Palatal mucosa as a route for systemic drug delivery: A review

Journal of Controlled Release 151 (2011) 2–9

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Journal of Controlled Release j o u r n a 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 r e l

Review

Palatal mucosa as a route for systemic drug delivery: A review Pragati Shakya c,⁎, N.V. Satheesh Madhav a, Ashok K. Shakya b, Kuldeep Singh c a b c

Faculty of Pharmacy, Dehradoon Institute of Technology, Mussorie diversion Road, Bagawantpur, Makkawala, Dehradoon, Uttarakhand 248009, India Faculty of Pharmacy and Medical Sciences, Al-Ahliyya, Amman University, P.O. Box-263, Amman 19328, Jordan Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, U.P., India

a r t i c l e

i n f o

Article history: Received 20 July 2010 Accepted 19 October 2010 Available online 6 November 2010 Keywords: Mucoadhesive Orotransmucosal Non-invasive route

a b s t r a c t Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive pre-systemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parenteral route of administration is the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last few decades pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Historically, oral transmucosal drug delivery has received intensive interest since ancient times for the most widely utilized route of administration for the systemic delivery of drugs. In more recent years, better systemic bioavailability of many drugs has been achieved by oromucosal route. Among the various transmucosal sites available, soft-palatal mucosa was also found to be the most convenient and easily accessible novel site for the delivery of therapeutic agents for systemic delivery as retentive dosage forms, because it has abundant vascularization and rapid cellular recovery time after exposure to stress. Smooth surface of the soft palate and its good flexibility are prerequisites to prevent mechanical irritation and local discomfort. The objective of this review is to provide an update on the most promising advances in novel non-invasive soft-palatal route and the conceptual and technical approaches to the design and formulation of soft-palatal drug delivery systems. In this area, the development of mucoadhesive delivery systems appears to be the most promising strategy. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2.

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4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The oral mucosa as a site for delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Anatomy, physiology and properties of the oral mucosa . . . . . . . . . . . . . . . . . 2.2. Permeability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Various transmucosal routes of drug delivery . . . . . . . . . . . . . . . . . . . . . . Soft palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Environmental and histo-morphological features of the soft palate . . . . . . . . . . . . 3.2. Soft palate mucosal structure and its suitability . . . . . . . . . . . . . . . . . . . . . Mucus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Mucus physiology for the development of soft-palatal transmucosal drug delivery systems . Prerequisites for successful transmucosal palatal drug-delivery system . . . . . . . . . . . . . . Formulation factors for designing palatal drug-delivery systems (Table 1) [58–63] . . . . . . . . 6.1. Mucoadhesive agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Permeation enhancers [73–75] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Mechanisms of action of permeation enhancers . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: +91 9453604762. E-mail address: [email protected] (P. Shakya). 0168-3659/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2010.11.003

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6.3.

Various transmucosal dosage forms. . . . . . . . . . . . . 6.3.1. Immobilised drug-delivery systems . . . . . . . . 7. Experimental methodology for palatal permeation studies [25,30,31] 8. Advantages and limitations of orosoft-palatal platform drug-delivery 8.1. Advantages . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Limitations . . . . . . . . . . . . . . . . . . . . . . . . 9. Possibilities for future research . . . . . . . . . . . . . . . . . . 10. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Oral drug delivery has, for decades, been the most widely utilized route of administration for the systemic delivery of drugs. The lack of efficacy of certain drugs due to decreased bioavailability, unpredictable and erratic absorption, GI intolerance, or pre-systemic elimination has prompted the examination of other potential route for administration. Moreover, the recent development of a large number of drugs has intensified investigation of mucosal delivery of drugs. Transmucosal routes of drug delivery (i.e., the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity) offer distinct advantages over peroral administration for systemic drug delivery. These advantages include possible bypass of first-pass effect, avoidance of pre-systemic elimination within the GI tract, and, depending on the particular drug, a better enzymatic flora for drug absorption. The oral cavity is highly acceptable by patients, the mucosa is relatively permeable with a rich blood supply, it is robust and shows short recovery times after stress or damage [1–3], and the virtual lack of Langerhans cells [4] makes the oral mucosa tolerant to potential allergens. The oral mucosa can be categorized into sublingual, gingival, buccal and soft-palatal mucosa through which systemic transmucosal drug delivery can be achieved. Conventional buccal and sublingual dosage forms are typically short acting because of limited contact time between the dosage form and the oral mucosa. Since administration of drugs through these routes interferes with eating, drinking and talking therefore, these routes are generally considered unsuitable for prolonged administration, whereas soft-palatal medication delivers steady infusion of drugs over an extended period of time, because of the function of the soft palate to cover the glottis while swallowing, it is more fitted for sustained and controlled drug delivery also due to the presence of immobile mucosa and lack of permeability in composition with sublingual mucosa. Even though the sublingual mucosa is relatively more permeable than the buccal mucosa but it is not suitable for an oral transmucosal delivery system because it lacks an expanse of smooth muscle and is constantly washed by a considerable amount of saliva making it difficult for device placement. Because of high permeability and 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. While buccal drug delivery has low flux due to less permeability which results in low drug bioavailability, other drawbacks include salivary dilution of the drug and inability to localize the drug within a specific site of the oral cavity. Therefore soft-palatal drug delivery is a feasible approach for correcting salivary dilution and achieving absorption site localization to retain the drug on the mucosa using a bio-adhesive system. 2. The oral mucosa as a site for delivery 2.1. Anatomy, physiology and properties of the oral mucosa The anatomy and physiology of the oral mucosa have been extensively reviewed in several publications [5]. Nevertheless, a brief overview in this chapter is essential. The oral mucosa is composed of

