Journal of Controlled Release 153 (2011) 106–116
`
`Contents lists available at ScienceDirect
`
`Journal of Controlled Release
`
`j ou r n a l h o m e pa g e : ww w. e l s ev i e r. c o m/ l o c a t e / j c o n re l
`
`Review
`Advances in oral transmucosal drug delivery
`Viralkumar F. Patel a, Fang Liu a, Marc B. Brown a,b,⁎
`a School of Pharmacy, University of Hertfordshire, Hatfield, AL10 9AB, UK
`b MedPharm Limited, Guilford, Surrey, GU2 7YN, UK
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 27 September 2010
`Accepted 24 January 2011
`Available online 4 February 2011
`
`Keywords:
`Transmucosal
`Permeation pathways
`Buccal absorption
`Mucoadhesive
`Dosage forms
`
`Contents
`
`The successful delivery of drugs across the oral mucosa represents a continuing challenge, as well as a great
`opportunity. Oral transmucosal delivery, especially buccal and sublingual delivery, has progressed far beyond
`the use of traditional dosage forms with novel approaches emerging continuously. This review highlights the
`physiological challenges as well as the advances and opportunities for buccal/sublingual drug delivery.
`Particular attention is given to new approaches which can extend dosage form retention time or can be
`engineered to deliver complex molecules such as proteins and peptides. The review will also discuss the
`physiology and local environment of the oral cavity in vivo and how this relates to the performance of
`transmucosal delivery systems.
`
`© 2011 Elsevier B.V. All rights reserved.
`
`1.
`2.
`3.
`4.
`5.
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`5.2.
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`Introduction .
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`Overview of the oral mucosa .
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`Physiological barriers for oral transmucosal drug delivery .
`Physiological opportunities for oral transmucosal drug delivery .
`Oral transmucosal drug delivery technologies
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`5.1. Mucoadhesive systems .
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`5.1.1.
`Theories of mucoadhesion .
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`5.1.2.
`Polymers for mucoadhesive systems .
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`Dosage forms .
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`5.2.1.
`Liquid dosage forms .
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`5.2.2.
`Semisolid dosage forms .
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`5.2.3.
`Solid dosage forms .
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`5.2.4.
`Sprays .
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`Conclusion .
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`6.
`References
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`
`106
`107
`107
`108
`109
`109
`110
`110
`111
`111
`111
`112
`114
`115
`115
`
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`
`1. Introduction
`
`The cost involved both in terms of money and time in the
`development of a single new chemical entity has made it mandatory
`for pharmaceutical companies to reconsider delivery strategies to
`improve the efficacy of drugs that have already been approved.
`However, despite the tremendous advances in drug delivery, the oral
`
`⁎ Corresponding author at: MedPharm Ltd, R&D Centre, Unit 3 / Chancellor Court, 50
`Occam Road, Surrey Research Park, Guildford, GU2 7YN, UK. Tel.: +44 1483501480;
`fax: +44 447742.
`E-mail address: marc.brown@medpharm.co.uk (M.B. Brown).
`
`0168-3659/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
`doi:10.1016/j.jconrel.2011.01.027
`
`route remains the preferred route for the administration of therapeutic
`agents due to low cost, ease of administration and high level of patient
`compliance. However, significant barriers are imposed on the per oral
`administration of drugs, such as hepatic first pass metabolism and drug
`degradation within the gastrointestinal (GI) tract prohibiting the oral
`administration of certain classes of drugs especially biologics e.g.
`peptides and proteins. Consequently, other absorptive mucosae are
`being considered as potential sites for drug administration including the
`mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity. These
`transmucosal routes of drug delivery offer distinct advantages over per
`oral administration for systemic drug delivery such as the possible
`bypass of the first pass effect and avoidance of presystemic elimination
`
`RBP_TEVA05017457
`
`DRL - EXHIBIT 1019
`DRL001
`
`

`
`V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106–116
`
`107
`
`within the GI tract [1]. Amongst these, delivery of drugs to the oral cavity
`has attracted particular attention due to its potential for high patient
`compliance and unique physiological features. Within the oral mucosal
`cavity, the delivery of drugs is classified into two categories: (i) local
`delivery and (ii) systemic delivery either via the buccal or sublingual
`mucosa. This review examines the physiological considerations of the
`oral cavity in light of systemic drug delivery and provides an insight into
`the advances in oral transmucosal delivery systems.
