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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 Faculty of Pharmacy, Dehradoon Institute of Technology, Mussorie diversion Road, Bagawantpur, Makkawala, Dehradoon, Uttarakhand 248009, Indiab Faculty of Pharmacy and Medical Sciences, Al-Ahliyya, Amman University, P.O. Box-263, Amman 19328, Jordanc Faculty of Pharmacy, Integral University, Kursi Road, Lucknow, 226026, U.P., India
Rapid developments in the field of molecular biology and gene technology resulted in generation of manymacromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great numberpossessing 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 theirextensive pre-systemic metabolism, instability in acidic environment resulting into inadequate and erraticoral absorption. Parenteral route of administration is the only established route that overcomes all thesedrawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have leastpatient compliance, require repeated administration, in addition to the other hazardous effects associatedwith this route. Over the last few decades pharmaceutical scientists throughout the world are trying toexplore transdermal and transmucosal routes as an alternative to injections. Historically, oral transmucosaldrug delivery has received intensive interest since ancient times for the most widely utilized route ofadministration for the systemic delivery of drugs. In more recent years, better systemic bioavailability of manydrugs has been achieved by oromucosal route. Among the various transmucosal sites available, soft-palatalmucosa was also found to be the most convenient and easily accessible novel site for the delivery oftherapeutic agents for systemic delivery as retentive dosage forms, because it has abundant vascularizationand rapid cellular recovery time after exposure to stress. Smooth surface of the soft palate and its goodflexibility are prerequisites to prevent mechanical irritation and local discomfort. The objective of this reviewis to provide an update on the most promising advances in novel non-invasive soft-palatal route and theconceptual and technical approaches to the design and formulation of soft-palatal drug delivery systems. Inthis area, the development of mucoadhesive delivery systems appears to be the most promising strategy.
Oral drug delivery has, for decades, been the most widely utilizedroute of administration for the systemic delivery of drugs. The lack ofefficacy of certain drugs due to decreased bioavailability, unpredict-able and erratic absorption, GI intolerance, or pre-systemic elimina-tion has prompted the examination of other potential route foradministration. Moreover, the recent development of a large numberof drugs has intensified investigation of mucosal delivery of drugs.Transmucosal routes of drug delivery (i.e., the mucosal linings of thenasal, rectal, vaginal, ocular, and oral cavity) offer distinct advantagesover peroral administration for systemic drug delivery. Theseadvantages include possible bypass of first-pass effect, avoidance ofpre-systemic elimination within the GI tract, and, depending on theparticular drug, a better enzymatic flora for drug absorption. The oralcavity is highly acceptable by patients, the mucosa is relativelypermeable with a rich blood supply, it is robust and shows shortrecovery times after stress or damage [1–3], and the virtual lack ofLangerhans cells [4] makes the oral mucosa tolerant to potentialallergens. The oral mucosa can be categorized into sublingual,gingival, buccal and soft-palatal mucosa through which systemictransmucosal drug delivery can be achieved. Conventional buccal andsublingual dosage forms are typically short acting because of limitedcontact time between the dosage form and the oral mucosa. Sinceadministration of drugs through these routes interferes with eating,drinking and talking therefore, these routes are generally consideredunsuitable for prolonged administration, whereas soft-palatal med-ication delivers steady infusion of drugs over an extended period oftime, because of the function of the soft palate to cover the glottiswhile swallowing, it is more fitted for sustained and controlled drugdelivery also due to the presence of immobile mucosa and lack ofpermeability in compositionwith sublingual mucosa. Even though thesublingual mucosa is relatively more permeable than the buccalmucosa but it is not suitable for an oral transmucosal delivery systembecause it lacks an expanse of smooth muscle and is constantlywashed by a considerable amount of saliva making it difficult fordevice placement. Because of high permeability and rich blood supply,the sublingual route is capable of producing a rapid onset of actionmaking it appropriate for drugs with short delivery period require-ments with infrequent dosing regimen. While buccal drug deliveryhas low flux due to less permeability which results in low drugbioavailability, other drawbacks include salivary dilution of the drugand inability to localize the drug within a specific site of the oralcavity. Therefore soft-palatal drug delivery is a feasible approach forcorrecting salivary dilution and achieving absorption site localizationto 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 beenextensively reviewed in several publications [5]. Nevertheless, a briefoverview in this chapter is essential. The oral mucosa is composed of
an outermost layer of stratified squamous epithelium, intermediatelayer, lamina propria followed by the submucosa as the innermostlayer [6]. The structure and biochemistry of the oral epithelium areillustrated by Squier et al. [7,8] and its biochemistry by Gerson et al.[9]. Oral epithelium consists of a stratified squamous epithelium. Oralmucosa can be categorized into sublingual, gingival, buccal and palatalmucosa through which oral transmucosal drug delivery can beachieved. A gel-like secretion known as mucus, which containsmostly water-insoluble glycoproteins, covers the entire oral cavity.Mucus is bound to the apical cell surface and acts as a protective layerto the cells below [10]. It is also a viscoelastic hydrogel, and primarilyconsists of 1–5% of the above-mentioned water-insoluble glycopro-teins, 95–99% water, and several other components in smallquantities, such as proteins, enzymes, electrolytes, and nucleic acids.This composition can vary based on the origin of the mucus secretionin the body [11,12].