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an outermost layer of stratified squamous epithelium, intermediate layer, lamina propria followed by the submucosa as the innermost layer [6]. The structure and biochemistry of the oral epithelium are illustrated by Squier et al. [7,8] and its biochemistry by Gerson et al. [9]. Oral epithelium consists of a stratified squamous epithelium. Oral mucosa can be categorized into sublingual, gingival, buccal and palatal mucosa through which oral transmucosal drug delivery can be achieved. A gel-like secretion known as mucus, which contains mostly water-insoluble glycoproteins, covers the entire oral cavity. Mucus is bound to the apical cell surface and acts as a protective layer to the cells below [10]. It is also a viscoelastic hydrogel, and primarily consists of 1–5% of the above-mentioned water-insoluble glycoproteins, 95–99% water, and several other components in small quantities, such as proteins, enzymes, electrolytes, and nucleic acids. This composition can vary based on the origin of the mucus secretion in the body [11,12]. 2.2. Permeability The oral mucosa in general is somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa and there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa. The permeability coefficient of a drug is a measure of the ease with which the drug can permeate a membrane. The permeability coefficient is a function of the membrane thickness (i.e., inverse to its thickness) degree of keratinization of these tissues, and the physicochemical properties of the drug (e.g., molecular weight, size, and lipophilicity). Drug permeability appears to be highest in the sublingual area and lowest at the gingival site [13]. It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the so-called membrane coating granules (MCG) [4,14–16]. 2.3. Various transmucosal routes of drug delivery Drugs for systemic medication are administered traditionally and routinely by oral and by parenteral routes. Although generally convenient, both routes have a number of disadvantages, especially for the delivery of peptides and proteins, a class of drug that has been rapidly emerging over the last decades [17]. Orally administered drugs are exposed to harsh environment of the gastrointestinal tract, potential chemical and enzymatic degradation [18]. After gastrointestinal absorption the drug has to pass the liver, where, dependent on the nature of the drug, extensive first-pass metabolism can take place with subsequent rapid clearance from the blood stream [19]. Low permeability across the gastrointestinal mucosa is also often encountered for macromolecular drugs [20]. Parenteral administration avoids drug degradation in the gastrointestinal tract and hepatic first-pass clearance but due to pain or discomfort during injection, patient compliance is poor, particularly if multiple daily injections are required as e.g. in the insulin therapy [21,22]. Injection related side effects like tissue necrosis and thrombophlebitis also lead to low patient acceptability. In addition, administration by injection requires

