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`RB Ex. 2037
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
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`

`
`J Pharm Pharmaceut Sci (www.ualberta.caI~csps)1 (1):15-30, 1998
`
`the mucosal membranes lining the cheeks (buccal
`
`cholesterol sulfate and glucosyl ceramides.
`
`These
`
`local delivery, which is drug
`mucosa), and (iii)
`delivery into the oral cavity.
`
`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
`
`B. Permeability
`
`leaky
`is a somewhat
`The oral mucosae in general
`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
`
`because of the
`different regions of the oral cavity
`diverse structures and functions of the different oral
`
`active basal cell layer, advancing through a number of
`
`mucosae.
`
`In general,
`
`the permeabilities of the oral
`
`differentiating intermediate layers to the superficial
`layers, where cells are shed from the surface of the
`
`mucosae decrease in the order of sublingual greater
`than buccal, and buccal greater than palatal (18). This
`
`epithelium (17). The epithelium of the buccal mucosa
`
`rank order is based on the relative thickness and degree
`
`layers thick, while that of the
`is about 40-50 cell
`sublingual epithelium contains somewhat fewer. The
`
`of keratinization of these tissues, with the sublingual
`
`mucosa being relatively thin and non-keratinized, the
`
`epithelial cells increase in size and become flatter as
`
`they travel from the basal
`layers.
`
`layers to the superficial
`
`The turnover time for the buccal epithelium has been
`
`thicker and non-keratinized, and the palatal
`buccal
`intermediate in thickness but keratinized.
`
`It is currently believed that the permeability barrier in
`the oral mucosa is a result of intercellular material
`
`is probably
`estimated at 5-6 days (18), and this
`representative of the oral mucosa as a whole. The oral
`
`derived
`granules’
`
`from the
`(MCG)
`
`coating
`‘membrane
`so-called
`(23). When cells
`go through
`
`mucosal thickness varies depending on the site:
`
`the
`
`buccal mucosa measures at 500-800 um, while the
`
`differentiation, MCGs start forming and at the apical
`cell surfaces they fuse with the plasma membrane and
`
`mucosal thickness of the hard and soft palates,
`
`the
`
`their contents are discharged into the intercellular
`
`floor of the mouth, the ventral tongue, and the gingivae
`measure at about 100-200 pm. The composition of the
`
`spaces at the upper one third of the epithelium. This
`
`barrier exists in the outermost 200um of the superficial
`
`epithelium also varies depending on the site in the oral
`
`layer. Permeation studies have been performed using a
`
`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
`
`number of very large molecular weight tracers, such as
`
`horseradish peroxidase (24) and lanthanum nitrate
`
`(25). When applied to the outer surface of the
`
`regions,
`and the buccal
`sublingual,
`the
`palate,
`however, are not keratinized (18). The keratinized
`
`lipids like ceramides and
`epithelia contain neutral
`acylceramides which have been associated with the
`
`relatively
`epithelia are
`These
`function.
`barrier
`impermeable to water.
`In contrast, non-keratinized
`
`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,
`
`epithelia, such as the floor of the mouth and the buccal
`
`while the more isodiametric cell layers are relatively
`
`epithelia, do not contain acylceramides and only have
`small amounts of ceramide (19-21). They also contain
`
`permeable.
`
`In both keratinized and non-keratinized
`
`epithelia, the limit of penetration coincided with the
`
`small amounts of neutral but polar
`
`lipids, mainly
`
`level where the MCGs could be seen adjacent to the
`
`16
`
`Page 2
`
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`

`
`J Pharm Pharmaceut Sci (www.ua|berta.cal~csps) 1 (1)115-30, 1998
`
`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
`
`The components of the MCGs in
`function (24).
`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
`
`the principle
`intercellular ground substance, mucus,
`components of which are complexes made up of
`
`proteins and carbohydrates. These complexes may be
`
`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
`
`It protects the soft tissues from abrasion by
`cavity.
`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
`
`free of association or some maybe attached to certain
`
`The are two permeation pathways for passive drug
`
`regions on the cell surfaces. This matrix may actually
`
`play a role in cell-cell adhesion, as well as acting as a
`
`transport across the oral mucosa: paracellular and
`transcellular routes. Permeants can use these two
`
`lubricant, allowing cells to move relative to one
`another (26). Along the same lines, the mucus is also
`
`route
`simultaneously, but one
`routes
`preferred
`over
`the
`other
`depending
`
`is usually
`on
`the
`
`believed to play a role in bioadhesion of mucoadhesive
`
`physicochemical properties of the diffusant. Since the
`
`drug delivery systems (27).
`
`In stratified squamous
`
`intercellular spaces and cytoplasm are hydrophilic in
`
`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
`
`low
`lipophilic compounds would have
`character,
`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
`
`carries a negative charge (due to the sialic acid and
`
`cell membrane acts as the major transport barrier for
`
`in
`role
`a
`play
`residues) which may
`sulfate
`mucoadhesion. At this pH mucus can form a strongly
`
`cohesive gel structure that will bind to the epithelial
`
`hydrophilic compounds. Since the oral epithelium is
`stratified,
`solute
`permeation may
`involve
`a
`combination of these two routes. The route that
`
`cell surface as a gelatinous layer (17).
`
`predominates, however,
`
`is generally the one that
`
`provides the least amount of hindrance to passage.
`
`17
`
`Page 3
`
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`
`

