Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2016 - 1/13
`
`

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`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2016 - 2/13
`
`

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`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2016 - 3/13
`
`

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`Journal of Controlled Release 140 (2009) 2–11
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`Contents lists available at ScienceDirect
`
`Journal of Controlled Release
`
`j o u r na l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j c o n re l
`
`Review
`Orotransmucosal drug delivery systems: A review
`N.V. Satheesh Madhav a, Ashok K. Shakya b, Pragati Shakya c,⁎, Kuldeep Singh c
`a Faculty of Pharmacy, Dehradoon Institute of Technology, Mussorie Diversion Road, Bagawantpur, Makkawala, Uttarakhand 248009 Dehradoon, India
`b Faculty of Pharmacy and Medical Sciences, Amman University, Po Box 263, Amman 19328, Jordan
`c Faculty of Pharmacy, Integral University Kursi Road, Lucknow, 226026, Uttar Pradesh, India
`
`a r t i c l e
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`i n f o
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`a b s t r a c t
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`Article history:
`Received 18 May 2009
`Accepted 27 July 2009
`Available online 6 August 2009
`
`Keywords:
`Transmucosal
`Soft palate
`Paracellular
`Transcellular
`Drug delivery
`
`Contents
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`Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages
`over both injectable and enteral methods and also enhances drug bioavailability because the mucosal
`surfaces are usually rich in blood supply, providing the means for rapid drug transport to the systemic
`circulation and avoiding, in most cases, degradation by first-pass hepatic metabolism. The systems contact
`with the absorption surface resulting in a better absorption, and also prolong residence time at the site
`of application to permit once or twice daily dosing. For some drugs, this results in rapid onset of action via
`a more comfortable and convenient delivery route than the intravenous route. Not all drugs, however, can
`be administered through the oral mucosa because of the characteristics of the oral mucosa and the
`physicochemical properties of the drug. Although many drugs have been evaluated for oral transmucosal
`delivery, few are commercially available. The clinical need for oral transmucosal delivery of a drug must be
`high enough to offset the high costs associated with developing this type of product. Transmucosal products
`are a relatively new drug delivery strategy. Transmucosal drug delivery promises four times the absorption
`rate of skin. Drugs considered for oral transmucosal delivery are limited to existing products, and until there
`is a change in the selection and development process for new drugs, candidates for oral transmucosal
`delivery will be limited. The present papers intend to overview a wide range of orotransmucosal routes being
`potentially useful for transmucosal drug delivery and remind us of the success achieved with these systems
`and the latest advancement in the field.
`
`© 2009 Elsevier B.V. All rights reserved.
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`1.
`2.
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`4.
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`Introduction .
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`Overview of the oral mucosa .
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`2.1.
`Structure .
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`2.2.
`Permeability
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`2.3.
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`3. Mucus .
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`3.1.
`Structure, function and composition .
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`Transmucosal drug absorption .
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`4.1.
`Principles of drug absorption via the oral transmucosa
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`4.2.
`Transmucosal drug absorption mechanisms (Fig. 1) .
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`4.3.
`Enhancement of transmucosal agent transport
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`Oral transmucosal routes .
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`5.1.
`Oral transmucosal (sublingual, buccal, soft palatal) administration .
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`Transmucosal drug delivery system .
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`6.1.
`Pharmaceutical consideration and formulation design for successful transmucosal drug delivery system .
`6.2.
`Oral transmucosal dosage forms
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`6.2.1.
`Solid forms .
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`6.2.2.
`Gum .
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`5.
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`6.
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`⁎ Corresponding author. Tel.: +91 9453604762.
`E-mail address: pragatimpharm@yahoo.co.in (P. Shakya).
`
`0168-3659/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
`doi:10.1016/j.jconrel.2009.07.016
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`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2016 - 4/13
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`

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`7.
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`Patches
`6.2.3.
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`Solution, suspension, and gel-forming liquids
`6.2.4.
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`6.2.5. Multiparticulates, microparticles, and nanoparticles
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`Current and future development of transmucosal drug delivery
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`7.1.
`Clinical application of oral transmucosal drug delivery
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`7.1.1.
`Recent advances in transmucosal drug delivery systems
`Advantages and limitations of oral transmucosal drug delivery .
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`8.
`Conclusions .
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`9.
`References .
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`N.V.S. Madhav et al. / Journal of Controlled Release 140 (2009) 2–11
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`3
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`1. Introduction
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`Oral administration of pharmaceutical compositions has some
`drawbacks. For instance, it is difficult to keep the medicament at the
`desired location so that it can be absorbed, distributed and metabolized
`easily. Accordingly, there has been much interest in the use of the
`mucosal lining of body cavities. Regions in the oral cavity where effective
`drug delivery can be achieved are buccal, sublingual, palatal and gingival.
