilic in character, lipophilic compounds would have low solubilities in this environment. The cell membrane, however, is rather lipophilic in nature and hydrophilic solutes will have difficulty permeating through the cell membrane due to a low partition coefficient. Therefore, the intercellular spaces pose as the major barrier to permeation of lipophilic compounds and the cell membrane acts as the major transport barrier for hydrophilic compounds. Since the oral epithelium is stratified, solute permeation may involve a combination of these two routes. The route that predominates, however, is generally the one that provides the least amount of hindrance to passage. IV. Buccal Mucosa as a Site for Drug Delivery As stated above in section I, there are three different categories of drug delivery within the oral cavity (i.e., sublingual, buccal, and local drug delivery). Selecting one over another is mainly based on anatomical and permeability differences that exist among the various oral mucosal sites. The sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailabilities of many drugs, and is convenient, accessible, and generally well accepted (18). The sublingual route is by far the most widely studied of these routes. Sublingual dosage forms are of two different designs, those composed of rapidly disintegrating tablets, and those consisting of soft gelatin capsules filled with liquid drug. Such systems create a very high drug concentration in the sublingual region before they are systemically absorbed across the mucosa. The buccal mucosa is considerably less permeable than the sublingual area, and is generally not able to provide the rapid absorption and good bioavailabilities seen with sublingual administration. Local delivery to tissues of the oral cavity has a number of applications, including the treatment of toothaches (30), periodontal disease (31, 32), bacterial and fungal infections (33), aphthous and dental stomatitis (34), and in facilitating tooth movement with prostaglandins (35).
Even though the sublingual mucosa is relatively more permeable than the buccal mucosa, it is not suitable for an oral transmucosal delivery system. The sublingual region lacks an expanse of smooth muscle or immobile mucosa and is constantly washed by a considerable amount of saliva making it difficult for device placement. Because of the high permeability and the rich blood supply, the sublingual route is capable of producing a rapid onset of action making it appropriate for drugs with short delivery period requirements with infrequent dosing regimen. Due to two important differences between the sublingual mucosa and the buccal mucosa, the latter is a more preferred route for systemic transmucosal drug delivery (18, 23). First difference being in the permeability characteristics of the region, where the buccal mucosa is less permeable and is thus not able to give a rapid onset of absorption (i.e., more suitable for a sustained release formulation). Second being that, the buccal mucosa has an expanse of smooth muscle and relatively immobile mucosa which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus the buccal mucosa is more fitted for sustained delivery applications, delivery of less permeable molecules, and perhaps peptide drugs.
Similar to any other mucosal membrane, the
buccal mucosa as a site for drug delivery has limitations as well. One of the major
disadvantages associated with buccal drug delivery is the low flux which results in low
drug bioavailability. Various compounds have been investigated for their use as buccal
penetration enhancers in order to increase the flux of drugs through the mucosa
A series of studies (42, 46, 47) on buccal permeation of buserelin and fluorescein isothiocyanate (FITC) labelled dextrans reported the enhancing effects of di- and tri-hydroxy bile salts on buccal penetration. Their results showed that in the presence of the bile salts, the permeability of porcine buccal mucosa to FITC increased by a 100-200 fold compared to FITC alone. The mechanism of penetration enhancement of FITC-labelled dextrans by sodium glycocholate (SGC) was shown to be concentration dependent (47). Below 10 mM SGC, buccal permeation was increased by increasing the intercellular transport and at 10 mM and higher concentrations by opening up a transcellular route. Gandhi and Robinson (41) investigated the mechanisms of penetration enhancement of transbuccal delivery of salicylic acid. They used sodium deoxycholate and sodium lauryl sulfate as penetration enhancers, both of which were found to increase the permeability of salicylic acid across rabbit buccal mucosa. Their results also supported that the superficial layers and protein domain of the epithelium may be responsible for maintaining the barrier function of the buccal mucosa.Table 1. List of compounds used as oral mucosal permeation enhancers
A number of research groups (1, 2, 36, 48-50) have studied the feasibility of buccal mucosal delivery of insulin using various enhancers in different animal models for in vivo studies. Aungst et al. (1, 2) who used sodium glycocholate, sodium lauryl sulfate, sodium salicylate, sodium EDTA (ethylenediamine tetraacetic acid), and aprotinin on rat buccal mucosa noticed an increase in insulin bioavailability from about 0.7% (without enhancer) to 26-27% in the presence of sodium glycocholate (5% w/v) and sodium lauryl sulfate (5% w/v). Similar results were obtained using dog as the animal model for the in vivo studies, where sodium deoxycholate and sodium glycocholate yielded the highest enhancement of buccal insulin absorption (36). These studies have all demonstrated the feasibility of buccal delivery of a rather large molecular weight peptide drug such as insulin. V. Experimental Methodology for Buccal Permeation Studies Before a buccal drug delivery system can be formulated, buccal absorption/permeation studies must be conducted to determine the feasibility of this route of administration for the candidate drug. These studies involve methods that would examine in vitro and/or in vivo buccal permeation profile and absorption kinetics of the drug.
At the present time, most of the in vitro studies examining drug transport across buccal mucosa have used buccal tissues from animal models. Animals are sacrificed immediately before the start of an experiment. Buccal mucosa with underlying connective tissue is surgically removed from the oral cavity, the connective tissue is then carefully removed and the buccal mucosal membrane is isolated. The membranes are then placed and stored in ice-cold (4°C) buffers (usually Krebs buffer) until mounted between side-by-side diffusion cells for the in vitro permeation experiments. The most significant questions concerning the use of animal tissues as in vitro models in this manner are the viability and the integrity of the dissected tissue. How well the dissected tissue is preserved is an important issue which will directly affect the results and conclusion of the studies. To date, there are no standard means by which the viability or the integrity of the dissected tissue can be assessed. Dowty et al. (58) studied tissue viability by using ATP levels in rabbit buccal mucosa. Using ATP levels as an indicator for tissue viability is not necessarily an accurate measure, however. Dowty et al. reported a 50% drop in the tissue ATP concentration during the initial 6 hours of the experiment without a corresponding drop in tissue permeability. Despite certain gradual changes, the buccal tissue seems to remain viable for a rather long period of time. Therefore, a decrease in ATP levels does not assure a drop in permeability characteristics of the tissue. The most meaningful method to assess tissue viability is the actual permeation experiment itself, if the drug permeability does not change during the time course of the study under the specific experimental conditions of pH and temperature, then the tissue is considered viable.