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trained personnel which add to the relatively high costs of parenteral medication. 3. Soft palate 3.1. Environmental and histo-morphological features of the soft palate The soft palate is a mobile flap suspended from the posterior border of the hard palate, sloping down the back between the oral and nasal parts of the pharynx. The soft palate (or velum, or muscular palate) is the soft tissue constituting the back of the roof of the mouth [23]. Velum route prevents mechanical irritation and local discomfort due to its smooth surface and good flexibility. The soft palate is a thick fold of mucosa enclosing an aponeurosis, muscular tissue, vessel nerves, lymphoid tissue, mucous glands and two small pits, the fovea palatine, one on each side of the midline is present. The anterior (oral) concave surface of the soft palate makes it suitable for self administration of drug delivery system with the help of thumb [24,25]. The mucous membrane on the oral surface of the soft palate is highly vascularized. The papillae of the connective tissue are few and short, the stratified squamous epithelium is nonkeratinized, and the lamina propria shows distinctive layer of elastic fibers separating it from the submucous [26–29]. Typical oral mucosa is continuous around the free border of the soft palate for a variable distance and is then replaced by nasal mucosa with its pseudo-stratified, ciliated columnar epithelium [30,31]. Oral side epithelium of the soft palate is covered consistently and uniformly with nonkeratinized stratified squamous epithelium of about 20–30 cell layers thick and therefore apparently well suited to withstand abrasive forces. The oral aspects of the palate, especially the anterior half are well endowed with seromucous glands, and to a lesser degree with fatty tissues. The glands function to aid in moisturizing the palatal cavity to facilitate the adhesion by the secretions of saliva (750 ml) from these glands [32]. These glandular secretions may serve as a glandular lubricant to reduce frictional forces. The arterial supply of the soft palate is usually derived from the ascending palatine branch of the facial artery and the greater palatine branch of the maxillary artery. The blood supply by the facial artery to the palatal region is 0.89 ml/min/100 cm2. The veins of the soft palate usually drain to the pterygoid venous plexus. The secretomotor supply to most of the mucosa of the soft palate travels via the lesser palatine nerve [33]. 3.2. Soft palate mucosal structure and its suitability Surrounding the oral epithelial cells is a thin layer of mucus, which plays a major role in cell-to-cell adhesion and oral lubrication, as well as mucoadhesion of mucoadhesive drug delivery systems [34]. The soft-palatal mucosa composed of stratum squamous epithelial cells, with thickness of about 100–200 μm consists of a nonkeratinized epithelial tissue with the absence of acrylamides with small amounts of lipids like cholesterol and glycosyl ceramides. The permeability of oral soft-palatal mucosa is about 4–4000 times more than the skin and the thickness of the palatal mucosa (158–224 μm) is intermediate between sublingual (111 μm) and buccal (594 μm) [35]. The mucosal pH of all oromucosal sites was ranged from 6.24 ± 0.05 to 7.36 ± 0.06 and mean pH values in the palate, buccal mucosa and the lingua were 6.8 ± 0.26, 7.34 ± 0.38, and 6.28 ± 0.36, respectively. The data obtained regarding different mucosal pH values may aid in exploring the optimal site for specific drug delivery since the palatal pH value (7.34 ± 0.38) is much more nearer to the pH value of blood as compared to the other oromucosal (buccal and sublingual) site and it also contains the lowest salivary secretion measured by the Periotron method [36] emphasizing a major role in maintenance of suitable microenvironment because the salivary system is a powerful buffering system [37] usually capable of maintaining a stable intraoral pH. The residual amounts of saliva on the oral mucosal tissues in the