2.2. Permeability
The oral mucosa in general is somewhat leaky epithelia interme-diate between that of the epidermis and intestinal mucosa and thereare considerable differences in permeability between differentregions of the oral cavity because of the diverse structures andfunctions of the different oral mucosa. The permeability coefficient ofa drug is a measure of the ease with which the drug can permeate amembrane. The permeability coefficient is a function of the mem-brane thickness (i.e., inverse to its thickness) degree of keratinizationof these tissues, and the physicochemical properties of the drug (e.g.,molecular weight, size, and lipophilicity). Drug permeability appearsto be highest in the sublingual area and lowest at the gingival site [13].It is currently believed that the permeability barrier in the oral mucosais a result of intercellular material derived from the so-calledmembrane coating granules (MCG) [4,14–16].
2.3. Various transmucosal routes of drug delivery
Drugs for systemic medication are administered traditionally androutinely by oral and by parenteral routes. Although generallyconvenient, both routes have a number of disadvantages, especiallyfor the delivery of peptides and proteins, a class of drug that has beenrapidly emerging over the last decades [17]. Orally administereddrugs are exposed to harsh environment of the gastrointestinal tract,potential chemical and enzymatic degradation [18]. After gastroin-testinal absorption the drug has to pass the liver, where, dependent onthe nature of the drug, extensive first-pass metabolism can take placewith subsequent rapid clearance from the blood stream [19]. Lowpermeability across the gastrointestinal mucosa is also often encoun-tered formacromolecular drugs [20]. Parenteral administration avoidsdrug degradation in the gastrointestinal tract and hepatic first-passclearance but due to pain or discomfort during injection, patientcompliance is poor, particularly if multiple daily injections arerequired as e.g. in the insulin therapy [21,22]. Injection related sideeffects like tissue necrosis and thrombophlebitis also lead to lowpatient acceptability. In addition, administration by injection requires
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trained personnel which add to the relatively high costs of parenteralmedication.
3. Soft palate
3.1. Environmental and histo-morphological features of the soft palate
The soft palate is a mobile flap suspended from the posteriorborder of the hard palate, sloping down the back between the oral andnasal parts of the pharynx. The soft palate (or velum, or muscularpalate) is the soft tissue constituting the back of the roof of the mouth[23]. Velum route prevents mechanical irritation and local discomfortdue to its smooth surface and good flexibility. The soft palate is a thickfold of mucosa enclosing an aponeurosis, muscular tissue, vesselnerves, lymphoid tissue, mucous glands and two small pits, the foveapalatine, one on each side of themidline is present. The anterior (oral)concave surface of the soft palate makes it suitable for selfadministration of drug delivery system with the help of thumb[24,25]. The mucousmembrane on the oral surface of the soft palate ishighly vascularized. The papillae of the connective tissue are few andshort, the stratified squamous epithelium is nonkeratinized, and thelamina propria shows distinctive layer of elastic fibers separating itfrom the submucous [26–29]. Typical oral mucosa is continuousaround the free border of the soft palate for a variable distance and isthen replaced by nasal mucosa with its pseudo-stratified, ciliatedcolumnar epithelium [30,31]. Oral side epithelium of the soft palate iscovered consistently and uniformly with nonkeratinized stratifiedsquamous epithelium of about 20–30 cell layers thick and thereforeapparently well suited to withstand abrasive forces. The oral aspectsof the palate, especially the anterior half are well endowed withseromucous glands, and to a lesser degree with fatty tissues. Theglands function to aid in moisturizing the palatal cavity to facilitatethe adhesion by the secretions of saliva (750 ml) from these glands[32]. These glandular secretions may serve as a glandular lubricant