`
`J Pharm Pharmaceut Sci (www.uaIberta.cal~csps) 1 (1):15-30, 1998
`
`Epithelium
`
`Lamina Propria
`
`Submucosa
`
`T
`
`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
`
`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
`
`categories of drug delivery within the oral cavity (i.e.,
`
`mucosa. The buccal mucosa is considerably less
`
`sublingual, buccal, and local drug delivery). Selecting
`one over another is mainly based on anatomical and
`
`permeable than the sublingual area, and is generally
`not able to provide the rapid absorption and good
`
`permeability differences that exist among the various
`oral mucosal sites. The sublingual mucosa is relatively
`
`bioavailabilities seen with sublingual administration.
`
`Local delivery to tissues of the oral cavity has a
`
`permeable, giving rapid absorption and acceptable
`
`number of applications,
`
`including the treatment of
`
`bioavailabilities of many drugs, and is convenient,
`accessible, and generally well accepted (18).
`The
`
`sublingual route is by far the most widely studied of
`
`toothaches (30), periodontal disease (31, 32), bacterial
`
`aphthous and dental
`(33),
`infections
`and fungal
`stomatitis (34), and in facilitating tooth movement
`
`these routes. Sublingual dosage forms are of two
`
`with prostaglandins (35).
`
`different
`
`designs,
`
`those
`
`composed
`
`of
`
`rapidly
`
`18
`
`Page 4
`
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`
`

`
`J Pharm Pharmaceut Sci (www.ualberta.caI~csps) 1 (1):15-30, 1998
`
`Even though the sublingual mucosa is relatively more
`permeable than the buccal mucosa, it is not suitable for
`
`releasing hormone (LHRH) (44), insulin (36), and OL-
`interferon (45) have all been studied.
`
`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),
`
`such as
`low molecular weight drugs
`ionizable
`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
`
`List of compounds used as oral mucosal
`Table 1.
`permeation enhancers
`
`Permeation Enhancer
`
`Reference(s)
`
`23-lauryl ether
`Aprotinin
`
`Azone
`Benzalkonium chloride
`
`Cetylpyridinium chloride
`Cetyltrimethylarnmonium
`bromide
`
`(48)
`(2)
`
`(43, 51, 52)
`(53)
`
`(37, 53-55)
`(53)
`
`Cyclodextrin
`Dextran sulfate
`
`Laurie acid
`
`Laurie 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 al
`
`1 cosides
`
`1
`
`(45)
`(48)
`
`(56)
`
`(3 6)
`
`(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)
`(3 6)
`(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.
`
`Page 5
`
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`
`