morning and afternoon were almost identical. The residual salivary thickness ranged from a low of 0.16 ± 0.03 to a high of 0.58 ± 0.05 in the lingual region; corresponding values for buccal ranged between 0.44 ± 0.06 to 1.13 ± 0.05 and 0.03 ± 0.003 mm on the soft palate [35]. Fortunately the enzyme activity is relatively low in the palatal mucosa comparatively with other mucosal area of the oral cavity [24,31]. Therefore the palatal mucosa is a better site for oromucosal absorption to explore drug delivery in a controlled and systemic manner. 4. Mucus 4.1. Mucus physiology for the development of soft-palatal transmucosal drug delivery systems The thickness of the mucus is dependent on its location [45]. The thickness of the mucus blanket is determined by the balance between the rate of secretion and the rate of degradation and shedding. Toxic and irritating substances can greatly stimulate mucus secretion, increasing the thickness of the mucus blanket while efficiently and rapidly moving the irritants away from the epithelium [46–48]. Secreting new mucus is markedly more efficient than simply washing the surface, because rinsing the surface fails to refresh the unstirred layer adhering to the epithelium. In contrast, by continuously secreting new mucus, the unstirred layer is continuously and rapidly replaced. Thus pathogens and drug-delivery nanoparticles must migrate upstream to reach the epithelium. Even in an absorptive epithelium such as the small intestine, where water is moving inward and being filtered through the mucus coat, nanoparticles must advance through a blanket of mucus gel that is moving outward if they are to reach the epithelial surface [49,50]. The thickness varies greatly depending on digestive activity [51]. The mucus blanket is much thinner on most other surfaces and the barrier motions opposing NP delivery are primarily due to the rate of mucus clearance or shedding. A number of excellent reviews on the properties and function of mucus have been published [37–40]. Absorption of drugs through the palatal mucosa. Convection is also inhibited by formation of a lipid-rich mucin layer at the surface of the gel [41] which helps in securing the drug-delivery systems at this site with suitability. Since there is little fluid movement within the gel, solutes are thought to penetrate purely by diffusion. The physical size and arrangement of mucin fibers contribute significantly to the kinetics of the diffusion process [42–44]. 5. Prerequisites for successful transmucosal palatal drug-delivery system An ideal palatal drug-delivery system must meet several prerequisites to be successful. The first prerequisite to target a palatal site is that the behavior of the dosage form must be reproducible. The second prerequisite for a transmucosal drug-delivery system is that it should rapidly attach to the mucosal surface and maintain a strong interaction to prevent displacement. Spontaneous adhesion of the system at the target site is critical and can be achieved through mucoadhesion promoters that use tethered polymers [53]. Contact time should also be sufficiently long at the target site, normally longer than that needed for complete drug release. As hydrophilic mucoadhesive polymers tend to lose adhesiveness upon hydration, restricted hydration and formation of a rigid gel network would be desirable for prolonged adhesion [54]. A short retention time, in relation to the drug release rate, will compromise bioavailability. The third prerequisite for a successful and effective orotransmucosal drug-delivery system is that the mucoadhesion performance should not be impacted by surrounding environmental pH. Studies have shown that the bioadhesiveness of polymers with ionizable groups is affected by surrounding pH, as already mentioned that palatal pH is much more

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nearer to the pH value of blood as compared to the other oromucosal (buccal and sublingual) site which makes it a suitable platform for mucoadhesive drug-delivery systems. The fact that these mucoadhesive polymers are stable in the acidic environment of the stomach and at pH ≤ 7.4 makes them ideal for targeted delivery to the palate, stomach and small intestine [36,55,56]. Although the prerequisites described earlier apply to mucoadhesive dosage forms, the potential impact of formulation excipients on the adhesive behavior of mucoadhesive drug-delivery systems and mucosal surfaces also should be carefully taken into account. For example, excipients containing hydroxyl groups could form hydrogen bonds with the hydrophilic functional group of mucoadhesive polymers and, as a result, prevent their interaction with the mucosal surface [57]. In addition, hydrophobic lubricants (e.g., magnesium stearate and talc) tend to hinder the formation of strong bio-adhesive bonds and thus reduce the mucoadhesive strength significantly [58]. Therefore, in developing a mucoadhesive transmucosal dosage form, palatal mucosa serves as an excellent platform for delivery of variety of APIs by the help of a mucoadhesion concept. 6. Formulation factors for designing palatal drug-delivery systems (Table 1) [58–63] 6.1. Mucoadhesive agents Mucoadhesion may be defined as a state in which two materials, one of which is mucus or a mucous membrane, are held together for an extended period of time [64]. For drug-delivery purpose, the term mucoadhesion implies attachment of a drug carrier to a mucus coat at a specific biological location [65]. For mucoadhesion to occur, a succession of phenomenon, whose role depends on the nature of the mucoadhesive is required. The first stage involves an intimate contact between a mucoadhesive and a mucus/mucus membrane, either from a good wetting of the mucoadhesive surface, or from the swelling of the mucoadhesive. In the second stage, after contact is established, penetration of the mucoadhesive into the crevices of the tissue surface or interpenetration of the chains of the mucoadhesive with those of the mucus takes place. Low chemical bonds can than settle [66,67]. On a molecular level, mucoadhesion can be explained based on molecular interactions for mucoadhesion to occur, which, the attractive interaction should be larger than nonspecific repulsion. Different situations for mucoadhesion are possible depending on the dosage form [68]. In the case of dry or partially hydrated formulations, polymer hydration and swelling properties probably play the main role. The polymer hydration and consequently the mucus dehydration could cause an increase in mucous cohesive properties that promote mucoadhesion. Swelling should favour polymer chain flexibility and interpenetration between polymer and mucin chains. The spreading coefficient and the capability to form physical or chemical bonds with mucin (which results in a strengthening of the mucoadhesive interface) increase when a fully hydrated dosage form (e.g. aqueous gels or liquids) is considered [69,70].