`
`2. Overview of the oral mucosa
`
`The anatomical and physiological properties of the oral mucosa
`have been extensively reviewed by several authors [1–3]. The oral
`cavity comprises the lips, cheek, tongue, hard palate, soft palate and
`floor of the mouth (Fig. 1). The lining of the oral cavity is referred to
`as the oral mucosa, and includes the buccal, sublingual, gingival,
`palatal and labial mucosa. The buccal, sublingual and the mucosal
`tissues at the ventral surface of the tongue account for about 60% of
`the oral mucosal surface area. The top quarter to one-third of the oral
`mucosa is made up of closely compacted epithelial cells (Fig. 2). The
`primary function of the oral epithelium is to protect the underlying
`tissue against potential harmful agents in the oral environment and
`from fluid loss [4]. Beneath the epithelium are the basement
`membrane, lamina propia and submucosa. The oral mucosa also
`contains many sensory receptors including the taste receptors of the
`tongue.
`Three types of oral mucosa can be found in the oral cavity; the
`lining mucosa is found in the outer oral vestibule (the buccal mucosa)
`and the sublingual region (floor of the mouth) (Fig. 1). The
`specialized mucosa is found on the dorsal surface of tongue, while
`the masticatory mucosa is found on the hard palate (the upper
`surface of the mouth) and the gingiva (gums) [5]. The lining mucosa
`comprises approximately 60%, the masticatory mucosa approxi-
`mately 25%, and the specialized mucosa approximately 15% of the
`total surface area of the oral mucosal lining in an adult human. The
`masticatory mucosa is located in the regions particularly susceptible
`to the stress and strains resulting from masticatory activity. The
`superficial cells of the masticatory mucosa are keratinized, and a
`thick lamina propia tightly binds the mucosa to the underlying
`periosteum. Lining mucosa on the other hand is not nearly as subject
`to masticatory loads and consequently, has a non-keratinized
`epithelium, which sits on a thin and elastic lamina propia and a
`submucosa. The mucosa of the dorsum of the tongue is a specialized
`gustatory mucosa, which has well papillated surfaces; which are both
`keratinized and some non-keratinized [6].
`
`Fig. 1. Schematic representation of the different linings of mucosa in mouth [7].
`
`Fig. 2. Schematic diagram of buccal mucosa [8].
`
`3. Physiological barriers for oral transmucosal drug delivery
`
`The environment of the oral cavity presents some significant
`challenges for systemic drug delivery. The drug needs to be released
`from the formulation to the delivery site (e.g. buccal or sublingual area)
`and pass through the mucosal layers to enter the systemic circulation.
`Certain physiological aspects of the oral cavity play significant roles in
`this process, including pH, fluid volume, enzyme activity and the
`permeability of oral mucosa. For drug delivery systems designed for
`extended release in the oral cavity (e.g. mucodhesive systems), the
`structure and turnover of the mucosal surface is also a determinant of
`performance. Table 1 provides a comparison of the physiological
`characteristics of the buccal mucosa with the mucosa of the GI tract.
`The principle physiological environment of the oral cavity, in terms
`of pH, fluid volume and composition, is shaped by the secretion of saliva.
`Saliva is secreted by three major salivary glands (parotid, submaxillary
`and sublingual) and minor salivary or buccal glands situated in or
`immediately below the mucosa. The parotid and submaxillary glands
`produce watery secretion, whereas the sublingual glands produce
`mainly viscous saliva with limited enzymatic activity. The main
`functions of saliva are to lubricate the oral cavity, facilitate swallowing
`and to prevent demineralization of the teeth. It also allows carbohydrate
`digestion and regulates oral microbial flora by maintaining the oral pH
`and enzyme activity [13,14]. The daily total salivary secretion volume
`is between 0.5 and 2.0 l. However, the volume of saliva constantly
`present in the mouth is around 1.1 ml, thus providing a relatively low
`fluid volume available for drug release from delivery systems
`compared to the GI tract. Compared to the GI fluid, saliva is relatively
`less viscous containing 1% organic and inorganic materials.
`In
`addition, saliva is a weak buffer with a pH around 5.5–7.0. Ultimately
`the pH and salivary compositions are dependent on the flow rate of
`saliva which in turn depends upon three factors: the time of day, the
`type of stimulus and the degree of stimulation [15]. For example, at
`high flow rates, the sodium and bicarbonate concentrations increase
`leading to an increase in the pH.