Buccal cell cultures have also been suggested as useful in vitro models for buccal drug permeation and metabolism (25, 59-61). However, to utilize these culture cells for buccal drug transport, the number of differentiated cell layers and the lipid composition of the barrier layers must be well characterized and controlled. This has not yet been achieved with the buccal cell cultures used thus far.
In vivo methods were first originated by Beckett and Triggs (62) with the so-called buccal absorption test. Using this method, the kinetics of drug absorption were measured. The methodology involves the swirling of a 25 ml sample of the test solution for up to 15 minutes by human volunteers followed by the expulsion of the solution. The amount of drug remaining in the expelled volume is then determined in order to assess the amount of drug absorbed. The drawbacks of this method include salivary dilution of the drug, accidental swallowing of a portion of the sample solution, and the inability to localize the drug solution within a specific site (buccal, sublingual, or gingival) of the oral cavity. Various modifications of the buccal absorption test have been carried out (63-66) correcting for salivary dilution and accidental swallowing, but these modifications also suffer from the inability of site localization. A feasible approach to achieve absorption site localization is to retain the drug on the buccal mucosa using a bioadhesive system (67-69). Pharmacokinetic parameters such as bioavailability can then be calculated from the plasma concentration vs. time profile.
Other in vivo methods include those carried out using a small perfusion chamber attached to the upper lip of anesthetized dogs (70, 71). The perfusion chamber is attached to the tissue by cyanoacrylate cement. The drug solution is circulated through the device for a predetermined period of time and sample fractions are then collected from the perfusion chamber (to determine the amount of drug remaining in the chamber) and blood samples are drawn after 0 and 30 minutes (to determine amount of drug absorbed across the mucosa).
Aside from the specific methodology employed to study buccal drug absorption/permeation characteristics, special attention is warranted to the choice of experimental animal species for such experiments. For in vivo investigations, many researchers have used small animals including rats (1, 36, 37) and hamsters (51, 54, 72) or permeability studies. However, such choices seriously limit the value of the data obtained since, unlike humans, most laboratory animals have an oral lining that is totally keratinized. The rat has a buccal mucosa with a very thick, keratinized surface layer. The rabbit is the only laboratory rodent that has non-keratinized mucosal lining similar to human tissue and has been extensively utilized in experimental studies (48, 55, 58, 73, 74). The difficulty in using rabbit oral mucosa, however, is the sudden transition to keratinized tissue at the mucosal margins making it hard to isolate the desired non-keratinized region (21). The oral mucosa of larger experimental animals that has been used for permeability and drug delivery studies include monkeys (75), dogs (34, 57, 65, 70), and pigs (42, 47, 76-80). Due to the difficulties associated with maintenance of monkeys, they are not very practical models for buccal drug delivery applications. Instead, dogs are much easier to maintain and considerably less expensive than monkeys and their buccal mucosa is non-keratinized and has a close similarity to that of the human buccal mucosa. Pigs also have non-keratinized buccal mucosa similar to that of human and their inexpensive handling and maintenance costs make them an equally attractive animal model for buccal drug delivery studies. In fact, the oral mucosa of pigs resembles that of human more closely than any other animal in terms of structure and composition (20, 81). However, for use in in vivo studies pigs are not as ideal as dogs due to their rapid growth which renders the animal handling rather difficult. Miniature breeds of pigs can be used but their high cost is a deterrent. For in vitro studies though, because of easy availability and low cost porcine tissue is more suited as compared to dog buccal tissue.VI. Buccal Drug Delivery Systems Other than the low flux associated with buccal mucosal delivery, a major limitation of the buccal route of administration is the lack of dosage form retention at the site of absorption. Consequently, bioadhesive polymers have extensively been employed in buccal drug delivery systems. Bioadhesive polymers are defined as polymers that can adhere onto a biological substrate. The term mucoadhesion is applied when the substrate is mucosal tissue (27). Polymers which can adhere to either hard or soft tissue have been used for many years in surgery and dentistry. Diverse classes of polymers have been investigated for their potential use as mucoadhesives. These include synthetic polymers such as monomeric a cyanoacrylate (82), polyacrylic acid (82), hydroxypropyl methylcellulose (17), and poly methacrylate derivatives as well as naturally occurring polymers such as hyaluronic acid (84) and chitosan (85). Other synthetic polymers such as polyurethanes, epoxy resins, polystyrene, and natural-product cement have also been extensively investigated (86).
In general, dosage forms designed for buccal administration should not cause irritation and should be small and flexible enough to be accepted by the patient. These requirements can be met by using hydrogels. Hydrogels are hydrophilic matrices that are capable of swelling when placed in aqueous media (87). Normally, hydrogels are crosslinked so that they would not dissolve in the medium and would only absorb water. When drugs are loaded into these hydrogels, as water is absorbed into the matrix, chain relaxation occurs and drug molecules are released through the spaces or channels within the hydrogel network. In a more broad meaning of the term, hydrogels would also include water-soluble matrices that are capable of swelling in aqueous media, these include natural gums and cellulose derivatives. These pseudo-hydrogels swell infinitely and the component molecules dissolve from the surface of the matrix. Drug release would then occur through the spaces or channels within the network as well as through the dissolution and/or the disintegration of the matrix. The use of hydrogels as adhesive preparations for transmucosal drug delivery has acquired considerable attention in recent years. Table 2 summarizes the related research on mucoadhesive polymers and delivery systems.
