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, University of Alberta, Faculty of Pharmacy and Pharmaceutical Sciences, Edmonton, Alberta, Canada
`T6G 2N8
`
`Contents
`
`Abstract
`
`I.
`II.
`
`III.
`IV.
`V.
`
`VI.
`VII.
`
`Introduction
`Overview of the oral mucosae
`A. Structure
`B. Permeability
`C. Environment
`Routes of drug absorption
`Buccal mucosa as a site for drug delivery
`Experimental methodology to investigate
`buccal drug permeation
`A. In vitro Methods
`B. In vivo Methods
`C. Experimental Animal Speciesv
`Buccal drug delivery systems
`Conclusion
`
`ABSTRACT: Within the oral mucosal cavity, the buccal
`region offers an attractive route of administration for
`systemic drug delivery. The mucosa has a rich blood
`supply and it is relatively permeable. It is the objective
`of this article to review buccal drug delivery by
`discussing the structure and environment of the oral
`mucosa and
`the experimental methods used
`in
`assessing buccal drug permeation/absorption. Buccal
`dosage forms will also be reviewed with an emphasis
`on bioadhesive polymeric based delivery systems.
`
`I. INTRODUCTION
`
`Amongst the various routes of drug delivery, oral route
`is perhaps the most preferred to the patient and the
`clinician alike. However, peroral administration of
`drugs has disadvantages such as hepatic first pass
`metabolism and enzymatic degradation within the GI
`tract, that prohibit oral administration of certain
`classes of drugs especially peptides and proteins.
`Consequently,
`other
`absorptive mucosae
`are
`
`15
`
`considered as potential sites for drug administration.
`Transmucosal routes of drug delivery (i.e., the mucosal
`linings of the nasal, rectal, vaginal, ocular, and oral
`cavity) offer distinct advantages over peroral
`administration for systemic drug delivery. These
`advantages include possible bypass of first pass effect,
`avoidance of presystemic elimination within the GI
`tract, and, depending on the particular drug, a better
`enzymatic flora for drug absorption.
`
`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
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`the mucosal membranes lining the cheeks (buccal
`mucosa), and (iii) local delivery, which is drug
`delivery into the oral cavity.
`
`cholesterol sulfate and glucosyl ceramides. These
`epithelia have been found to be considerably more
`permeable to water than keratinized epithelia (18-20).
`
`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
`
`16
`
`B. Permeability
`
`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
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`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.
`
`C. Environment
`
`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).
`
`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.
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`Epithelium
`
`Lamina Propria
`
`Submucosa
`
`Figure 1. Structure of the oral mucosae. From reference (18) with permission.
`
`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).
`
`18
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`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 (Table 1). Since the buccal
`epithelium is similar in structure to other stratified
`epithelia of the body, enhancers used to improve drug
`permeation in other absorptive mucosae have been
`shown to work in improving buccal drug penetration
`(36). Drugs investigated for buccal delivery using
`various permeation/absorption enhancers range in both
`molecular weight and physicochemical properties.
`Small molecules such as butyric acid and butanol (37),
`ionizable
`low molecular weight drugs such as
`acyclovir (38, 39), propranolol (40), and salicylic acid
`(41), large molecular weight hydrophilic polymers
`such as dextrans (42), and a variety of peptides
`including octreotide
`(43),
`leutinizing hormone
`
`19
`
`releasing hormone (LHRH) (44), insulin (36), and -
`interferon (45) have all been studied.
`
`Table 1. List of compounds used as oral mucosal
`permeation enhancers
`
`Permeation Enhancer
`23-lauryl ether
`Aprotinin
`Azone
`Benzalkonium chloride
`Cetylpyridinium chloride
`Cetyltrimethylammonium
`bromide
`Cyclodextrin
`Dextran sulfate
`Lauric acid
`Lauric acid/Propylene
`glycol
`Lysophosphatidylcholine
`Menthol
`Methoxysalicylate
`Methyloleate
`Oleic acid
`Phosphatidylcholine
`Polyoxyethylene
`Polysorbate 80
`Sodium EDTA
`Sodium glycocholate
`
`Sodium glycodeoxycholate
`Sodium lauryl sulfate
`
`Sodium salicylate
`Sodium taurocholate
`Sodium taurodeoxycholate
`Sulfoxides
`Various alkyl glycosides
`
`Reference(s)
`(48)
`(2)
`(43, 51, 52)
`(53)
`(37, 53-55)
`(53)
`
`(45)
`(48)
`(56)
`(36)
`
`(49)
`(56)
`(48)
`(40)
`(40)
`(56)
`(48)
`(37, 45, 54)
`(2, 43, 48)
`(1, 36, 39, 43, 44, 46, 47,
`49, 57)
`(36, 41, 42, 44, 46-48)
`(2, 36, 37, 41, 45, 48, 53,
`54)
`(2, 56)
`(43-48, 54)
`(46, 47, 49)
`(36)
`(50)
`
`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.