`Saliva provides a water rich environment of the oral cavity which
`can be favorable for drug release from delivery systems especially
`those based on hydrophilic polymers. However, saliva flow decides
`the time span of the released drug at the delivery site. This flow can
`lead to premature swallowing of the drug before effective absorption
`occurs through the oral mucosa and is a well accepted concept known
`as “saliva wash out”. However, there is little research on to what
`extent this phenomenon affects the efficiency of oral transmucosal
`
`RBP_TEVA05017458
`
`DRL - EXHIBIT 1019
`DRL002
`
`

`
`108
`
`V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106–116
`
`Table 1
`Comparison of different mucosa [9–12].
`
`Absorptive
`site
`
`Estimated
`Surface area
`
`Oral cavity 100 cm2
`(0.01 m2)
`0.1–0.2 m2
`100 m2
`
`Stomach
`Small
`intestine
`Large
`intestine
`Rectum
`
`0.5–1.0 m2
`
`200–400 cm2
`(0.04 m2)
`
`Local
`pH
`
`Percent
`total
`surface
`area
`
`Mean
`fluid
`volume
`(ml)
`
`Relative
`enzyme
`activity
`
`Relative
`drug
`absorption
`capacity
`
`0.01
`
`5.8–7.6
`
`0.9
`
`Moderate Moderate
`
`0.20
`98.76
`
`0.99
`
`0.04
`
`1.0–3.0 118
`5.0–7.0 212
`
`High
`High
`
`Moderate
`High
`
`6.0–7.4 187
`
`Moderate Low
`
`7.0–7.4 –
`
`Low
`
`Low
`
`delivery from different drug delivery systems and thus further
`research needs to be conducted to better understand this effect.
`Drug permeability through the oral (e.g. buccal/sublingual)
`mucosa represents another major physiological barrier for oral
`transmucosal drug delivery. The oral mucosal thickness varies
`depending on the site as does the composition of the epithelium.
`The characteristics of the different regions of interest in the oral cavity
`are shown in Table 2. The mucosa of areas subject to mechanical stress
`(the gingiva and hard palate) is keratinized similar to the epidermis.
`The mucosa of the soft palate, sublingual, and buccal regions, however,
`are not keratinized. 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 ceramides [16]. 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 [17,18].
`Within the oral mucosa, the main penetration barrier exists in the
`outermost quarter to one third of the epithelium [23,24]. The relative
`impermeability of the oral mucosa is predominantly due to intercellular
`materials derived from the so-called membrane coating granules Q
`(MCGs) [2]. MCGs are spherical or oval organelles that are 100–300 nm
`in diameter and found in both keratinized and non-keratinized epithelia
`[25]. They are found near the upper, distal, or superficial border of the
`cells, although a few occur near the opposite border [25]. Several
`hypotheses have been suggested to describe the functions of MCGs,
`including membrane thickening, cell adhesion, production of a cell
`surface coat, cell desquamation and as a permeability barrier. Hayward
`[25] summarized that the MCGs discharge their contents into the
`intercellular space to ensure epithelial cohesion in the superficial layers,
`and this discharge forms a barrier to the permeability of various
`compounds. Cultured oral epithelium devoid of MCGs has been shown
`to be permeable to compounds that do not typically penetrate the oral
`epithelium [26]. In addition, permeation studies conducted using tracers
`of different sizes have demonstrated that these tracer molecules did not
`penetrate any further than the top 1–3 cell layers. When the same tracer
`molecules were introduced sub-epithelially, they penetrated through
`
`Table 2
`Characteristics of oral mucosa.
`
`the intercellular spaces. This limit of penetration coincides with the level
`where MCGs are observed. This same pattern is observed in both
`keratinized and non-keratinized epithelia [3], which indicates that
`MCGs play a more significant role as a barrier to permeation compared
`to the keratinization of the epithelia [27].