Table 2. Related research on mucoadhesive polymers and delivery systems
Nagai et al. (35) studied the applicability of hydroxypropyl cellulose (HPC) as a mucoadhesive agent, they found this high viscosity grade material to be a suitable adhesive for topical mucus membranes. They reported the combination of HPC and carbopol 934P (CP) to produce a preferable material for mucoadhesive dosage forms. They examined directly compressed tablets of these polymers by placing them on an agar gel bed. HPC tablets showed a slight adhesion but dissolved easily on the gel bed. On the other hand, CP tablets showed strong adhesion but the swollen CP tablets seemed too hard. The combination of HPC and CP provided the mucoadhesion and adequate softness to prepare the tablets. Satoh et al. (88) measured the bioadhesive property of tablets consisting of HPC and CP using mouse peritoneal membrane. The adhesive force of the HPC-CP tablet was affected by the mixing ratio of HPC and CP. The adhesion force showed a minimum value at the mixing ratio of 3:2 (HPC:CP) due to the formation of an inter-polymer complex between HPC and CP in the acidic pH range.
Complex formation between CP and HPC seemed to suppress the interaction between molecules of hydrogel and the mucus membrane, and the adhesion force was therefore most reduced at a mixture ratio of 1:4 (HPC/CP). Inter-polymer complexation and its effect on bioadhesive strength was also studied by Gupta et al. (89). They reported that CP shows strong complexation with poly(vinyl pyrrolidone) and hydroxypropyl cellulose, but very little with sodium carboxy methyl cellulose. The degree of complexation was higher at acidic pH and decreased with an increase in pH. Anlar et al. (90) reported on formulation and evaluation of buccoadhesive controlled release systems for the delivery of morphine sulfate. They prepared tablets by direct compression of carbomer and hydroxypropyl methyl cellulose (HPMC) and found the drug release behavior to be non-Fickian and also confirmed interpolymer complex formation between HPMC and carbomer in acidic pH medium.
Anders and Merkle (91), developed and evaluated adhesive patches for buccal administration, consisting of two-ply laminates of an impermeable backing layer and a hydrocolloid polymer layer containing the drug. The polymers used HPC, HEC, PVP, and PVA. The integrity of the laminate was based on adhesive bonds between the hydrocolloid layer and an agarose layer grafted to one side of the backing layer sheet. Their work showed that among the cellulose ethers studied HEC and HPC possessed superior mucosal adhesion. Ishida et al. (30) utilized similar materials in a lidocaine delivery system for toothache. They used an HPC-CP powder mixture as a peripheral base aiming at strong adhesion, but an HPC-CP freeze-dried mixture was used as a core base. HPC and CP formed a complex during the freeze drying process, and this contributed to the ease of admixing by blockage of the functional group of CP. Guo (92) used a two roll milling method to prepare a new bioadhesive polymer patch formulation for controlled drug delivery consisting of CP, PIB, and PIP. It was found that the surface properties of buccal patches were not only dependent on the CP content but also dependent on the PIB:PIP ratio. The strongest peel strength was found on buccal patches with a CP:PIB:PIP ratio of 50:43.75:6.25.
Watanabe et al. (93) reported on hydrogels formed by the combination of natural gums, xantham gum, and locust bean gum, which are applicable in buccal delivery systems. Xantham gum is a natural gum obtained through fermentation of glucose by Xanthamonas campestris. Locust bean gum and xantham gum alone cannot form a hydrogel. However, when a mixture of these gums is dissolved in a neutral medium at 90°C and then cooled with ice for 30 min, a clear, strong hydrogel is formed. The mechanism of gel formation was reported to be the formation of a three dimensional network by interaction between the double helix structure of xantham gum and the straight molecular chain of locust bean gum. The gel strength of the hydrogels was affected by the mixing ratio of the gums, and the addition of sucrose improved the sustained release properties of the hydrogels. The hydrogel consisting of xantham gum and locust bean gum showed only a low mucoadhesion, but it can be applied to a buccal delivery system because of its safety, gel strength, sustained release properties and good feel in the mouth.
Anders et al. (94) designed a bilayer patch (polytef-disk) consisting of protirelin for thyroid gland diagnosis. The patch had a backing layer of teflon and mucoadhesive layer of protirelin dispersed in hydroxyethylcellulose. Veillard et al. (70) reported the use of a unidirectional buccal patch which consisted of three layers: an impermeable backing layer, a rate limiting center membrane containing the drug, and a mucoadhesive layer containing bioadhesive polymer polycarbophil. The bioadhesive polymer swells, creating a flexible network through which diffusion of drug takes place. This patch was tested in dog buccal mucosa and was shown to remain in place for up to 17 hours without any obvious discomfort.
Chng et al. (82) synthesized and evaluated a series of crosslinked, swellable polymers of acrylic acid and methacrylic acid, differing in charge densities and hydrophobicity. They found that an increase in the number of hydrophobic groups in the polymer structure reduced hydration whereas the density of the polymer was unaffected. Furthermore, polymers of acrylic acid loosely crosslinked (0.3 % w/w) with 3 different agents, divinyl glycol, 2,5-dimethyl-1,5-hexadiene, and divinyl benzene, showed the same degree of bioadhesion while poly(methacrylic acid) crosslinked with divinyl benzene showed reduced bioadhesion. The small percent of crosslinking agent, irrespective of physicochemical properties, did not contribute substantially to bioadhesion, whereas the starting monomer had a large effect. The effect of pH on the bioadhesion of poly(acrylic acid) crosslinked with divinyl glycol was also studied at constant temperature, ionic strength, and osmolality. It was found that the polymer showed maximum adhesion at pH 5 and 6 and a minimum at pH 7.