`Buccal and sublingual sectors are the most commonly used routes for
`drug delivery and they may be used for the treatment of local or systemic
`diseases. The permeability of the oral mucosa is probably related to the
`physical characteristics of the tissues. The sublingual mucosa is more
`permeable and thinner than the buccal mucosa and because of the
`considerable surface area and high blood flow; it is a feasible site when a
`rapid onset is desired. The sublingual route is generally used for drug
`delivery in the treatment of acute disorders, but it is not always useful. It
`is because its surface is constantly washed by saliva and tongue activity
`which makes it difficult to keep the dosage form in contact with the
`mucosa. Unlike the sublingual mucosa, the buccal mucosa offers many
`advantages because of its smooth and relatively immobile surface and
`its suitability for the placement of controlled-release system which is
`well accepted by patients. The buccal mucosa is a useful route for the
`treatment of either local or systemic therapies overcoming the draw-
`backs of conventional administration routes. The buccal mucosa is
`relatively permeable, robust in comparison to the other mucosal tissues
`and is more tolerant to potential allergens which have a reduced
`tendency to irreversible irritation or damage. So, it has been largely
`investigated as a potential site for controlled drug delivery in various
`chronic systemic therapies. However, salivary production and compo-
`sition may contribute to chemical modification of certain drugs [1].
`Moreover; involuntary swallowing can result in drug loss from the site of
`absorption. Furthermore, constant salivary scavenging within the oral
`cavity makes it very difficult for dosage forms to be retained for an
`extended period of time in order to facilitate absorption in this site. The
`relatively small absorption area and the barrier property of the buccal
`mucosa contribute to the inherent limitations of this delivery route. Both
`the buccal and sublingual membranes offer advantages over other
`routes for administration. For example, drugs administered through the
`buccal and sublingual routes have a rapid onset of action and improved
`bioavailability of certain drugs. These routes can bypass the first-pass
`effect and exposure of the drugs to the gastrointestinal fluids. Additional
`advantages include easy access to the membrane sites so that the
`delivery system can be applied, localized, and removed easily. Further,
`there is good potential for prolonged delivery through the mucosal
`membrane within the oral mucosal cavity [2]. The palatal mucosa is
`intermediate in thickness and keratinized thus lessening its permeabil-
`ity. All of these epithelia are coated with a layer of mucus. Bioadhesive
`polymer can significantly improve the performance of many drugs, as
`they are having prolonged contact time with these tissues. These patient
`compliance controlled drug delivery products have improved drug
`bioavailability at suitable cost.
`Drug selection for oral transmucosal delivery is limited by the
`physicochemical properties of the drugs themselves. To be delivered
`transmucosally, drugs must have unique physicochemical properties,
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`i.e. a proper balance between solubility and lipophilicity. Generally
`only a few milligrams of drug can cross the oral mucosa, even if
`the drug has a favorable profile for oral mucosal delivery. Presently,
`new classes of drugs are typically not developed specifically for
`oral transmucosal delivery. Therefore, drugs considered for oral
`transmucosal delivery are limited to the existing products. Until
`there is a drastic change in the selection and development process of
`new drugs, candidates for oral transmucosal delivery will continue to
`be limited. Many products on the market, however, have shown
`unique properties and advantages of this delivery route. The key in the
`future will be to involve drug delivery and formulation scientists early
`in the drug selection process, so that more drugs that are suitable
`for delivery routes other than oral and parental can be developed [3].
`
`2. Overview of the oral mucosa
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`2.1. Structure
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`The oral mucosa is composed of an outermost layer of stratified
`squamous epithelium 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 super-
`ficial layers, where cells are shed from the surface of the epithelium
`[4]. 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.