`The cells of the oral epithelia are surrounded by an intercellular
`ground substance called mucus, the principle components of which
`are complexes made up of proteins and carbohydrates; its thickness
`ranges from 40 to 300 μm [28]. In the oral mucosa, mucus is secreted
`by the major and minor salivary glands as part of saliva. Although
`most of the mucus is water (≈ 95–99% by weight) the key
`macromolecular components are a class of glycoprotein known as
`mucins (1–5%). Mucins are large molecules with molecular masses
`ranging from 0.5 to over 20 MDa and contain large amounts of
`carbohydrate. Mucins are made up of basic units (≈400–500 kDa)
`linked together into linear arrays. These big molecules are able to join
`together to form an extended three-dimensional network [29] which
`acts as a lubricant allowing cells to move relative to one another, and
`may also contribute to cell–cell adhesion [14]. At physiological pH, the
`mucus network carries a negative charge due to the sialic acid and
`sulfate residues and forms a strongly cohesive gel structure that will
`bind to the epithelial cell surface as a gelatinous layer [30–32]. This gel
`layer is believed to play a role in mucoadhesion for drug delivery
`systems which work on the principle of adhesion to the mucosal
`membrane and thus extend the dosage form retention time at the
`delivery site.
`Another factor of the buccal epithelium that can affect the
`mucoadhesion of drug delivery systems is the turnover time. The
`turnover time for the buccal epithelium has been estimated to be 3–
`8 days compared to about 30 days for the skin [2].
`
`4. Physiological opportunities for oral transmucosal drug delivery
`
`Despite the challenges, the oral mucosa, due to its unique
`structural and physiological properties, offers several opportunities
`for systemic drug delivery. As the mucosa is highly vascularized any
`drug diffusing across the oral mucosa membranes has direct access to
`the systemic circulation via capillaries and venous drainage and will
`bypass hepatic metabolism. The rate of blood flow through the oral
`mucosa is substantial, and is generally not considered to be the rate-
`limiting factor in the absorption of drugs by this route (Table 2).
`For oral delivery through the GI tract, the drug undergoes a rather
`hostile environment before absorption. This includes a drastic change in
`GI pH (from pH 1–2 in the stomach to 7–7.4 in the distal intestine),
`unpredictable GI transit, the presence of numerous digestive enzymes
`and intestinal flora [33,34]. In contrast to this harsh environment of the
`GI tract, the oral cavity offers relatively consistent and friendly
`physiological conditions for drug delivery which are maintained by
`the continuous secretion of saliva. Compared to secretions of the GI tract,
`saliva is a relatively mobile fluid with less mucin, limited enzymatic
`activity and virtually no proteases [35].
`Enzyme degradation in the GI tract is a major concern for oral drug
`delivery. In comparison, the buccal and sublingual regions have less
`enzymes and lower enzyme activity, which is especially favorable to
`protein and peptide delivery. The enzymes that are present in buccal
`mucosa are believed to include aminopeptidases, carboxypeptidases,
`
`Tissue
`
`Structure
`
`Thickness (μm) [20]
`
`Turnover time (days) [22]
`
`Surface area (cm2±SD) [6]
`
`Permeability [19]
`
`Residence time [19]
`
`Blood flow* [21]
`
`Buccal
`Sublingual
`Gingival
`Palatal
`
`NK
`NK
`K
`K
`
`500–600
`100–200
`200
`250
`
`5–7
`20
`–
`24
`
`50.2±2.9
`26.5±4.2
`–
`20.1±1.9
`
`Intermediate
`Very good
`Poor
`Poor
`
`Intermediate
`Poor
`Intermediate
`Very good
`
`20.3
`12.2
`19.5
`7.0
`
`NK is nonkeratinized tissue, K is Keratinized tissue and * In rhesus monkeys (ml/min/100 g tissue).
`
`RBP_TEVA05017459
`
`DRL - EXHIBIT 1019
`DRL003
`
`

`
`V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106–116
`
`109
`
`Table 3
`Permeabilities of water for human skin and oral mucosa regions (Adapted from Squier
`and co-workers [38]).
`
`Table 4
`Regional difference in permeability expressed in terms of a uniform permeability
`barrier (Adapted from Squier and Hall [39]).
`
`Kp (×10− 7±SEM cm/min)
`44 ±4b
`
`Tissue
`region
`
`Thickness (μm ± SEM)
`
`Regiona
`
`Skin
`Oral mucosa
`Hard palate
`Buccal mucosa
`Lateral border of tongue
`Floor of mouth
`
`470 ±27
`579 ±16
`772 ±23
`973 ±33
`
`a Human (n= 58).
`b Permeability constant (Kp) significantly different compared to oral mucosa at
`p b 0.05.
`
`dehydrogenases and esterases. Aminopeptidases may represent a
`major metabolic barrier to the buccal delivery of peptide drugs.