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Table 2 List of most common classes used as oral mucosal permeation enhancers. Class of compounds

Examples

Fatty acids Bile salts

Lauric acid, oleic acid, etc. Sodium taurocholate, sodium taurodeoxycholate, sodium glycocholate, sodium glycodeoxycholate etc. Cetylpyridinium chloride, cetyltrimethylammonium bromide, sodium lauryl sulphate etc. Methoxysalicylate, methyloleate etc. Propylene glycols, glycerol etc. Polyoxyethylene, polysorbate etc.

Surfactants Esters Alcohols Polymers

6.2. Permeation enhancers [73–75] Permeation enhancers are also required when a drug has to reach the systemic circulation through the transmucosal route to exert its action. These must be non-irritant and have a reversible effect: the epithelium should recover its barrier properties after the drug has been absorbed. The most common classes of permeation enhancers used for the orotransmucosal route (buccal, sublingual etc.) can also use for the palatal formulations (Table 2). 6.2.1. Mechanisms of action of permeation enhancers Mechanisms by which penetration enhancers are thought to improve mucosal absorption are as follows [76,77]. Changing mucus rheology: Mucus forms a viscoelastic layer of varying thickness that affects drug absorption. Further, saliva covering the mucus layers also hinders the absorption. Some permeation enhancers act by reducing the viscosity of the mucus and saliva overcomes this barrier. Increasing the fluidity of lipid bilayer membrane: The most accepted mechanism of drug absorption through the mucosa is the intracellular route. Some enhancers disturb the intracellular lipid packing by interaction with either lipid or protein components. Acting on the components at tight junctions: Some enhancers act on desmosomes, a major component at the tight junctions thereby increasing drug absorption. By overcoming the enzymatic barrier: These act by inhibiting the various peptidases and proteases present within the mucosa, thereby overcoming the enzymatic barrier. In addition, changes in membrane fluidity also alter the enzymatic activity indirectly. Increasing the thermodynamic activity of drugs: Some enhancers increase the solubility of the drug thereby altering the partition coefficient. This leads to increased thermodynamic activity resulting in a better absorption. Surfactants such as anionic, cationic, nonionic and bile salts increase permeability of drugs by perturbation of intercellular lipids whereas chelators act by interfering with the calcium ions, fatty acids by increasing fluidity of phospholipids and positively charged polymers by ionic interaction with negative charge on the mucosal surface. 6.3. Various transmucosal dosage forms The development and use of fast-dissolving tablet dosage forms in clinical practice have shown that administration of drugs via the oral

Table 1 Various factors considered during the formulation of palatal drug delivery. Factors

Explanation

Size and concentration (low) of the drug molecule Mucosal contact time Degree of the drug's ionization and lipid solubility pH of the absorption site Venous drainage of the mucosal tissues Vehicle of drug delivery Mucoadhesive agents Permeation enhancers Enzyme inhibitors

Drugs with high concentration are problematic for this route of delivery because of the small surface area of soft palate Involuntary swallowing of the system may possible if the mucoadhesion concept of the dosage forms fails Drugs not absorbed by passive diffusion cannot be administered pH of the palatal mucosa 7.34 ± 0.38 (near to blood pH) Venous drainage is not subjected to hepatic first-pass metabolism Vehicles having unpleasant taste, odour may require suitable processant To maintain an intimate and prolonged contact of the formulation with the site To improve drug permeation across mucosa To eventually protect the drug from the degradation by means of mucosal enzymes