`
`J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 1 (1):15-30, 1998
`
`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
`
`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
`
`higher concentrations by opening up a transcellular
`
`sacrificed
`
`immediately
`
`before
`
`the
`
`start of
`
`an
`
`investigated the
`route. Gandhi and Robinson (41)
`mechanisms
`of
`penetration
`enhancement
`of
`
`underlying
`Buccal mucosa with
`experiment.
`connective tissue is surgically removed from the oral
`
`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
`
`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
`
`buccal mucosa. Their results also supported that the
`
`between side-by-side diffusion cells for the in vitro
`
`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
`
`significant
`The most
`experiments.
`permeation
`questions concerning the use of animal tissues as in
`
`vitro models in this manner are the viability and the
`
`the
`How well
`integrity of the dissected tissue.
`dissected tissue is preserved is an important
`issue
`
`studied the feasibility of buccal mucosal delivery of
`insulin using various enhancers in different animal
`
`which will directly affect the results and conclusion of
`the studies. To date, there are no standard means by
`
`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
`
`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
`
`about 0.7% (without enhancer)
`
`to 26-27% in the
`
`et al. (58) reported a 50% drop in the tissue ATP
`
`presence of sodium glycocholate (5% w/v) and sodium
`
`concentration during the
`
`initial
`
`6 hours of
`
`the
`
`lauryl sulfate (5% w/v). Similar results were obtained
`
`experiment without a corresponding drop in tissue
`
`using dog as the animal model for the in vivo studies,
`
`where sodium deoxycholate and sodium glycocholate
`
`the
`permeability. Despite certain gradual changes,
`buccal tissue seems to remain viable for a rather long
`
`yielded the highest enhancement of buccal
`
`insulin
`
`absorption (36). These studies have all demonstrated
`
`period of time. Therefore, a decrease in ATP levels
`does not assure a drop in permeability characteristics
`
`the feasibility of buccal delivery of a rather large
`
`of the tissue. The most meaningful method to assess
`
`molecular weight peptide drug such as insulin.
`
`tissue viability is the actual permeation experiment
`
`V. EXPERIMENTAL METHODOLOGY FOR BUCCAL
`
`PERMEATION STUDIES
`
`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.
`
`Before
`
`a buccal drug delivery system can be
`
`formulated, buccal absorption/permeation studies must
`
`Buccal cell cultures have also been suggested as useful
`in vitro models
`for buccal drug permeation and
`
`be conducted to determine the feasibility of this route
`
`metabolism (25, 59-61). However,
`
`to utilize these
`
`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.
`
`culture cells for buccal drug transport, the number of
`
`differentiated cell layers and the lipid composition of
`
`layers must be well characterized and
`the barrier
`controlled. This has not yet been achieved with the
`buccal cell cultures used thus far.
`
`20
`
`Page 6
`
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`
`

`
`J Pharm Pharmaceut Sci (www.ualberta.caI~csps) 1 (1):15-30, 1998
`
`B. In vivo Methods
`
`the
`studies. However, such choices seriously limit
`value of the data obtained since, unlike humans, most
`
`In vivo methods were first originated by Beckett and
`Triggs (62) with the so-called buccal absorption test.
`
`laboratory animals have an oral lining that is totally
`
`keratinized. The rat has a buccal mucosa with a very
`
`Using this method,
`
`the kinetics of drug absorption
`
`were measured. The methodology
`
`involves
`
`the
`
`thick, keratinized surface layer. The rabbit is the only
`laboratory rodent
`that has non-keratinized mucosal
`
`swirling of a 25 ml sample of the test solution for up to
`
`lining similar to human tissue and has been extensively
`
`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
`
`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
`
`order to assess the amount of drug absorbed. The
`
`mucosal margins making it hard to isolate the desired
`
`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-
`
`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
`
`66) correcting for salivary dilution and accidental
`
`models for buccal drug delivery applications.
`
`Instead,
`
`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).
`Pharrnacokinetic
`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
`
`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
`
`Aside from the specific methodology employed to
`study
`buccal
`drug
`absorption/permeation
`characteristics, special attention is warranted to the
`
`mucosal delivery, a major limitation of the buccal
`route of administration is the lack of dosage form
`
`retention at
`
`the site of absorption. Consequently,
`
`choice of experimental
`experiments.
`For
`in
`
`such
`for
`species
`animal
`vivo
`investigations, many
`
`researchers have used small animals including rats (1,
`
`36, 37) and hamsters (51, 54, 72) for permeability
`
`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
`
`21
`
`Page 7
`
`Page 7
`
`