`Proteolytic activity has been identified in buccal tissue homogenates
`from various species and a number of peptides have been shown to
`undergo degradation [36]. Bernkop-Schnurch and co-workers [37]
`studied the peptidase activity on the surface of porcine buccal mucosa
`and found that no carboxypeptidase or dipeptidyl peptidase IV
`activity was detected on the buccal mucosa, while aminopeptidase
`N activity was detected using Leu-p-nitroanilide. However, this study
`represents only the surface of procine mucosa and hence more
`research will be required to fully characterize the levels and type of
`different enzymes presents especially in human buccal mucosa.
`The buccal and sublingual routes are the focus for drug delivery via
`the oral mucosa because of the higher overall permeability compared to
`the other mucosa of the mouth. The effective permeability coefficient
`values reported in the literature across the buccal mucosa for different
`molecules, range from a lower limit of 2.2×109 cm/s for dextran 4000
`across rabbit buccal membrane to an upper limit of 1.5×105 cm/s for
`both benzylamine and amphetamine across rabbit and dog buccal
`mucosa, respectively [2]. The oral mucosa is believed to be 4–4000 times
`more permeable than that of skin [24]. Squier and co-workers [38]
`revealed that the permeability of water through the buccal mucosa was
`approximately 10 times higher, whilst in floor of the mouth the
`permeability was approximately 20 times higher than skin (Table 3). In
`another study by Squier and Hall [39], the permeability constant was
`calculated for water and Horseradish peroxidase across skin and oral
`mucosal surface (Table 4).
`Drugs can be transported across epithelial membranes by passive
`diffusion, carrier-mediated active transport or other specialized
`mechanisms. Most studies of buccal absorption indicate that the
`predominant mechanism is passive diffusion across lipid membranes
`via either the paracellular or transcellular pathways (Fig. 3) [40–44];
`although these may actually be the same pathway. The hydrophilic
`nature of the paracellular spaces and cytoplasm provides a permeability
`barrier to lipophilic drugs but can be favorable for hydrophilic drugs. In
`contrast, the transcellular pathway involves drugs penetrating through
`one cell and the next until entering the systemic circulation. The
`lipophilic cell membrane offers a preferable route for lipophilic drugs
`compared to hydrophilic compounds [1]. Drugs can transverse both
`pathways simultaneously although one route could be predominant
`depending on the physicochemical properties of the drug [31].
`Although passive diffusion is the predominant mechanism of
`absorption from the oral mucosa, specialized transport mechanisms
`have also been reported for a few drugs and nutrients. A study by
`Kurosaki and co-workers [45] reported that the rate of absorption of
`D-glucose from the dorsal and ventral surface of the tongue was
`significantly greater than that of L-glucose, which indicated the
`occurrence of some specialized transport mechanism. In addition, the
`existence of sodium-dependant D-glucose transport system was
`reported across stratified cell layer of human oral mucosal cells [46].
`Table 5 provides examples of several drugs transported via different
`mechanisms across the buccal mucosa.
`
`Total
`epithelium
`
`Permeability
`barrier
`
`69 ±4
`208 ±9
`772 ±20
`
`16 ±1
`35 ±4
`282 ±17
`
`Mean Kp expressed in terms of a
`uniform barrier of 100 μm thick
`(±SEM×10−7)
`Water
`
`Horseradish
`peroxidise
`
`21.1±4.3
`98.3±16.0
`173.2 ±24.6
`
`9.4±1.8
`79.5±11.4
`99.1±10.6
`
`192 ±7
`
`23 ±1
`
`1271.3±203.1
`
`331.6 ±51.9
`
`Skin
`Gingiva
`Buccal
`mucosa
`Floor of
`mouth
`
`5. Oral transmucosal drug delivery technologies
`
`Continuous research into the improvement of the oral transmucosal
`delivery of drugs has resulted in the development of several
`conventional and novel dosage forms like solutions, tablets/lozenges,
`chewing gums, sprays, patches and films, hydrogels, hollow fibers and
`microspheres. These dosage forms can be broadly classified into liquid,
`semi-solid, solid or spray formulations [54]. Oral transmucosal systems
`for systemic drug delivery are usually designed to deliver the drug for
`either i) rapid drug release for immediate and quick action, ii) pulsatile
`release with rapid appearance of drug into systemic circulation and
`subsequent maintenance of drug concentration within therapeutic
`profile or iii) controlled release for extended period of time (as depicted
`in Fig. 4).