Park and Robinson (86) examined a large number of polymers as to their bioadhesive potential and to derive meaningful information on the structural requirements for bioadhesion. They concluded that charged carboxylated polyanions are good potential bioadhesives for drug delivery. To understand the role of the carboxyl groups in mucoadhesion, acrylic acid-acrylamide random copolymers [P(AA-co-AM)] were synthesized (95) and the adhesion strength of the crosslinked polymers to the gastric mucus layer as a function of pH, initial concentration of the crosslinking agent, degree of swelling, and carboxyl group density were examined. From the study on mucoadhesion of various P(AA-co-AM), it was found that at least 80% of the vinyl groups of the polymer must possess carboxyl groups in the protonated form. The dependence of mucoadhesion on pH and carboxyl-group density suggests that mucoadhesion occurs through hydrogen bonding. In addition, the density of the crosslinking agent significantly affects mucoadhesion. As the density of the crosslinking agent is lowered, the mucoadhesive strength increases, although the density of carboxyl groups in the test surface area is reduced. It was concluded that for mucoadhesion to occur, polymers must have functional groups that are able to form hydrogen bonds above the critical concentration (80% for vinyl polymers), and the polymer chains should be flexible enough to form as many hydrogen bonds as possible. Similar results were achieved by Garcia-Gonzalez et al. (96) who evaluated the effects of poly(acrylic acid) (PAA) molecular weight and the concentration of crosslinking agent (sucrose) on swelling and drug (metoclopramide) release characteristics of PAA (carbopol) hydrogels. They reported that both factors and the interaction term had significant effects on hydrogel swelling and drug release. In particular, they found that increased sucrose concentration (high crosslinking density) led to reduced swelling and reduced drug release efficiency.
Leung and Robinson (83, 97) studied the contribution of anionic polymer structural features to mucoadhesion using 0.2% crosslinked copolymers of acrylic acid and methyl methacrylate. Their results showed that the expanded nature of both the interacting mucus and polymer networks influences the strength of mucoadhesion. They concluded that mucoadhesive polymer with the desired mucoadhesive strength can be designed by controlling the percentage of charged groups and the corresponding openness of the network.
Bodde et al. (16) investigated relationships between structure and adhesion for mucoadhesive polymers. Their study was based on an assumption that bioadhesion should possess two properties: (i) optimal polarity to make sure the polymer is "wetted" by the mucus, and (ii) optimal fluidity to allow for the mutual adsorption and interpenetration of polymer and mucus to take place. They studied acrylic polymer films, designed for buccal drug delivery. The films were made either through mixing or copolymerization of poly(butyl acrylate) and poly(acrylic acid). In both cases satisfactory mucoadhesion was found within a range of compositions optimized for surface polarity and the fluidity of the polymer film.
In an attempt to enhance the intrinsic mucoadhesive properties of poly(acrylic acid), Shojaei and Li (105-107) designed and formulated a series of novel copolymers of acrylic acid and poly ethyleneglycol monomethylether monomethacrylate [P(AA-co-PEG)]. The addition of PEG into the polymer increased the potential for hydrogen bond formation, since the lone pair electrons of oxygen in the repeat unit (CH2CH2O) of PEG served as hydrogen bond acceptors (107). The surface properties of PAA for mucoadhesion were also improved by the PEG incorporation (107). Using these copolymers, a patch device was prepared for buccal acyclovir delivery and the feasibility of such delivery was proven in vitro with the incorporation of sodium glycocholate as the permeation enhancer (39).
Using copolymeric hydrogel discs of HEMA (monomer) and Polymeg® (macromer) a buccal mucoadhesive device for controlled release of buprenorphine was developed (98). The hydrogel containing a monomer:macromer ratio of 80:20 (w/w) yielded the best result both in terms of adhesion and drug release. The device was applied for a 3 hour application time and steady state levels were maintained for the time of application. Formulation of another buccal delivery system was reported by DeGrande et al. (69, 99) from the 3M company. The buccal patch device (Cydot; 3M Pharmaceutical, St. Paul, MN) consists of a flexible mucoadhesive matrix composed of a blend of poly(acrylic acid) (Carbopol 934P; B.F. Goodrich, Cleveland, OH) and poly(isobutylene) (Vistanex; Exxon Chemical Company, Houston, TX). The patch device is unidirectional with a polyurethane backing layer. The patch is intended for application to the upper gum and in vivo studies in human subjects have revealed effective bioadhesive characteristics for 12 hours of application (69). Several investigators have reported on the development of TmTs (transmucosal therapeutic systems) devices with a field-shaped bilayer design consisting of fast-release and sustained-release layers (44, 103, 104). The fast release layer contains PVP as the bioadhesive component and is designed to adhere to the buccal mucosa and the sustained release layer consists of a mixture of PVP and poly(acrylic acid) and is intended to adhere to the gingival mucosa (103). Most recently, a TmTs formulation was reported for the buccal delivery of LHRH (luetinizing hormone releasing hormone) (44) with results indicating the feasibility of controlled release transmucosal delivery of the peptide drug.VI. Conclusion The buccal mucosa offers several advantages for controlled drug delivery for extended periods of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract are avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. However, the need for safe and effective buccal permeation/absorption enhancers is a crucial component for a prospective future in the area of buccal drug delivery. References 1. Aungst, B.J., Rogers, N.J., and Shefter, E., Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter, The J. Pharmacol. Exp. Ther., 244:23-27, 1988.
2. Aungst, B.J. and Rogers, N.J., Site dependence of absorption-promoting actions of Laureth-9, Na salicylate, Na2EDTA, and Aprotinin on rectal, nasal, and buccal insulin delivery, Pharm. Res., 5:305-308, 1988.