`
`J Pharm Pharmaceut Sci (www.ualberta.caI~csps)1 (1)215-30, 1998
`
`when the substrate is mucosal tissue (27). Polymers
`which can adhere to either hard or soft tissue have
`
`(87). Normally, hydrogels are crosslinked so that
`
`they
`
`would not dissolve in the medium and would only
`
`been used for many years in surgery and dentistry.
`
`absorb water. When drugs are loaded into these
`
`Diverse classes of polymers have been investigated for
`their potential use as mucoadhesives. These include
`
`hydrogels, as water is absorbed into the matrix, chain
`relaxation occurs and drug molecules are released
`
`synthetic polymers such as monomeric oc cyanoacrylat
`
`acid
`polyacrylic
`(82),
`methylcellulose
`(17),
`and
`
`hydroxypropyl
`(82),
`poly methacrylate
`
`through the spaces or channels within the hydrogel
`network.
`In a more broad meaning of the term,
`
`hydrogels would also include water-soluble matrices
`
`as naturally occurring
`as well
`(83)
`derivatives
`polymers such as hyaluronic acid (84) and chitosan
`
`that are capable of swelling in aqueous media, these
`include natural gums and cellulose derivatives. These
`
`(85). Other synthetic polymers such as polyurethanes,
`epoxy resins, polystyrene, and natural-product cement
`
`‘pseudo-hydrogels’ swell infinitely and the component
`molecules dissolve from the surface of the matrix.
`
`have also been extensively investigated (86).
`
`buccal
`for
`designed
`forms
`dosage
`general,
`In
`administration should not cause irritation and should
`
`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
`
`be small and flexible enough to be accepted by the
`
`transmucosal drug delivery has acquired considerable
`
`patient. These requirements can be met by using
`
`hydrogels. Hydrogels are hydrophilic matrices that are
`
`attention in recent years. Table 2 summarizes the
`related research on mucoadhesive polymers
`and
`
`capable of swelling when placed in aqueous media
`
`delivery systems.
`
`Table 2- Related research on mucoadhesive polymers and delivery systems.
`
`
`
`Bioadhesive Polym:i'(s) Studied
`HPC and CP
`
`HPC and CP
`
`CP, HPC, PVP, CMC
`
`Mlnvestigation 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
`
`Reference
`
`(57)
`
`(88)
`
`(89)
`
`CP and HPMC
`
`Formulation and evaluation of buccoadhesive controlled
`
`(90)
`
`release delivery systems
`
`HPC, HEC, PVP, and PVA
`
`Tested mucosal adhesion on patches with two-ply
`
`(91)
`
`HPC and CP
`
`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
`
`CP, PIP, and PIB
`
`Used a two roll milling method to prepare a new
`
`bioadhesive patch formulation
`
`Xanthum gum and Locust bean gum
`
`Hydrogel formation by combination of natural gums
`
`Chitosan, HPC, CMC, Pectin, Xantham Evaluate mucoadhesive properties by routinely
`
`gum, and Polycarbophil
`
`measuring the detachment force form pig intestinal
`mucosa
`
`22
`
`(30)
`
`(92)
`
`(93)
`
`(85)
`
`Page 8
`
`Page 8
`
`

`
`J Pharm Pharmaceut Sci (www.uaIberta.caI~csps) 1 (1):15-30, 1998
`.u— —.«um :.-j
`
`Table 2- Related research on mucoadhesive polymers and delivery systems - continued
`
`Bioadhesive Polymer(s) Studied
`
`Investigation Objectives
`
`Reference
`
`Hyaluronic acid benzyl esters,
`Polycarbophil, and HPMC
`
`Hydroxyethylcellulose
`
`Polycarbophil
`
`Evaluate mucoadhesive properties
`
`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
`
`Poly(acrylic acid) and
`
`Poly(methacrylic acid)
`
`Synthesized and evaluated crosslinked polymers
`
`differing in charge densities and hydrophobicity
`
`(84)
`
`(94)
`
`(70)
`
`(82)
`
`Number of Polymers including HPC,
`
`Measurement of bioadhesive potential and to derive
`
`(86)
`
`HPMC, CP, CMC.
`
`meaningful information on the structural requirement for
`bioadhesion
`
`Poly(acrylic acid-co-acrylamide)
`
`Adhesion strength to the gastric mucus layer as a
`function of crosslinking agent, degree of swelling, and
`
`(95)
`
`carboxyl group density
`
`Poly(acrylic acid)
`
`Effects of PAA molecular weight and crosslinking
`
`(96)
`
`concentration on swelling and drug release
`characteristics
`
`Poly(acrylic acid-co-methyl
`
`Effects of polymer structural features on mucoadhesion
`
`(83, 97)
`
`methacrylate)
`
`Poly(acrylic acid-co- butylacrylate)
`
`Relationships between structure and adhesion for
`
`mucoadhesive polymers
`HEMA copolymerized with Polymeg® Bioadhesive buccal hydrogel for controlled release
`(polytetramethylene glycol)
`delivery of buprenorphine
`Cydot® by 3M (bioadhesive polymeric
`Patch system for buccal mucoadhesive drug delivery
`blend of CP and PIB)
`
`(16)
`
`(98)
`
`(69, 99)
`
`(44)
`
`Formulation consisting of PVP, CP,
`and cetylpyridinium chloride (as
`stabilizer)
`
`CMC, Carbopol 974P, Carbopol EX—
`55, Pectin (low viscosity), Chitosan
`chloride,
`
`Device for oramucosal delivery of LHRH - device
`containing a fast release and a slow release layer
`
`Mucoadhesive gels for intraoral delivery
`
`(100)
`
`CMC, CP, Polyethylene oxide,
`
`Buccal mucoadhesive device for controlled release
`
`(101)
`
`Polymethylvinylether/Maleic
`
`anticandidal device - CMC tablets yielded the highest
`
`anhydride (PME/l\/IA), and Tragacanth
`
`adhesive force
`
`HPMC and Polycarbophil (PC)
`
`Buccal mucoadhesive tablets with optimum blend ratio
`
`(102)
`
`of 80:20 PC to HPMC yielding the highest force of
`adhesion
`
`
`"13./__l:3‘Poly(acryl_ic acid)
`
`Transmucosal controlled delivery of isosorbide dinitrate
`
`(103, 104)
`
`23
`
`Page 9
`
`Page 9
`
`