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`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.
`
`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.
`
`20
`
`A. In vitro Methods
`
`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. (58) 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.
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`
`B. In vivo Methods
`
`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).
`
`C. Experimental Animal Species
`
`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) for permeability
`
`21
`
`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
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`
`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 cyanoacrylat
`(82),
`polyacrylic
`acid
`(82),
`hydroxypropyl
`methylcellulose
`(17),
`and
`poly methacrylate
`derivatives (83) 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).
`
`for buccal
`forms designed
`In general, dosage
`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.
`
`Bioadhesive Polymer(s) Studied
`HPC and CP
`
`HPC and CP
`
`CP, HPC, PVP, CMC
`
`CP and HPMC
`
`HPC, HEC, PVP, and PVA
`
`HPC and CP
`
`CP, PIP, and PIB
`
`Xanthum gum and Locust bean gum
`Chitosan, HPC, CMC, Pectin, Xantham
`gum, and Polycarbophil
`
`Investigation Objectives
`Preferred mucoadhesive strength on CP, HPC, and HPC-
`CP combination
`Measured Bioadhesive property using mouse peritoneal
`membrane
`Studied inter polymer complexation and its effects on
`bioadhesive strength
`Formulation and evaluation of buccoadhesive controlled
`release delivery systems
`Tested mucosal adhesion on patches with two-ply
`laminates with an impermeable backing layer and
`hydrocolloid polymer layer
`Used HPC-CP powder mixture as peripheral base for
`strong adhesion and HPC-CP freeze dried mixture as
`core base
`Used a two roll milling method to prepare a new
`bioadhesive patch formulation
`Hydrogel formation by combination of natural gums
`Evaluate mucoadhesive properties by routinely
`measuring the detachment force form pig intestinal
`mucosa
`
`Reference
`(57)
`
`(88)
`
`(89)
`
`(90)
`
`(91)
`
`(30)
`
`(92)
`
`(93)
`(85)
`
`22
`
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`
`J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 1 (1):15-30, 1998
`
`Table 2- Related research on mucoadhesive polymers and delivery systems - continued
`
`Bioadhesive Polymer(s) Studied
`Hyaluronic acid benzyl esters,
`Polycarbophil, and HPMC
`Hydroxyethylcellulose
`
`Polycarbophil
`
`Poly(acrylic acid) and
`Poly(methacrylic acid)
`Number of Polymers including HPC,
`HPMC, CP, CMC.
`
`Poly(acrylic acid-co-acrylamide)
`
`Poly(acrylic acid)
`
`Poly(acrylic acid-co-methyl
`methacrylate)
`Poly(acrylic acid-co- butylacrylate)
`
`HEMA copolymerized with Polymeg®
`(polytetramethylene glycol)
`Cydot® by 3M (bioadhesive polymeric
`blend of CP and PIB)
`Formulation consisting of PVP, CP,
`and cetylpyridinium chloride (as
`stabilizer)
`CMC, Carbopol 974P, Carbopol EX-
`55, Pectin (low viscosity), Chitosan
`chloride,
`CMC, CP, Polyethylene oxide,
`Polymethylvinylether/Maleic
`anhydride (PME/MA), and Tragacanth
`HPMC and Polycarbophil (PC)
`
`PVP, Poly(acrylic acid)
`
`Investigation Objectives
`Evaluate mucoadhesive properties
`
`Reference
`(84)
`
`Design and synthesis of a bilayer patch (polytef-disk) for
`thyroid gland diagnosis
`Design of a unidirectional buccal patch for oral mucosal
`delivery of peptide drugs
`Synthesized and evaluated crosslinked polymers
`differing in charge densities and hydrophobicity
`Measurement of bioadhesive potential and to derive
`meaningful information on the structural requirement for
`bioadhesion
`Adhesion strength to the gastric mucus layer as a
`function of crosslinking agent, degree of swelling, and
`carboxyl group density
`Effects of PAA molecular weight and crosslinking
`concentration on swelling and drug release
`characteristics
`Effects of polymer structural features on mucoadhesion
`
`Relationships between structure and adhesion for
`mucoadhesive polymers
`Bioadhesive buccal hydrogel for controlled release
`delivery of buprenorphine
`Patch system for buccal mucoadhesive drug delivery
`
`Device for oramucosal delivery of LHRH - device
`containing a fast release and a slow release layer
`
`Mucoadhesive gels for intraoral delivery
`
`Buccal mucoadhesive device for controlled release
`anticandidal device - CMC tablets yielded t