3. Lee, W.E., Permeation enhancers for the nasal delivery of protein and peptide therapeutics, Bio Pharm, 3:22-25, 1990.
4. Tengamnuay, P. and Mitra, A.K., Bile salt-fatty acid mixed micelles as nasal absorption promoters of peptides. I. Effects of ionic strength. adjuvant composition, and lipid structure on the nasal absorption of [D-Arg2]Kyotorphin, Pharm. Res., 7:127-133, 1990.
5. Shao, Z. and Mitra, A.K., Nasal membrane and intracellular protein and enzyme release by bile salts and bile salt-fatty acid mixed micelles: correlation with facilitated drug transport, Pharm. Res., 9:1992, 1992.
6. Shao, Z. and Mitra, A.K., Bile salt fatty acid mixed micelles as nasal absorption promoters. III. Effects on nasal transport and enzymatic degradation of acyclovir prodrugs, Pharm. Res., 11:243-250, 1994.
7. Soyani, A.P. and Chien, Y.W., Systemic delivery of peptides and proteins across absorptive mucosae, Crit. Rev. Therap. Drug Carrier Systems, 13:85-184, 1996.
8. Adjei, A., Sundberg, D., Miller, J., and Chun, A., Bioavailability of leuprolide acetate following nasal inhalation delivery to rats and healthy humans, Pharm. Res., 9:244-249, 1992.
9. Shimamoto, T., Pharmaceutical aspects. Nasal and depot formulations of leuprolide, J. Androl., 8:S14-S16, 1987.
10. Dal Negra, R., Turco, P., Pomari, C., and Trevisan, F., Calcitonin nasal spray in patienmts with chronic asthma: a double-blind crossover study vs placebo, Int. J. Clin. Pharmacol. Ther. Toxicol., 29:144-146, 1991.
11. Plosker, G.L. and McTavish, D., Intranasal salcatonin (salmon calcitonin). A review of its pharmacological properties and role in the management of postmenopausal osteoporosis, Drugs Aging, 8:378-400, 1996.
12. Reginster, J.Y. and Lecart, M.P., Efficacy and safety of drugs for Paget's disease of bone, Bone, 17:485S-488S, 1995.
13. Rathbone, M.J. and Hadgraft, J., Absorption of drugs from the human oral cavity, Int. J. Pharm., 74:9-24, 1991.
14. de Vries, M.E., Bodde, H.E., Verhoef, J.C., and Junginger, H.E., Developments in buccal drug delivery, Crit. Rev. Ther. Drug Carr. Sys., 8:271-303, 1991.
15. Squier, C.A., The permeability of oral mucosa, Crit. Rev. Oral Biol. Med., 2:13-32, 1991.
16. Bodde, H.E., De Vries, M.E., and Junginger, H.E., Mucoadhesive polymers for the buccal delivery of peptides, structure-adhesiveness relationships, J. Control. Rel., 13:225-231, 1990.
17. Gandhi, R.E. and Robinson, J.R., Bioadhesion in drug delivery, Ind. J. Pharm. Sci., 50:145-152, 1988.
18. Harris, D. and Robinson, J.R., Drug delivery via the mucous membranes of the oral cavity, J. Pharm. Sci., 81:1-10, 1992. Reproduced with permission of the American Pharmaceutical Association.
19. Wertz, P.W. and Squier, C.A., Cellular and molecular basis of barrier function in oral epithelium, Crit. Rev. Ther. Drug Carr. Sys., 8:237-269, 1991.
20. Squier, C.A., Cox, P., and Wertz, P.W., Lipid content and water permeability of skin and oral mucosa, The J. Invest. Dermat., 96:123-126, 1991.
21. Squier, C.A. and Wertz, P.W. Structure and function of the oral mucosa and implications for drug delivery, in eds. M.J. Rathbone, Oral Mucosal Drug Delivery, Marcel Dekker, Inc., New York, New York, 1-26, 1996.
22. Galey, W.R., Lonsdale, H.K., and Nacht, S., The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water, J. Invest. Dermat., 67:713-717, 1976.
23. Gandhi, R.B. and Robinson, J.R., Oral cavity as a site for bioadhesive drug delivery, Adv. Drug Del. Rev., 13:43-74, 1994.
24. Squier, C.A. and Hall, B.K., The permeability of mammalian non-keratinized oral epithelia to horseraddish peroxidase applied in vivo and in vitro, Arch. Oral Biol., 29:45-50, 1984.
25. Hill, M.W. and Squier, C.A., The permeability of oral palatal mucosa maintained in organ culture, J. Anat., 128:169-178, 1979.
26. Tabak, L.A., Levine, M.J., Mandel, I.D., and Ellison, S.A., Role of salivary mucins in the protection of the oral cavity, J. Oral Pathol., 11:1-17, 1982.
27. Peppas, N.A. and Buri, P.A., Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues, J. Control. Rel., 2:257-275, 1985.
28. Rathbone, M., Drummond, B., and Tucker, I., Oral cavity as a site for systemic drug delivery, Adv. Drug Del. Rev., 13:1-22, 1994.
29. Edgar, W.M., Saliva: its secretion, composition and functions, Br. Dent. J., 172:305-312, 1992.
30. Ishida, M., Nambu, N., and Nagai, T., Mucosal dosage form of lidocaine for toothache using hydroxypropyl cellulose and carbopol, Chem. Pharm. Bull., 30:980-984, 1982.
31. Collins, A.E.M., Deasy, P.B., Mac Carthy, D.J., and Shanley, D.B., Evaluation of a controlled release compact containing tetracycline hydrochloride bonded to tooth for the treatment of periodontal disease, Int. J. Pharm., 51:103-114, 1989.