`Several companies are currently engaged in development and
`commercialization of drug delivery technologies based on oral
`transmucosal systems. Table 6 shows a list of products commercially
`approved for oral transmucosal administration. A list of companies
`currently engaged in developing technology platforms for oral
`transmucosal drug delivery system is shown in Table 7. The majority
`of the commercially available formulations are solid dosage forms
`such as tablets and lozenges. A few companies have had successes in
`developing technology platforms for films or patches with most
`aimed at achieving rapid drug release and clinical response. The
`limitations associated with such type of dosage forms include
`uncontrolled swallowing of released drug into GI tract and difficulties
`in holding the dosage form at the site of absorption. These are the
`areas where more research focus is required, especially using
`mucoadhesive systems.
`
`5.1. Mucoadhesive systems
`
`Other than the low surface area available for drug absorption in the
`buccal cavity, the retention of the dosage form at the site of absorption is
`another factor which determines the success or failure of buccal drug
`delivery system. The utilization of mucoadhesive systems is essential to
`maintain an intimate and prolonged contact of the formulation with the
`oral mucosa allowing a longer duration for absorption. Some adhesive
`systems deliver the drug towards the mucosa only with an impermeable
`product surface exposed to the oral cavity which prevents the drug
`
`Fig. 3. Schematic representation of different route of drug permeation.
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`polymer network strands are longer or if the degree of cross-linking
`within such a system is reduced [84]. According to the adhesion theory,
`adhesion is defined as being the result of various surface interactions
`(primary and secondary bonding) between the adhesive polymer and
`mucus substrate. Primary bonds due to chemisorption result in adhesion
`due to ionic, covalent and metallic bonding, which is generally
`undesirable due to their permanency [85]. The diffusion–interlocking
`theory proposes the time-dependent diffusion of mucoadhesive poly-
`mer chains into the glycoprotein chain network of the mucus layer. This
`is a two-way diffusion process with penetration rate being dependent
`upon the diffusion coefficients of both interacting polymers [78].
`
`5.1.2. Polymers for mucoadhesive systems
`The polymeric attributes that are pertinent to high levels of
`retention at applied and targeted sites via mucoadhesive bonds
`include hydrophilicity, negative charge potential and the presence of
`hydrogen bond forming groups. Additionally, the surface free energy
`of the polymer should be adequate so that ‘wetting’ with the mucosal
`surface can be achieved. The polymer should also possess sufficient
`flexibility to penetrate the mucus network, be biocompatible, non-
`toxic and economically favorable [86]. According to the literature
`mucoadhesive polymers are divided into first generation mucoadhe-
`sive polymers and second generation novel mucoadhesive polymers.
`The first generation polymers are divided into three major groups
`according to their surface charges which include anionic, cationic and
`non-ionic polymers. The anionic and cationic polymers exhibit
`stronger mucoadhesion [87].
`Anionic polymers are the most widely employed mucoadhesive
`polymers within pharmaceutical formulations due to their high
`mucoadhesive functionality and low toxicity. Such polymers are
`characterized by the presence of carboxyl and sulfate functional
`groups that give rise to a net overall negative charge at pH values
`exceeding the pKa of the polymer. Typical examples include
`polyacrylic acid (PAA) and its weakly cross-linked derivatives and
`sodium carboxymethyl cellulose (Na CMC). PAA and Na CMC possess
`excellent mucoadhesive characteristics due to the formation of strong
`hydrogen bonding interactions with mucin [88]. Among the cationic
`polymer systems, undoubtedly chitosan is the most extensively
`investigated within the current scientific literature [89]. Chitosan is
`a cationic polysaccharide, produced by the deacetylation of chitin, the
`most abundant polysaccharide in the world, next to cellulose [89].
`Chitosan is a popular polymer to use due to its biocompatibility,
`biodegradability and favorable toxicological properties [90]. Chitosan
`has been reported to bind via ionic interactions between primary
`amino functional groups and the sialic acid and sulphonic acid
`substructures of mucus [91]. The major benefit of using chitosan
`within pharmaceutical applications has been the ease with which
`
`4
`
`9
`
`14
`
`19
`
`24
`
`Quick release
`
`Time (hr)
`Pulsatile release
`
`Controlled release
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`-1
`
`Presence of drug in systemic circulation
`
`Fig. 4. Schematic representation of different type of mucosal drug delivery system.