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mucosa was feasible. However, because of the aforementioned limitations of this type of dosage form, research in this area has focused on the development of alternative oral mucosal drug-delivery systems. Essentially, the research has revolved around developing strategies for prolonging the duration of the absorption process. This necessitates that the drug-delivery system must ensure that the drug is released in a controlled manner and that a sufficiently high drug concentration is delivered to the mucosal surface. Two approaches are theoretically possible to achieve these aims: 1. Immobilised drug-delivery systems—The design of “immobilised” drug-delivery systems that can be retained on the mucosal surface by the adhesive properties of the system itself [78,79]. 2. Non-attached drug-delivery systems—The development of “nonattached” or “mobile” drug-delivery systems that would be physically maintained within the oral cavity in contact with a mucosal surface by a conscious effort of the patient. Three types of non-attached drug-delivery systems can be indentified [80–88] (i) Fast dissolving tablet dosage forms (ii) Chewing gum formulations (iii) Microporous hollow fibers.

carefully removed and the soft palate mucosal membrane is isolated. The membranes are then placed and stored in ice-cold (4 °C) buffers (usually Krebs buffer) until mounted between side-by-side diffusion cells for the in vitro permeation experiments. The most significant questions concerning the use of animal tissues as in vitro models in this manner are the viability and the integrity of the dissected tissue. How well the dissected tissue is preserved is an important issue which will directly affect the results and conclusion of the studies. The most meaningful method to assess tissue viability is the actual permeation experiment itself, if the drug permeability does not change during the time course of the study under the specific experimental conditions of pH and temperature, then the tissue is considered viable. In vivo methods can also be use successfully for the palatal permeation study. 8. Advantages and limitations of orosoft-palatal platform drug-delivery system 8.1. Advantages

Advantages

Explanation

Self administration is possible

Accessibility of soft palate is very easy with the help of thumb Prevent mechanical irritation and local discomfort Due to hepatic first-pass metabolism Improved patient compliance By removing the delivery system

Smooth surface of the soft palate

6.3.1. Immobilised drug-delivery systems In recent years, oral mucosal drug-delivery systems that are designed to remain in contact with the oral mucosa for prolonged periods have been a subject of growing interest. Such systems offer advantages over non-attached systems. These include: (i) the immobilisation allows an intimate contact to be developed between the drug dosage form and the mucosa; (ii) a high drug concentration can be maintained at the absorptive surface for a prolonged period of time; (iii) the dosage form can be immobilised specifically at any part of the mucosa: buccal, labial, sublingual, palatal or gingival mucosa; and (iv) the system itself can protect the drug from environmental degradation. The design of immobilised oral mucosal drug-delivery systems is rather sophisticated because it is necessary to impart two specific properties to the delivery system (i): immobilisation and (ii) controlled-release behaviour. Such a combination of different properties within a single system can be achieved by the use of polymers. Immobilisation on the mucosa can be achieved by bioadhesion or mucoadhesion. Development of mucoadhesive drug-delivery systems intended for oral administration has been the subject of intensive research recently (Table 3). 7. Experimental methodology for palatal permeation studies [25,30,31] Before a palatal drug-delivery system can be formulated, palatal absorption/permeation studies must be conducted to determine the feasibility of this route of administration for the candidate drug. This study involves in vitro palatal permeation profile and absorption kinetics. Animals are sacrificed immediately before the start of an experiment. Palatal mucosa with underlying connective tissue is surgically removed from the oral cavity, the connective tissue is then

Table 3 Different types of immobilised drug delivery systems. Immobilised system

References

Powders Microspheres Tablets Hydrogels Film Patches

[91] [92] [94–108] [109–115] [16–117] [118–122]

Increased therapeutic value Simplified medication Drug input can be terminated at any point of time Low dose of drug provide equivalent therapeutics effect in comparison with orally administered drug.