32. Elkayam, R., Friedman, M., Stabholz, A., Soskolne, A.w., Sela, M.N., and Golub, L., Sustained release device containing minocycline for local treatment of periodontal disease, J. Control. Rel., 7:231-236, 1988.
33. Samaranayake, L. and Ferguson, M., Delivery of antifungal agents to the oral cavity, Adv. Drug Del. Rev., 13:161-179, 1994.
34. Nagai, T., Adhesive topical drug delivery system, J. Control. Rel., 2:121-134, 1985.
35. Nagai, T. and Machida, Y., Mucosal adhesive dosage forms, Pharm. Int., 196-200, 1985.
36. Aungst, B.J. and Rogers, N.J., Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery, Int. J. Pharm., 53:227-235, 1989.
37. Siegel, I.A. and Gordon, H.P., Surfactant-induced increase of permeability of rat oral mucosa to non-electolytes in vivo, Arch. Oral Biol., 30:43-47, 1985.
38. Shojaei, A.H. and Li, X., In vitro permeation of acyclovir through porcine buccal mucosa, Proceedings of International Symposium on Controlled Release of Bioactive Materials, 23:507-508, 1996.
39. Shojaei, A.H. and Li, X., Determination of transport route of acyclovir across buccal mucosa, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 24:427-428, 1997.
40. Manganaro, A.M. and Wertz, P.W., The effects of permeabilizers on the in vitro penetration of propranolol through porcine buccal epithelium, Mil. Med., 161:669-672, 1996.
41. Gandhi, R. and Robinson, J., Mechanisms of penetration enhancement for transbuccal delivery of salicylic acid, Int. J. Pharm., 85:129-140, 1992.
42. Hoogstraate, A.J., Verhoef, J.C., Tuk, B., Pijpers, A., van leengoed, L.A.M.G., Vheijden, J.H.M., Junjinger, H.E., and Bodde, H.E., Buccal delivery of fluorescein isothiocyanate-dextran 4400 and the peptide drug buserelin with glycodeoxycholate as an absorption enhancer in pigs, J. Control. Rel., 41:77-84, 1996.
43. Wolany, G.J.M., Munzer, J., Rummelt, A., and Merkle, H.P., Buccal absorption of Sandostatin (octreotide) in conscious beagle dogs, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 17:224-225, 1990.
44. Nakane, S., Kakumoto, M., Yulimatsu, K., and Chien, Y.W., Oramucosal delivery of LHRH: Pharmacokinetic studies of controlled and enhanced transmucosal permeation, Pharm. Dev. Tech., 1:251-259, 1996.
45. Steward, A., Bayley, D.L., and Howes, C., The effect of enhancers on the buccal absorption of hybrid (BDBB) alpha-interferom, Int. J. Pharm., 104:145-149, 1994.
46. Senel, S., Hoogstraate, A.J., Spies, F., Verhoef, J.C., Bos-van Geest, A., Junginger, H.E., and Bodde, H.E., Enhancement of in vitro permeability of porcine buccal mucosa by bile salts: kinetic and histological studies, J. Control. Rel., 32:45-56, 1994.
47. Hoogstraate, A.J., Senel, S., Cullander, C., Verhoef, J., Junginger, H.E., and Bodde, H.E., Effects of bile salts on transport rates and routes of FTIC-labelled compounds across porcine buccal epithelium in vitro, J. Control. Rel., 40:211-221, 1996.
48. Oh, C.K. and Ritschel, W.A., Biopharmaceutic aspects of buccal absorption of insulin, Meth. Find Exp. Clin. Pharmacol., 12:205-212, 1990.
49. Zhang, J., Niu, S., Ebert, C., and Stanley, T.H., An in vivo dog model for studying recovery kinetics of the buccal mucosa permeation barrier after exposure to permeation enhancers: apparent evidence of effective enhancement without tissue damage, Int. J. Pharm., 101:15-22, 1994.
50. Aungst, B.J., Site-dependence and structure-effect relationships for alkylglycosides as transmucosal absorption promoters for insulin, Int. J. Pharm., 105:219-225, 1994.
51. Kurosaki, Y., Hisaichi, S., Hong, L., Nakayama, T., and Kimura, T., Enhanced permeability of keratinized oral-mucosa to salicylic acid with 1-dodecylacycloheptan-2-one (Azone). In vitro studies in hamster cheek pouch, Int. J. Pharm., 49:47-55, 1989.
52. Kurosaki, Y., Hisaichi, S., Nakayama, T., and Kimura, T., Enhancing effect of 1-dodecylazacycloheptan-2-one (Azone) on the absorption of salicyclic acid from keratinized oral mucosa and the duration of enhancement in vivo, Int. J. Pharm., 51:47-54, 1989.
53. Siegel, I.A. and Gordon, H.P., Effects of surfactants on the permeability of canine oral mucosa in vitro, Tox. Lett., 26:153-157, 1985.
54. Kurosaki, Y., Hisaichi, S., Hamada, C., Nakayama, T., and Kimura, T., Effects of surfactants on the absorption of salicylic acid from hamster cheek pouch as a model of keratinized oral mucosa, Int. J. Pharm., 47:13-19, 1988.
55. Siegel, I.A., Izutsu, K.T., and Watson, E., Mechanisms of non-electrolyte penetration across dog and rabbit oral mucosa in vitro, Arch. Oral Biol., 26:357-361, 1981.
56. Coutel-Egros, A., Maitani, Y., Veillard, M., Machida, Y., and Nagai, T., Combined effects of pH, cosolvent and penetration enhancers on the in vitro buccal absorption of propranolol through excised hamster cheek pouch, Int. J. Pharm., 84:117-128, 1992.
57. Ishida, M., Machida, Y., Nambu, N., and Nagai, T., New mucosal dosage form of insulin, Chem. Pharm. Bull., 29:810-816, 1981.