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`2.2. Permeability
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`The oral mucosa in general is 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 [5]. 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 permeability of the oral
`mucosae decrease in the order of, sublingual greater than buccal,
`and buccal greater than palatal [6]. This ranking 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. Intercellular spaces at the upper one-third of the
`epithelium. This barrier exists in the outermost 200 µm of the superficial
`layer. Permeation studies have been performed using a number of very
`large molecular weight tracers, such as horseradish peroxidase and
`lanthanum nitrate. When applied to the outer surface of the epithelium,
`these tracers can only penetrate 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 are
`the main barrier to permeation, while the more isodiametric cell layers
`
`Teva Pharm. v. Indivior, IPR2016-00280
`INDIVIOR EX. 2016 - 5/13
`
`

`
`4
`
`N.V.S. Madhav et al. / Journal of Controlled Release 140 (2009) 2–11
`
`are relatively permeable. In both keratinized and non-keratinized
`epithelia, the limit of penetration coincided with the level where the
`membrane coating granules could be seen adjacent to the superficial
`plasma membranes of the epithelial cells. Since the same result was
`obtained in both keratinized and non-keratinized epithelia, keratiniza-
`tion by itself is not expected to play a significant role in the barrier
`function [7]. The components of the membrane coating granules in
`keratinized and non-keratinized epithelia are however different [8]. The
`membrane coating granules of keratinized epithelium are composed of
`lamellar lipid stacks, whereas the non-keratinized epithelium contains
`membrane coating granules that are non-lamellar. The membrane
`coating granule lipids of keratinized epithelia include sphingomyelin,
`glucosylceramides, ceramides, and other non-polar lipids, however for
`non-keratinized epithelia, the major membrane coating granule lipid
`components are cholesterol esters, cholesterol, and glycosphingolipids
`[9]. Aside from the membrane coating granules the basement mem-
`brane 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.
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`2.3. 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 may be attached to certain regions on
`the cell surfaces. This matrix may actually play a role in cell–cell
`adhesion, as well as act as a lubricant, allowing cells to move relative to
`one another [10]. Along the same lines, the mucus is also believed to play
`a role in bioadhesion of mucoadhesive drug delivery systems [11]. 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. Up to 70% of the total mucin found in
`saliva is contributed by the minor salivary glands [12]. 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. 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’
`[13]. The turnover time for the buccal epithelium has been estimated
`5–6 days, 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
`mucosa of areas subject to mechanical stress (the gingivae and hard
`palate) is keratinized similar to the epidermis. The mucosae of the soft
`palate, the sublingual, and the 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 [14].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 [15,16]. 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
`mineralization of the tooth enamel after eruption and helps in
`demineralization of the enamel in the early stages of dental caries
`[17]. 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 [18]. 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 and 2 l 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.
`
`3. Mucus
`
`3.1. Structure, function and composition
`
`The epithelial cells of buccal mucosa are surrounded by the
`intercellular ground substance called mucus with the thickness ranging
`from 40 µm to 300 µm [19]. Although most of 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. They contain
`large amounts of carbohydrate (for gastrointestinal mucins 70–80%
`carbohydrate, 12–25% protein and up to≈5% ester sulfate). Undegraded
`mucins from a variety of sources are made up of multiples of a basic
`unit (≈400–500 kDa), linked together into linear arrays to give the
`macroscopic mucins with molecular masses claimed to be as high as
`≈50 MDa [20]. It serves as an effective delivery vehicle by acting as a
`lubricant allowing cells to move relative to one another and is believed
`to play a major role in adhesion of mucoadhesive drug delivery systems
`[21]. At buccal pH, mucus can form a strongly cohesive gel structure
`that binds to the epithelial cell surface as a gelatinous layer. Mucus
`molecules are able to join together to make polymers or an extended
`three-dimensional network. Different types of mucus are produced, for
`example G, L, S, P and mucus, which form different network of gels.
`
`4. Transmucosal drug absorption
`
`4.1. Principles of drug absorption via the oral transmucosa
`
`A thorough description of the oral mucosa and its function is
`available elsewhere [22]. We have only included those details relevant
`to the oral mucosal delivery of drugs. The oral cavity comprises the lips,
`cheek (buccal), tongue, hard palate, soft palate and floor of the mouth.
`The lining of the oral cavity is referred to as the oral mucosa, and
`includes the buccal, sublingual, gingival, palatal and labial mucosae.
`The mucosal tissues in the cheeks (buccal), the floor of the mouth
`(sublingual) and the ventral surface of the tongue account for about
`60% of the oral mucosal surface area. The buccal and sublingual tissues
`are the primary focus for drug delivery via the oral mucosa because
`they are more permeable than the tissues in other regions of the
`mouth. The surface area of the oral mucosa (200 cm2)[23] is relatively
`small compared with the gastrointestinal tract (350000 cm2) and skin
`(20000 cm2)[24]. However, the oral mucosa is highly vascularized,
`and therefore any drug diffusing into the oral mucosa membranes has
`direct access to the systemic circulation via capillaries and venous
`drainage. Thus, drugs that are absorbed through the oral mucosa
`directly enter the systemic circulation, bypassing the gastrointestinal
`tract and first-pass metabolism in the liver. 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
`[25]. The oral mucosa is made up of closely compacted epithelial cells,
`which comprise the top quarter to one-third of the epithelium [26–28].