Direct access to systemic circulation

8.2. Limitations 1. Drugs which are not absorbed by passive diffusion cannot be administered. 2. Unpleasant taste drug and odour cannot be administered. 3. Irritating drugs to the mucosa cannot be applied. 4. Drug unstable at oral pH cannot be administered. 5. Involuntary swallowing of dosage form is possible. 6. If the dosage form fails to adhere to the particular adhesive site the hazard of swallowing the delivery system is a concern. 7. Swallowing of saliva can potentially lead to loss of dissolved or suspended drug if the dosage form is not protected by impermeable membrane. 9. Possibilities for future research Colloidal dosage forms including liposomes, nanoparticles, and nanocapsules, are widely investigated as drug carriers for different purposes. However, only a few studies have been devoted to investigate their potential in oral mucosal drug delivery. Looking at the potential of colloidal systems as oral mucosal delivery systems, various major features are of interest. First, the very large specific surface of those systems is likely to favour a large contact between the dosage form and the oral mucosa. Second, immobilisation of particles on the mucosal surface can be obtained by adsorption or adhesion phenomena. As a result, a high drug concentration in front of the oral mucosal surface might be obtained. Third, controlled release of the drug is possible from such systems. Fourth entrapped drug can be protected from saliva, which is of importance for drugs subject to degradation in this fluid. Further studies are necessary for the assessment of the potential of colloidal systems in oral mucosal drug delivery. A few major limitations have been identified for these systems which would limit their application. Because of their limited loading capacities, they would be restricted to the delivery of potent

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drugs only. Despite their ability to interact strongly with mucosal surfaces, which favours drug delivery, interaction is not immediate and therefore the administration procedure should allow for a sufficient contact time between the colloidal particles and the mucosa. Vaccination against debilitating infectious diseases has proven remarkable in prevention of these diseases and has contributed significantly to an increase in life expectancy, especially in children, in many parts of the world. In order to have adequate mucosal protection, there are several factors that can influence the effectiveness of vaccines. The most critical factor in mucosal vaccine effectiveness is the route of administration and potential for the antigen to be processed by the antigen-presenting immune cells, such as macrophages and dendritic cells. Presently, most vaccines are administered via the parenteral route or via other invasive routes. Invasive mode of vaccine administration can trigger the systemic immune response, but may not essentially provide adequate mucosal immune protection. On the other hand, effective mucosal vaccines will not only elicit superior local immune protection, but also has been shown to trigger systemic response analogous to that of the parenterally-delivered vaccine. As such, it is critically important to examine the development of mucosal vaccination strategies that can effectively trigger systemic as well as mucosal immunity. Mucosal vaccines have currently been investigated using a broad spectrum of nanocarrier systems such as multiple emulsions, liposomes, polymeric nanoparticles, dendrimers, ISCOMs etc. More importantly, mucosal delivery of nanocarrier antigens and vaccines can trigger immunization at different mucosal barriers which is the body's imperative first line of defense in addition to systemic immune response. From the future perspective, development of vaccines using combined strategic approach like nanocarriers delivered by the orosoft-palatal mucosal route is a concern. 10. Conclusion The palatal mucosa offers several advantages for controlled drug delivery for extended periods of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract are avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Palatal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. References [1] M.J. Rathbone, J. Hadgraft, Absorption of drugs from the human oral cavity, Int. J. Pharm. 74 (1991) 9–24. [2] M.E. de Vries, H.E. Bodde, J.C. Verhoef, H.E. Junginger, Developments in buccal drug delivery, Crit. Rev. Ther. Drug Carrier Syst. 8 (1991) 271–303. [3] H.E. Bodde, M.E. De Vries, H.E. Junginger, Mucoadhesive polymers for the buccal delivery of peptides, structure–adhesiveness relationships, J. Control. Release 13 (1990) 225–231; G.R. Mettam, L.B. Adams, How to Prepare an Electronic Version of Your Article, in: B.S. Jones, R.Z. Smith (Eds.), Introduction to the Electronic Age, E-Publishing Inc., New York, 1999, pp. 281–304. [4] R.B. Gandhi, J.R. Robinson, Oral cavity as a site for bioadhesive drug delivery, Adv. Drug Deliv. Rev. 13 (1994) 43–74. [5] C.A. Squier, P.W. Wertz, Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in: RathboneM.J. (Ed.), Oral Mucosal Drug Delivery, Marcel Dekker, 1996, pp. 1–25. [6] A. Siegel, Permeability of the Oral Mucosa, in: J. Meyer, C.A. Squier, S.J. Gerson (Eds.), The Structure and the Function of Oral Mucosa, Pergamon Press, Oxford, 1984, pp. 95–108. [7] C.A. Squier, N.W. Johnson, R.M. Hopps, The Organization of Oral Mucosa, Human Oral Mucosa, Development, Structure and Function, Blackwell Scientific Publications, Oxford, 1976, pp. 7–15.

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