58. Dowty, M.E., Knuth, K.E., Irons, B.K., and Robinson, J.R., Transport of thyrotropin releasing hormone in rabbit buccal mucosa in vitro, Pharm. Res., 9:1113-1122, 1992.
59. Tavakoli-Saberi, M.R. and Audus, K.L., Cultured buccal epithelium: an in vitro model derived from the hamster pouch for studying drug transport and metabolism, Pharm. Res., 6:160-162, 1989.
60. Tavakoli-Saberi, M.R., Williams, A., and Audus, K.L., Aminopeptidase activity in human buccal epithelium and primary cultures of hamster buccal epithelium, Pharm. Res., 6:S-197, 1989.
61. Leipold, H.R. and Quadros, E., Nicotine permeation through buccal cultures, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 20:242-243, 1993.
62. Beckett, A.H. and Triggs, E.J., Buccal absorption of basic drugs and its application as an in vivo model of passive drug transfer through lipid membranes, J. Pharm. Pharmacol., 19:31S-41S, 1967.
63. Schurmann, W. and Turner, P., A membrane model of the human oral mucosa as derived from buccal absorption performance and physicochemical properties of the beta-blocking drugs atenolol and propranolol, J. Pharm. Pharmacol., 30:137-147, 1978.
64. Tucker, I.G., A method to study the kinetics of oral mucosal drug absorption from solutions, J. Pharm. Pharmacol., 40:679-683, 1988.
65. Barsuhn, C.L., Olanoff, L.S., Gleason, D.D., Adkins, E.L., and Ho, N.F.H., Human buccal absorption of flubriprofen, Clin. Pharmacol. Ther., 44:225-231, 1988.
66. Gonzalez-Younes, I., Wagner, J.G., and Gaines, D.A., Absorption of flubriprofen through human buccal mucosa, J. Pharm. Sci., 80:820-823, 1991.
67. Benes, L., et al. Plasma melatonin (M) and sulfatoxymelatonin (aMT6s) kinetics after transmucosal administration to humans, in eds. Y. Touitou, J. Arendt, andP. Pevet, Melatonin and the pineal gland-From basic science to clinical application, Elsevier Science Publishers B.V., New York, 347-350, 1993.
68. McQuinn, R.L., Kvam, D.C., Maser, M.J., Miller, A.L., and Oliver, A., Sustained oral mucosal delivery in human volunteers of buprenorphine from thin non-eroding mucoadhesive polymeric disks, J. Control. Rel., 34:243-250, 1995.
69. Benes, L., et al., Transmucosal, oral controlled-release, transdermal drug administration in human subjects: A crossover study with melatonin, Journal of Pharm. Sci., 86:1115-1119, 1997.
70. Veillard, M.M., Longer, M.A., Martens, T.W., and Robinson, J.R., Preliminary studies of oral mucosal delivery of peptide drugs, J. Control. Rel., 6:123-131, 1987.
71. Yamahara, H. and Lee, V.H., Drug Metabolism in the Oral Cavity, Adv. Drug Del. Rev., 12:25-39, 1993.
72. Tanaka, M., Yanagibashi, N., Fukuda, H., and Nagai, T., Absorption of salicylic through the oral mucous membrane of hamster cheek pouch, Chem. Pharm. Bull., 28:1056-1061, 1980.
73. Siegel, I.A. and Gordon, H.P., Surfactant-induced alterations of permeability of rabbit oral mucosa in vitro, Exp. Mol. Path., 44:132-137, 1986.
74. Dowty, M.E., Knuth, K.E., and Robinson, J.R., Enzyme characterization studies on the rate-limiting barrier in rabbit buccal mucosa, Int. J. Pharm., 88:293-302, 1992.
75. Mehta, M., Kemppainen, B.W., and Staffford, R.G., In vitro penetration of tritium-labelled water (THO) and [3H]PbTx-3 (a red tide toxin) through monkey buccal mucosa and skin, Tox. Lett., 55:185-194, 1991.
76. Lesch, C.A., Squier, C.A., Cruchley, A., Williams, D.M., and Speight, P., The permeability of human oral mucosa and skin to water, J. Dent. Res., 68:1345-1349, 1989.
77. Quadros, E., Cassidy, J., Gniecko, K., and LeRoy, S., Buccal and colonic absorption of CGS 16617, a novel ACE inhibitor, J. Control. Rel., 19:77-86, 1991.
78. Squier, C.A. and Hall, B.K., The permeability of skin and oral mucosa to water and horseradish peroxidase as related to the thickness of the permeability barrier, The J. Invest. Dermat., 84:1985.
79. Hoogstraate, A.J., Cullander, C., Nagelkerke, J.F., Verhoel, J., Junginger, H.E., and Bodde, H.E., Diffusion rates and transport pathways of FITC-labelled model compounds through buccal epithelium, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 20:234-235, 1993.
80. Hoogstraate, A.J., Bodde, H.E., Cullander, C., and Junginger, H.E., Diffusion rates and transport pathways of FITC-labelled model compounds through buccal epithelium, Pharm. Res., 9:S-188, 1992.
81. Collins, P., Laffoon, J., and Squier, C.A., Comparative study of porcine oral epithelium, J. Dent. Res., 60:543, 1981.
82. Ch'ng, H.S., Park, H., Kelly, P., and Robinson, J.R., Bioadhesive polymers as platforms for oral controlled drug delivery II: Synthesis and evaluation of some swelling, water-insoluble bioadhesive polymers, J. Pharm. Sci., 74:399-405, 1985.
83. Leung, S.S. and Robinson, J.R., Polymer structure features contributing to mucoadhesion: II., J. Control. Rel., 12:187-194, 1990.
84. Sanzgiri, Y.D., Topp, E.M., Benedetti, L., and Stella, V.J., Evaluation of mucoadhesive properties of hyaluronic caid benzyl esters, Int. J. Pharm., 107:91-97, 1994.