toreduce frictional forces. The arterial supply of the soft palate is usuallyderived from the ascending palatine branch of the facial artery and thegreater palatine branch of the maxillary artery. The blood supply bythe facial artery to the palatal region is 0.89 ml/min/100 cm2. Theveins of the soft palate usually drain to the pterygoid venous plexus.The secretomotor supply to most of the mucosa of the soft palatetravels 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, whichplays a major role in cell-to-cell adhesion and oral lubrication, as wellas mucoadhesion of mucoadhesive drug delivery systems [34]. Thesoft-palatal mucosa composed of stratum squamous epithelial cells,with thickness of about 100–200 μm consists of a nonkeratinizedepithelial tissue with the absence of acrylamides with small amountsof lipids like cholesterol and glycosyl ceramides. The permeability oforal soft-palatal mucosa is about 4–4000 timesmore than the skin andthe thickness of the palatal mucosa (158–224 μm) is intermediatebetween sublingual (111 μm) and buccal (594 μm) [35]. The mucosalpH of all oromucosal sites was ranged from 6.24±0.05 to 7.36±0.06and mean pH values in the palate, buccal mucosa and the lingua were6.8±0.26, 7.34±0.38, and 6.28±0.36, respectively. The dataobtained regarding different mucosal pH values may aid in exploringthe 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 ascompared to the other oromucosal (buccal and sublingual) site and italso contains the lowest salivary secretion measured by the Periotronmethod [36] emphasizing a major role in maintenance of suitablemicroenvironment because the salivary system is a powerfulbuffering system [37] usually capable of maintaining a stable intraoralpH. The residual amounts of saliva on the oral mucosal tissues in the
morning and afternoon were almost identical. The residual salivarythickness ranged from a low of 0.16±0.03 to a high of 0.58±0.05 inthe lingual region; corresponding values for buccal ranged between0.44±0.06 to 1.13±0.05 and 0.03±0.003 mmon the soft palate [35].Fortunately the enzyme activity is relatively low in the palatal mucosacomparatively with other mucosal area of the oral cavity [24,31].Therefore the palatal mucosa is a better site for oromucosalabsorption to explore drug delivery in a controlled and systemicmanner.
4. Mucus
4.1. Mucus physiology for the development of soft-palatal transmucosaldrug delivery systems
The thickness of the mucus is dependent on its location [45]. Thethickness of the mucus blanket is determined by the balance betweenthe rate of secretion and the rate of degradation and shedding. Toxicand irritating substances can greatly stimulate mucus secretion,increasing the thickness of the mucus blanket while efficiently andrapidly moving the irritants away from the epithelium [46–48].Secreting newmucus is markedly more efficient than simply washingthe surface, because rinsing the surface fails to refresh the unstirredlayer adhering to the epithelium. In contrast, by continuouslysecreting new mucus, the unstirred layer is continuously and rapidlyreplaced. Thus pathogens and drug-delivery nanoparticles mustmigrate upstream to reach the epithelium. Even in an absorptiveepithelium such as the small intestine, where water is moving inwardand being filtered through the mucus coat, nanoparticles mustadvance through a blanket of mucus gel that is moving outward ifthey are to reach the epithelial surface [49,50]. The thickness variesgreatly depending on digestive activity [51]. The mucus blanket ismuch thinner on most other surfaces and the barrier motionsopposing NP delivery are primarily due to the rate of mucus clearanceor shedding. A number of excellent reviews on the properties andfunction of mucus have been published [37–40]. Absorption of drugsthrough the palatal mucosa. Convection is also inhibited by formationof a lipid-rich mucin layer at the surface of the gel [41] which helps insecuring the drug-delivery systems at this site with suitability. Sincethere is little fluid movement within the gel, solutes are thought topenetrate purely by diffusion. The physical size and arrangement ofmucin fibers contribute significantly to the kinetics of the diffusionprocess [42–44].