`
`J Pharm Pharmaceut Sci (www.ua|berta.ca/~csps) 1 (1):15-30, 1998
`_._.-._
`
`Table 2- Related research on mucoadhesive polymers and delivery systems - continued
`
`Bioadhesive Polymer(s) Studied
`
`Investigation Objectives
`
`Reference
`
`Poly(acrylic acid-co-poly
`
`To enhance the mucoadhesive properties of PAA for
`
`(105-107)
`
`ethyleneglycol) copolymer of acrylic
`
`buccal mucoadhesive drug delivery
`
`acid and poly ethyleneglycol
`
`monomethyl-ether monomethacryalte
`
`Poly acrylic acid and poly ethylene
`glycol
`
`To enhance mucoadhesive properties of PAA by
`
`(108)
`
`interpolymer complexation through template
`
`Drum dried waxy maize starch
`(DDWM), Carbopol 974P, and sodium delivery
`._..: jw«g..........._ —_
`—_ —_._ ..
`stearylfumarate
`
`W
`polymerizatioriw
`Bioadhesive erodible buccal tablet for progesterone
`
`(109)
`
`Abbreviations: CP = Carbopol 934P, HPC = Hydroxy propyl cellulose,
`
`PVP = Poly(vinyl pyrrolidone), CMC = Sodium carboxymethyl cellulose,
`
`HPMC = Hydroxy propyl methyl cellulose, HEC = Hydroxy ethyl cellulose,
`
`PVA = Poly(vinyl alcohol), PIB = Poly(isobutylene), PIP = Po1y(isoprene).
`
`Nagai
`
`et
`
`al.
`
`(35)
`
`studied the
`
`applicability of
`
`force was therefore most reduced at a mixture ratio of
`
`hydroxypropyl cellulose (HPC) as a mucoadhesive
`
`agent, they found this high viscosity grade material to
`be a suitable adhesive for topical mucus membranes.
`
`Inter-polymer complexation and its
`1:4 (HPC/CP).
`effect on bioadhesive strength was also studied by
`
`Gupta et al. (89). They reported that CP shows strong
`
`They reported the combination of HPC and carbopol
`
`complexation with
`
`poly(viny1
`
`pyrrolidone)
`
`and
`
`for
`to produce a preferable material
`934P (CP)
`mucoadhesive dosage forms. They examined directly
`
`compressed tablets of these polymers by placing them
`
`hydroxypropyl cellulose, but very little with sodium
`
`carboxy methyl cellulose. The degree of complexation
`was higher at acidic pH and decreased with an increase
`
`on an agar gel bed. HPC tablets showed a slight
`
`adhesion but dissolved easily on the gel bed. On the
`
`in pH. Anlar et al. (90) reported on formulation and
`evaluation of buccoadhesive controlled release systems
`
`other hand, CP tablets showed strong adhesion but the
`swollen CP tablets seemed too hard. The combination
`
`for the delivery of morphine sulfate. They prepared
`
`tablets by direct
`
`compression of carbomer
`
`and
`
`of HPC and CP provided the mucoadhesion and
`
`hydroxypropyl methyl cellulose (HPMC) and found
`
`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
`
`the drug release behavior to be non-Fickian and also
`confirmed interpolymer complex formation between
`HPMC and carbomer in acidic pH medium.
`
`was affected by the mixing ratio of HPC and CP. The
`
`Anders and Merkle (91), developed and evaluated
`
`adhesion force showed a minimum value at the mixing
`ratio of 3:2 (HPC:CP) due to the formation of an inter-
`
`adhesive patches for buccal administration, consisting
`
`of two-ply laminates of an impermeable backing layer
`
`polymer complex between HPC and CP in the acidic
`pH range.
`
`and a hydrocolloid polymer layer containing the drug.
`The polymers used HPC, HEC, PVP, and PVA. The
`
`Complex formation between CP and HPC seemed to
`
`integrity of the laminate was based o