85. Lehr, C.M., Bouwstra, J.A., Schact, E.H., and Junginger, H.E., In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers, Int. J. Pharm., 78:43-48, 1992.
86. Park, K. and Robinson, J.R., Bioadhesive polymers as platforms for oral-controlled drug delivery: method to study bioadhesion, Int. J. Pharm., 19:107-127, 1984.
87. Nagai, T. and Machida, Y., Buccal delivery systems using hydrogels, Adv. Drug Del. Rev., 11:179-191, 1993.
88. Satoh, K., Takayama, K., Machida, Y., Suzuki, Y., Nakagaki, M., and Nagai, T., Factors affecting the bioadhesive property of tablets consisting of hydroxypropyl cellulose and carboxyvinyl polymer., Chem. Pharm. Bull., 37:1366-1368, 1989.
89. Gupta, A., Garg, S., and Khar, R.K., Interpolymer complexation and its effect on bioadhesion strength and dissolution characteristics of buccal drug delivery systems, Drug Dev. Ind. Pharm., 20:315-325, 1994.
90. Anlar, S., Capan, Y., Guven, O., Gogus, A., Dlakara, T., and Hincal, A.A., Formulation and in-vitro-in vivo evaluation of buccoadhesive morphine sulfate tablets, Pharm. Res., 11:231-236, 1994.
91. Anders, R. and Merkle, H., Evaluation of laminated muco-adhesive patches for buccal drug delivery, Int. J. Pharm., 49:231-240, 1989.
92. Guo, J.-H., Investigating the surface properties and bioadhesion of buccal patches, J. Pharm. Pharmacol., 46:647-650, 1994.
93. Watanabe, K., Yakou, S., Takayama, K., Machida, Y., and Nagai, T., Drug release behaviors from hydrogel prepared with water soluble dietary fibers, J. Pharm. Sci. Techn. Jpn., 51:29-35, 1991.
94. Anders, R., Merkle, H.P., Schurr, W., and Ziegler, R., Buccal absorption of protirelin: an effective way to stimulate thyrotropin and prolactin, J. Pharm. Sci., 72:1481-1483, 1983.
95. Park, H. and Robinson, J.R., Mechanisms of mucoadhesion of poly(acrylic acid) hydrogels, Pharm. Res., 4:457-464, 1987.
96. Garcia-Gonzalez, N., Kellaway, I., Blanco-Fuente, H., Anguiano-Igea, S., Delgado-Charro, B., Otero-Espinar, F., and Blanco-Mendez, J., Design and evaluation of buccoadhesive metoclopramide hydrogels composed of poly(acrylic acid) crosslinked with sucrose, Int. J. Pharm., 100:65-70, 1993.
97. Leung, S. and Robinson, J.R., The contribution of anionic polymer structural features to mucoadhesion, J. Control. Rel., 5:223-231, 1988.
98. Cassidy, J.P., Landzert, N.M., and Quadros, E., Controlled buccal delivery of buprenorphine, J. Control. Rel., 25:21-29, 1993.
99. DeGrande, G., Benes, L., Horriere, F., Karsenty, F., LaCoste, C., McQuinn, R., Guo, J., and Scherrer, R. Specialized oral mucosal drug delivery systems: Patches, in eds. M.J. Rathbone, Oral Mucosal Drug Delivery, Marcel Dekker, Inc., New York, 285-318, 1996.
100. Nguyen-Xuan, T., Towart, R., Terras, A., Jacques, Y., Buri, P., and Gurny, R., Mucoadhesive semi-solid formulations for intraoral use containing sucralfate, Eur. J. Pharm. Biopharm., 43:133-137, 1996.
101. Nair, M. and Chien, Y.W., Development of anticandidal delivery systems: (II) Mucoadhesive devices for prolonged drug delivery in the oral cavity, Drug Dev. Ind. Pharm., 22:243-253, 1996.
102. Taylan, B., Yilmaz, C., Guven, O., Kes, S., and Hincal, A.A., Design and evaluation of sustained-release and buccal adhesive propranolol hydrochloride tablets, J. Control. Rel., 38:11-20, 1996.
103. Yukimatsu, K., Nozaki, Y., Makumoto, M., and Ohta, M., Development of a trans-mucosal controlled-release device for systemic of antianginal drugs pharmacokinetics and pharmacodynamics, Drug Dev. Ind. Pharm., 20:503-534, 1994.
104. Nozaki, Y., Ohta, M., and Chien, Y.W., Transmucosal controlled systemic delivery of isosorbide dinitrate: in vivo/in vitro correlation, J. Control. Rel., 43:105-114, 1997.
105. Shojaei, A.H. and Li, X., Novel copolymers of acrylic acid and poly ethylene glycol monomethylether monomethacrylate for buccal mucoadhesion: Preparation and surface characterization, Pharm. Res., 12 (S1):S210, 1995.
106. Li, X. and Shojaei, A.H., Novel copolymers of acrylic acid and poly ethylene glycol monomethylether monomethacrylate for buccoadhesion: In vitro assessment of buccoadhesion and analysis of surface free energy, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 23:165-166, 1996.
107. Shojaei, A.H. and Li, X., Mechanisms of buccal mucoadhesion of novel copolymers of acrylic acid and polyethylene glycol monomethylether monomethacrylate, J. Control. Rel., 47:151-161, 1997.
108. Choi, H.K., Kim, O.J., Jung, C.K., Cho, Y.J., and Cho, C.S., Interpolymer complex prepared by template polymerization for transmucosal drug delivery, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 24:415-416, 1997.
109. Voorspoels, J., Comhaire, F., De Sy, W., and Remon, J.P., Buccal absorption of progesterone in the dog, Proceed. Int. Symp. Control. Rel. Bioact. Mater., 24:185-186, 1997.
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