`
`Table 5
`Examples of drugs transported via different mechanisms through buccal mucosa.
`
`Name of Drug
`
`Transport
`mechanism
`
`Path way
`
`Tissue
`
`References
`
`5-Aza-2′-
`deoxycytidine
`2′, 3′-
`dideoxycytidine
`Flecainide
`Sotalol
`Nicotine
`
`Lamotrigine
`Galantamine
`
`Naltrexone
`Buspirone
`Ondansatron
`HCl
`Monocarboxylic
`acids
`Glucose
`
`Passive
`
`Not defined
`
`Buccal mucosa
`
`Passive
`
`Not defined
`
`Buccal mucosa
`
`Passive
`Passive
`Passive
`
`Passive
`Passive
`
`Passive
`Passive
`Passive
`
`Buccal mucosa
`Paracellular
`Buccal mucosa
`Paracellular
`TR146 Cell culture
`Paracellular,
`and buccal mucosa
`Transcellular
`Transcellular Buccal mucosa
`Not defined Human oral
`epithelium and
`buccal mucosa
`Buccal mucosa
`Not defined
`Transcellular Buccal mucosa
`Not defined
`Buccal mucosa
`
`[40]
`
`[41]
`
`[42]
`[42]
`[43]
`
`[44]
`[47]
`
`[48]
`[49]
`[50]
`
`Carrier
`mediated
`Carrier
`mediated
`
`Carrier
`mediated
`Carrier
`mediated
`
`Primary cultured
`epithelial cells
`Buccal, oral mucosal
`cells and dorsum of
`tongue
`
`[51,52]
`
`[53]
`
`release into oral cavity [76]. For example, Lopez and co-workers [77]
`designed bilaminated films to provide unidirectional release of drug and
`avoid buccal leakage. They contained a bioadhesive layer made up of
`chitosan, polycarbophil, sodium alginate and gellan gum while backing
`layer made up of ethyl cellulose.
`
`5.1.1. Theories of mucoadhesion
`The most widely investigated group of mucoadhesives used in buccal
`drug delivery systems are hydrophilic macromolecules containing
`numerous hydrogen bond-forming groups [78]. The presence of
`hydroxyl, carboxyl or amine groups on the molecules favors adhesion.
`They are called ‘wet’ adhesives as they are activated by moistening and
`will adhere non-specifically to many surfaces. Unless water uptake is
`restricted, they may over hydrate to form slippery mucilage. For dry or
`partially hydrated dosage forms two basic steps in mucoadhesion have
`been identified [79]. Step one is the ‘contact stage’ where intimate
`contact is formed between the mucoadhesive and mucous membrane.
`Within the buccal cavity the formulation can usually be readily placed
`into contact with the required mucosa and held in place to allow
`adhesion to occur. Step two is the ‘consolidation’ stage where various
`physicochemical interactions occur to consolidate and strengthen the
`adhesive joint, leading to prolonged adhesion.
`Mucoadhesion is a complex process and numerous theories have
`been presented to explain the mechanisms involved. These theories
`include mechanical-interlocking, electrostatic, diffusion–interpenetra-
`tion, adsorption and fracture processes [80], whilst undoubtedly the
`most widely accepted theories are founded upon surface energy
`thermodynamics and interpenetration/diffusion [81]. The wettability
`theory is mainly applicable to liquid or low viscosity mucoadhesive
`systems and is essentially a measure of the spreadability of the drug
`delivery system across the biological substrate [82]. The electronic
`theory describes that adhesion occurs by means of electron transfer
`between the mucus and the mucoadhesive system arising through
`differences in their electronic structures. The electron transfer between
`the mucus and the mucoadhesive results in the formation of a double
`layer of electrical charges at the mucus and mucoadhesive interface. The
`net result of such a process is the formation of attractive forces within
`this double layer [83]. According to fracture theory, the adhesive bond
`between systems is related to the force required to separate both
`surfaces from one another. This “fracture theory” relates the force for
`polymer detachment from the mucus to the strength of their adhesive
`bond. The work of fracture has been found to be greater when the
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`Table 6
`Commercially available oral transmucosal drug delivery systems [35].
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`
`111
`
`dosage forms are usually employed to exert local action into the oral
`cavity and several antibacterial mouthwashes and mouth-freshener
`are commercially available for this purpose. The limitation associated
`with these liquid dosage forms are that they are not readily retained
`or targeted to buccal muco