5. Prerequisites for successful transmucosal palatal drug-deliverysystem
An ideal palatal drug-delivery system must meet several pre-requisites to be successful. The first prerequisite to target a palatal siteis that the behavior of the dosage form must be reproducible. Thesecond prerequisite for a transmucosal drug-delivery system is that itshould rapidly attach to the mucosal surface and maintain a stronginteraction to prevent displacement. Spontaneous adhesion of thesystem at the target site is critical and can be achieved throughmucoadhesion promoters that use tethered polymers [53]. Contacttime should also be sufficiently long at the target site, normally longerthan that needed for complete drug release. As hydrophilic mucoad-hesive polymers tend to lose adhesiveness upon hydration, restrictedhydration and formation of a rigid gel network would be desirable forprolonged adhesion [54]. A short retention time, in relation to thedrug release rate, will compromise bioavailability. The third prereq-uisite for a successful and effective orotransmucosal drug-deliverysystem is that themucoadhesion performance should not be impactedby surrounding environmental pH. Studies have shown that the bio-adhesiveness of polymers with ionizable groups is affected bysurrounding 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 formucoadhesive drug-delivery systems. The fact that these mucoadhe-sive polymers are stable in the acidic environment of the stomach andat pH≤7.4 makes them ideal for targeted delivery to the palate,stomach and small intestine [36,55,56]. Although the prerequisitesdescribed earlier apply to mucoadhesive dosage forms, the potentialimpact of formulation excipients on the adhesive behavior ofmucoadhesive drug-delivery systems and mucosal surfaces alsoshould be carefully taken into account. For example, excipientscontaining hydroxyl groups could form hydrogen bonds with thehydrophilic functional group of mucoadhesive polymers and, as aresult, prevent their interaction with the mucosal surface [57]. Inaddition, hydrophobic lubricants (e.g., magnesium stearate and talc)tend to hinder the formation of strong bio-adhesive bonds and thusreduce the mucoadhesive strength significantly [58]. Therefore, indeveloping a mucoadhesive transmucosal dosage form, palatalmucosa serves as an excellent platform for delivery of variety ofAPIs 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 foran extended period of time [64]. For drug-delivery purpose, the termmucoadhesion implies attachment of a drug carrier to a mucus coat ata specific biological location [65]. For mucoadhesion to occur, asuccession of phenomenon, whose role depends on the nature of themucoadhesive is required. The first stage involves an intimate contactbetween a mucoadhesive and a mucus/mucus membrane, either froma good wetting of the mucoadhesive surface, or from the swelling ofthe mucoadhesive. In the second stage, after contact is established,penetration of themucoadhesive into the crevices of the tissue surfaceor interpenetration of the chains of the mucoadhesive with those ofthemucus takes place. Low chemical bonds can than settle [66,67]. Onamolecular level, mucoadhesion can be explained based onmolecularinteractions for mucoadhesion to occur, which, the attractiveinteraction should be larger than nonspecific repulsion. Differentsituations for mucoadhesion are possible depending on the dosageform [68]. In the case of dry or partially hydrated formulations,polymer hydration and swelling properties probably play the mainrole. The polymer hydration and consequently themucus dehydrationcould cause an increase in mucous cohesive properties that promotemucoadhesion. Swelling should favour polymer chain flexibility andinterpenetration between polymer and mucin chains. The spreadingcoefficient and the capability to form physical or chemical bonds withmucin (which results in a strengthening of the mucoadhesiveinterface) increase when a fully hydrated dosage form (e.g. aqueousgels or liquids) is considered [69,70].
Table 1Various factors considered during the formulation of palatal drug delivery.
Factors Explanation
Size and concentration (low) of the drug molecule Drugs with high concentration areMucosal contact time Involuntary swallowing of the systeDegree of the drug's ionization and lipid solubility Drugs not absorbed by passive diffupH of the absorption site pH of the palatal mucosa 7.34±0.3Venous drainage of the mucosal tissues Venous drainage is not subjected toVehicle of drug delivery Vehicles having unpleasant taste, oMucoadhesive agents To maintain an intimate and prolonPermeation enhancers To improve drug permeation acrossEnzyme inhibitors To eventually protect the drug from
6.2. Permeation enhancers [73–75]
Permeation enhancers are also required when a drug has to reachthe systemic circulation through the transmucosal route to exert itsaction. These must be non-irritant and have a reversible effect: theepithelium should recover its barrier properties after the drug hasbeen absorbed. The most common classes of permeation enhancersused for the orotransmucosal route (buccal, sublingual etc.) can alsouse for the palatal formulations (Table 2).