`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 [29]. In order for a drug to pass through the oral mucosa,
`it must first diffuse through the lipophilic cell membrane, and then
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`pass through the hydrophilic interior of the cells of the oral epithelium.
`Thus, the oral mucosa provides both hydrophilic and hydrophobic
`barriers that must be overcome for efficient mucosal delivery. An
`enzymatic barrier also exists at the mucosa, which causes rapid
`degradation of peptides and proteins, limiting their transport across
`the oral mucosa. Although these layers provide a unique challenge for
`drug delivery via the oral mucosa, several different approaches in the
`design and formulation of suitable delivery systems have been
`developed to circumvent these barriers.
`
`4.2. Transmucosal drug absorption mechanisms (Fig. 1)
`
`Drug absorption through a mucosal surface is generally efficient
`because the stratum corneum epidermis, the major barrier to absorption
`across the skin, is absent. Mucosal surfaces are usually rich in blood
`supply, providing the means for rapid drug transport to the systemic
`circulation and avoiding, in most cases, degradation by first-pass hepatic
`metabolism. The amount of drug absorbed depends on the drug
`concentration, vehicle of drug delivery, mucosal contact time, venous
`drainage of the mucosal tissues, degree of the drug's ionization and the
`pH of the absorption site, size of the drug molecule, and relative lipid
`solubility. There are two routes potentially involved in drug permeation
`across epithelial membranes: transcellular route and paracellular route.
`Paracellular transport is the transport of molecules around or between
`cells. Tight junctions or similar interconnections exist between cells. The
`intercellular tight junction is one of the major barriers to paracellular
`transport of macromolecules and polar compounds. Tight junction
`structure and permeability can be regulated by many potential
`physicochemical factors, including the concentration of cAMP and
`intracellular calcium concentrations. The mechanism of absorption
`enhancement of hydrophilic drugs by methylated cyclodextrins may be
`related to a temporary change in mucosal permeability and opening of
`the tight junctions [30,31]. Poly-(acrylic acid) derivatives such as
`Carbomer 934® and Chitosans have been extensively studied for their
`possible uses as absorption enhancers that cause the loosening of tight
`junctions [32,33]. Absorption enhancer alters membrane, lipid–proteins
`interactions and lipid bilayer and facilitates transcellular routes while
`
`Fig. 1. Mucus interaction with drug delivery systems.
`
`in the paracellular route the absorption enhancer disrupts intracellular
`occluding junctional complexes and opens the paracellular route
`[34]. The structure of the epithelial membrane is frequently simplified
`to consist of a lipid pathway and an aqueous pore pathway, in which
`the absorption of a drug is determined by the magnitude of its parti-
`tion coefficient and molecular size until the diffusion through the
`aqueous diffusion layer (Pa) becomes a rate-limiting steps in the course
`of transmembrane permeation. Transmucosal permeation of polar
`molecules (such as peptide based pharmaceuticals), may be by way of
`paracellular route, however several barriers exist during the course of
`paracellular permeation [35].
`
`lamina, whose barrier function is dependent upon the
`1) Basal
`molecular weight of the permeant molecule and its reactivity with
`the barrier as well as the structural and functional factors of the
`barrier.
`2) Membrane coating granules, which extrudes into the intercellular
`region of both keratinized and non-keratinized oral epithelium and
`prevent the transmucosal penetration of water-soluble peptide or
`protein, such as horse radish peroxidase.
`3) The keratin layer, whose barrier function in oral mucosa is not as
`well as defined as in the skin. Although the rate of permeation
`of water was shown to be greater in non-keratinized than in
`keratinized oral epithelium.
`
`Drug absorption via the oral mucosa is a passive diffusion process. By
`simplifying the oral mucosa into a hydrophobic membrane, Fick's first
`law can be used to describe the drug absorption process. Parameters
`such as diffusion coefficient, partition coefficient and thickness of the
`tissue are inherent properties of the drug and the mucosa. Other
`parameters, such as surface area, duration of drug delivery and
`concentration are controlled by the dosage form and formulation. Free
`drug concentration is a key issue in terms of developing transmucosal
`drug delivery dosage forms [36]. The effective formulation must not only
`release the drug to the mucosal surface, but do so with the drug in its
`free form. If the drug is bound to other components in the formulation, it
`is not available for transmucosal delivery and the bioavailability will be
`greatly reduced. The unique properties of the oral mucosa have also
`imposed unique drug delivery challenges for formulation scientists.
`In general,
`lipophilic compounds have much higher permeability
`coefficients than hydrophilic compounds. However, the aqueous
`solubility's of lipophilic compounds are usually much lower than
`those of hydrophilic compounds. Thus, the amount of drug absorbed
`may not be high for lipophilic compounds if their hydrophobicity is
`too high. There is a fine balance between partition coefficient and solu-
`bility for a drug to be suitable for oral mucosal delivery. Due to these
`constraints, the potency of the drug is important for selecting
`appropriate candidates. The amount of drug that can be delivered via
`the oral mucosa is limited to a few milligrams. Occasionally, permeation
`enhancers are used to promote drug absorption, especially for
`hydrophilic drugs. Their exact mechanism of action is unknown, and
`may be different for different types of enhancers. It is believed that the
`enhancers form aqueous pores on the cell surfaces, thereby increasing
`the permeability of hydrophilic compounds. The use of permeation
`enhancers, however, must consider issues such as local tissue irritation,
`long term tissue toxicity and enhanced permeability to pathological
`micro-organisms. Despite considerable research on oral mucosal
`permeation with enhancers, no product has yet to be commercially
`developed using a permeation enhancer.
`
`4.3. Enhancement of transmucosal agent transport
`
`Non-enhanced drug delivery is based solely on diffusion. Hydrophilic,
`ionic drugs usually diffuse through the intercellular space, while
`hydrophobic are able to pass through cellular membranes. Depending
`on physicochemical properties of the drug, the mucosa may have
`insufficient permeability and could represent a major limitation in the
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`development of a transmucosal drug delivery system. In addition, the
`limitation of the available absorption area and the short time of
`exposure, because of the washing effect of saliva, can decrease
`absorption efficiency even more. Permeation of drugs throughout
`epithelial barriers could be promoted by ‘penetration enhancers’
`utilizing different techniques, usually subdivided into chemical or
`physical methods. Penetration enhancers are capable of decreasing the
`barrier properties of the mucosa by increasing cell membrane fluidity,
`extracting the structural intercellular and/or intracellular lipids, altering
`cellular proteins, or altering the mucus structure and rheology [37–39].
`Chemical enhancers could be added to a pharmaceutical formulation,
`alone or in combination, in order to increase the permeation rate,
`without damage to, or irritation of, the mucosa. Enhancer efficacy
`depends on the physicochemical properties of the drug, the adminis-
`tration site and the nature of the vehicle. Penetration enhancers are
`thought to improve mucosal absorption by different mechanisms, for
`example, reducing the viscosity and/or elasticity of the mucus layer, or
`by transiently altering the lipid bilayer membrane, or overcoming the
`enzymatic barrier, or increasing the thermodynamic activity of the
`permeant. Various chemicals have been used as permeation enhancers
`across the epithelial tissues; among them chelators (e.g. sodium EDTA or
`salicylates), surfactants (e.g. sodium dodecyl sulfate, polyoxyethylene-9-
`lauryl ether, polyoxyethylene-20-cetyl ether and benzalkonium chlo-
`ride), bile salts (e.g. sodium deoxycholate, sodium glycocholate, sodium
`taurocholate and sodium glycodeoxycholate), fatty acids (e.g. oleic acid,
`capric acid and lauric acid) and non-surfactants (e.g. cyclodextrins
`and azones1). Recently, chitosan and its derivates have been extensively
`used to enhance permeation across either monostratified or pluristra-
`tified epithelia of small polar molecules and hydrophilic large molecules
`either in animal models or in human beings [40].Through the mechanical
`penetration enhancers, drug absorption can also be enhanced mechan-
`ically, for example, by removing the outermost layers from epithelium to
`decrease the barrier thickness, or electrically, for example, by application
`of electric fields or by sonophoresis. The latter acts by reducing,
`temporarily, the density of lipids in the intercellular domain of the
`membrane. This ‘disruption’ occurs due to a combination of micro-
`mechanical, thermic and cavitation effects that effectively ‘open up’ the
`intracellular pathways, allowing substances to penetrate. After chemical
`enhancement, the most efficient permeation enhancement methods for
`intraoral applications are probably the electrical mechanisms, such as
`electrophoresis (iontophoresis), electro-osmosis and electroporation.
`Electrophoretic enhancement in the oral cavity has been reported for a
`number of applications [41]. It is most effective for water-soluble,
`ionized compounds. The rate of migration is limited by the maximum
`electric current which can be applied across the mucosa; generally,
`currents below 0.5 mA/cm2 can be applied without adverse effects [42].
`Another means of increasing the drug transport rate is by utilizing
`electro-osmosis. Human tissue possesses fixed negative charge, and
`binds mobile, positive, counter ions, forming an electrically charged
`double layer in the tissue capillaries. When an electric field is applied
`across the tissue, there is a net fl