6.2.1. Mechanisms of action of permeation enhancersMechanisms by which penetration enhancers are thought to
improve mucosal absorption are as follows [76,77]. Changing mucusrheology: Mucus forms a viscoelastic layer of varying thickness thataffects drug absorption. Further, saliva covering the mucus layers alsohinders the absorption. Some permeation enhancers act by reducingthe viscosity of themucus and saliva overcomes this barrier. Increasingthe fluidity of lipid bilayer membrane: The most accepted mechanismof drug absorption through themucosa is the intracellular route. Someenhancers disturb the intracellular lipid packing by interaction witheither lipid or protein components. Acting on the components at tightjunctions: Some enhancers act on desmosomes, a major component atthe tight junctions thereby increasing drug absorption. By overcomingthe enzymatic barrier: These act by inhibiting the various peptidasesand proteases present within the mucosa, thereby overcoming theenzymatic barrier. In addition, changes inmembrane fluidity also alterthe enzymatic activity indirectly. Increasing the thermodynamicactivity of drugs: Some enhancers increase the solubility of the drugthereby altering the partition coefficient. This leads to increasedthermodynamic activity resulting in a better absorption. Surfactantssuch as anionic, cationic, nonionic and bile salts increase permeabilityof drugs by perturbation of intercellular lipidswhereas chelators act byinterfering with the calcium ions, fatty acids by increasing fluidity ofphospholipids and positively charged polymers by ionic interactionwith negative charge on the mucosal surface.
6.3. Various transmucosal dosage forms
The development and use of fast-dissolving tablet dosage forms inclinical practice have shown that administration of drugs via the oral
problematic for this route of delivery because of the small surface area of soft palatem may possible if the mucoadhesion concept of the dosage forms failssion cannot be administered8 (near to blood pH)hepatic first-pass metabolism
dour may require suitable processantged contact of the formulation with the sitemucosathe degradation by means of mucosal enzymes
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mucosa was feasible. However, because of the aforementionedlimitations of this type of dosage form, research in this area hasfocused on the development of alternative oral mucosal drug-deliverysystems. Essentially, the research has revolved around developingstrategies for prolonging the duration of the absorption process. Thisnecessitates that the drug-delivery system must ensure that the drugis released in a controlled manner and that a sufficiently high drugconcentration is delivered to themucosal surface. Two approaches aretheoretically possible to achieve these aims:
1. Immobilised drug-delivery systems—The design of “immobilised”drug-delivery systems that can be retained on the mucosal surfaceby the adhesive properties of the system itself [78,79].
2. Non-attached drug-delivery systems—The development of “non-attached” or “mobile” drug-delivery systems that would bephysically maintained within the oral cavity in contact with amucosal surface by a conscious effort of the patient.
Three types of non-attached drug-delivery systems can beindentified [80–88]
6.3.1. Immobilised drug-delivery systemsIn recent years, oral mucosal drug-delivery systems that are
designed to remain in contact with the oral mucosa for prolongedperiods have been a subject of growing interest. Such systems offeradvantages over non-attached systems. These include: (i) theimmobilisation allows an intimate contact to be developed betweenthe drug dosage form and the mucosa; (ii) a high drug concentrationcan be maintained at the absorptive surface for a prolonged period oftime; (iii) the dosage form can be immobilised specifically at any partof the mucosa: buccal, labial, sublingual, palatal or gingival mucosa;and (iv) the system itself can protect the drug from environmentaldegradation. The design of immobilised oral mucosal drug-deliverysystems is rather sophisticated because it is necessary to impart twospecific properties to the delivery system (i): immobilisation and(ii) controlled-release behaviour. Such a combination of differentproperties within a single system can be achieved by the use ofpolymers. Immobilisation on the mucosa can be achieved by bioadhe-sion or mucoadhesion. Development of mucoadhesive drug-deliverysystems intended for oral administration has been the subject ofintensive research recently (Table 3).
7. Experimental methodology for palatal permeation studies[25,30,31]
Before a palatal drug-delivery system can be formulated, palatalabsorption/permeation studies must be conducted to determine thefeasibility of this route of administration for the candidate drug. Thisstudy involves in vitro palatal permeation profile and absorptionkinetics. Animals are sacrificed immediately before the start of anexperiment. Palatal mucosa with underlying connective tissue issurgically removed from the oral cavity, the connective tissue is then
Table 3Different types of immobilised drug delivery systems.
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 diffusioncells for the in vitro permeation experiments. The most significantquestions concerning the use of animal tissues as in vitro models inthis manner are the viability and the integrity of the dissected tissue.Howwell the dissected tissue is preserved is an important issuewhichwill directly affect the results and conclusion of the studies. The mostmeaningful method to assess tissue viability is the actual permeationexperiment itself, if the drug permeability does not change during thetime course of the study under the specific experimental conditions ofpH and temperature, then the tissue is considered viable. In vivomethods can also be use successfully for the palatal permeation study.
8. Advantages and limitations of orosoft-palatal platformdrug-delivery system
8.1. Advantages
Advantages
Explanation
Self administration is possible
Accessibility of soft palate is veryeasy with the help of thumb
Smooth surface of the soft palate
Prevent mechanical irritation andlocal discomfort
Increased therapeutic value
Due to hepatic first-pass metabolism Simplified medication Improved patient compliance Drug input can be terminated at anypoint of time
By removing the delivery system
Low dose of drug provide equivalenttherapeutics effect in comparisonwith orally administered drug.
Direct access to systemic circulation
8.2. Limitations
1. Drugs which are not absorbed by passive diffusion cannot beadministered.
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 imperme-able membrane.
9. Possibilities for future research
Colloidal dosage forms including liposomes, nanoparticles, andnanocapsules, are widely investigated as drug carriers for differentpurposes. However, only a few studies have been devoted toinvestigate their potential in oral mucosal drug delivery. Looking atthe potential of colloidal systems as oral mucosal delivery systems,various major features are of interest. First, the very large specificsurface of those systems is likely to favour a large contact between thedosage form and the oral mucosa. Second, immobilisation of particleson the mucosal surface can be obtained by adsorption or adhesionphenomena. As a result, a high drug concentration in front of the oralmucosal surface might be obtained. Third, controlled release of thedrug is possible from such systems. Fourth entrapped drug can beprotected from saliva, which is of importance for drugs subject todegradation in this fluid. Further studies are necessary for theassessment of the potential of colloidal systems in oral mucosaldrug delivery. A few major limitations have been identified for thesesystems which would limit their application. Because of their limitedloading capacities, they would be restricted to the delivery of potent
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drugs only. Despite their ability to interact strongly with mucosalsurfaces, which favours drug delivery, interaction is not immediateand therefore the administration procedure should allow for asufficient contact time between the colloidal particles and themucosa.Vaccination against debilitating infectious diseases has provenremarkable in prevention of these diseases and has contributedsignificantly to an increase in life expectancy, especially in children, inmany parts of the world. In order to have adequate mucosalprotection, there are several factors that can influence the effective-ness of vaccines. The most critical factor in mucosal vaccineeffectiveness is the route of administration and potential for theantigen to be processed by the antigen-presenting immune cells, suchas macrophages and dendritic cells. Presently, most vaccines areadministered via the parenteral route or via other invasive routes.Invasive mode of vaccine administration can trigger the systemicimmune response, but may not essentially provide adequate mucosalimmune protection. On the other hand, effective mucosal vaccineswill not only elicit superior local immune protection, but also has beenshown to trigger systemic response analogous to that of theparenterally-delivered vaccine. As such, it is critically important toexamine the development of mucosal vaccination strategies that caneffectively trigger systemic as well as mucosal immunity. Mucosalvaccines have currently been investigated using a broad spectrum ofnanocarrier systems such as multiple emulsions, liposomes, polymer-ic nanoparticles, dendrimers, ISCOMs etc. More importantly, mucosaldelivery of nanocarrier antigens and vaccines can trigger immuniza-tion at different mucosal barriers which is the body's imperative firstline of defense in addition to systemic immune response. From thefuture perspective, development of vaccines using combined strategicapproach like nanocarriers delivered by the orosoft-palatal mucosalroute is a concern.
10. Conclusion
The palatal mucosa offers several advantages for controlled drugdelivery for extended periods of time. The mucosa is well suppliedwith both vascular and lymphatic drainage and first-pass metabolismin the liver and pre-systemic elimination in the gastrointestinal tractare avoided. The area is well suited for a retentive device and appearsto be acceptable to the patient. With the right dosage form design andformulation, the permeability and the local environment of themucosa can be controlled and manipulated in order to accommodatedrug permeation. Palatal drug delivery is a promising area forcontinued research with the aim of systemic delivery of orallyinefficient drugs as well as a feasible and attractive alternative fornon-invasive delivery of potent peptide and protein drug molecules.
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