Journal of Controlled Release 153 (2011) 106116

Contents lists available at ScienceDirect

Journal of Controlled Release

j ourna l homepage: www.e lsev ie r.com/ locate / jconre lReview

Advances in oral transmucosal drug delivery

Viralkumar F. Patel a, Fang Liu a, Marc B. Brown a,b,a School of Pharmacy, University of Hertfordshire, Hatfield, AL10 9AB, UKb MedPharm Limited, Guilford, Surrey, GU2 7YN, UK Corresponding author at: MedPharm Ltd, R&D CentrOccam Road, Surrey Research Park, Guildford, GU2 7YNfax: +44 447742.

E-mail address: marc.brown@medpharm.co.uk (M.B

0168-3659/$ see front matter 2011 Elsevier B.V. Adoi:10.1016/j.jconrel.2011.01.027a b s t r a c ta r t i c l e i n f oArticle history:Received 27 September 2010Accepted 24 January 2011Available online 4 February 2011

Keywords:TransmucosalPermeation pathwaysBuccal absorptionMucoadhesiveDosage formsThe successful delivery of drugs across the oral mucosa represents a continuing challenge, as well as a greatopportunity. Oral transmucosal delivery, especially buccal and sublingual delivery, has progressed far beyondthe use of traditional dosage forms with novel approaches emerging continuously. This review highlights thephysiological challenges as well as the advances and opportunities for buccal/sublingual drug delivery.Particular attention is given to new approaches which can extend dosage form retention time or can beengineered to deliver complex molecules such as proteins and peptides. The review will also discuss thephysiology and local environment of the oral cavity in vivo and how this relates to the performance oftransmucosal delivery systems.e, Unit 3 / Chancellor Court, 50, UK. Tel.: +44 1483501480;

. Brown).

ll rights reserved. 2011 Elsevier B.V. All rights reserved.Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062. Overview of the oral mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1073. Physiological barriers for oral transmucosal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1074. Physiological opportunities for oral transmucosal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085. Oral transmucosal drug delivery technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

5.1. Mucoadhesive systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095.1.1. Theories of mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105.1.2. Polymers for mucoadhesive systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

5.2. Dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115.2.1. Liquid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115.2.2. Semisolid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115.2.3. Solid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125.2.4. Sprays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151. Introduction

The cost involved both in terms of money and time in thedevelopment of a single new chemical entity has made it mandatoryfor pharmaceutical companies to reconsider delivery strategies toimprove the efficacy of drugs that have already been approved.However, despite the tremendous advances in drug delivery, the oralroute remains the preferred route for the administration of therapeuticagents due to low cost, ease of administration and high level of patientcompliance. However, significant barriers are imposed on the per oraladministration of drugs, such as hepatic first pass metabolism and drugdegradation within the gastrointestinal (GI) tract prohibiting the oraladministration of certain classes of drugs especially biologics e.g.peptides and proteins. Consequently, other absorptive mucosae arebeing considered as potential sites for drug administration including themucosal linings of thenasal, rectal, vaginal, ocular, and oral cavity. Thesetransmucosal routes of drug delivery offer distinct advantages over peroral administration for systemic drug delivery such as the possiblebypass of the first pass effect and avoidance of presystemic elimination

http://dx.doi.org/10.1016/j.jconrel.2011.01.027mailto:marc.brown@medpharm.co.ukhttp://dx.doi.org/10.1016/j.jconrel.2011.01.027http://www.sciencedirect.com/science/journal/01683659

107V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116within theGI tract [1]. Amongst these, delivery of drugs to theoral cavityhas attracted particular attention due to its potential for high patientcompliance and unique physiological features. Within the oral mucosalcavity, the delivery of drugs is classified into two categories: (i) localdelivery and (ii) systemic delivery either via the buccal or sublingualmucosa. This review examines the physiological considerations of theoral cavity in light of systemic drug delivery and provides an insight intothe advances in oral transmucosal delivery systems.Fig. 2. Schematic diagram of buccal mucosa [8].2. Overview of the oral mucosa

The anatomical and physiological properties of the oral mucosahave been extensively reviewed by several authors [13]. The oralcavity comprises the lips, cheek, tongue, hard palate, soft palate andfloor of the mouth (Fig. 1). The lining of the oral cavity is referred toas the oral mucosa, and includes the buccal, sublingual, gingival,palatal and labial mucosa. The buccal, sublingual and the mucosaltissues at the ventral surface of the tongue account for about 60% ofthe oral mucosal surface area. The top quarter to one-third of the oralmucosa is made up of closely compacted epithelial cells (Fig. 2). Theprimary function of the oral epithelium is to protect the underlyingtissue against potential harmful agents in the oral environment andfrom fluid loss [4]. Beneath the epithelium are the basementmembrane, lamina propia and submucosa. The oral mucosa alsocontains many sensory receptors including the taste receptors of thetongue.

Three types of oral mucosa can be found in the oral cavity; theliningmucosa is found in the outer oral vestibule (the buccalmucosa)and the sublingual region (floor of the mouth) (Fig. 1). Thespecialized mucosa is found on the dorsal surface of tongue, whilethe masticatory mucosa is found on the hard palate (the uppersurface of the mouth) and the gingiva (gums) [5]. The lining mucosacomprises approximately 60%, the masticatory mucosa approxi-mately 25%, and the specialized mucosa approximately 15% of thetotal surface area of the oral mucosal lining in an adult human. Themasticatory mucosa is located in the regions particularly susceptibleto the stress and strains resulting from masticatory activity. Thesuperficial cells of the masticatory mucosa are keratinized, and athick lamina propia tightly binds the mucosa to the underlyingperiosteum. Lining mucosa on the other hand is not nearly as subjectto masticatory loads and consequently, has a non-keratinizedepithelium, which sits on a thin and elastic lamina propia and asubmucosa. The mucosa of the dorsum of the tongue is a specializedgustatorymucosa, which haswell papillated surfaces; which are bothkeratinized and some non-keratinized [6].Fig. 1. Schematic representation of the different linings of mucosa in mouth [7].3. Physiological barriers for oral transmucosal drug delivery

The environment of the oral cavity presents some significantchallenges for systemic drug delivery. The drug needs to be releasedfrom the formulation to the delivery site (e.g. buccal or sublingual area)and pass through the mucosal layers to enter the systemic circulation.Certain physiological aspects of the oral cavity play significant roles inthis process, including pH, fluid volume, enzyme activity and thepermeability of oral mucosa. For drug delivery systems designed forextended release in the oral cavity (e.g. mucodhesive systems), thestructure and turnover of the mucosal surface is also a determinant ofperformance. Table 1 provides a comparison of the physiologicalcharacteristics of the buccal mucosa with the mucosa of the GI tract.

The principle physiological environment of the oral cavity, in termsof pH,fluid volumeand composition, is shapedby the secretion of saliva.Saliva is secreted by three major salivary glands (parotid, submaxillaryand sublingual) and minor salivary or buccal glands situated in orimmediately below the mucosa. The parotid and submaxillary glandsproduce watery secretion, whereas the sublingual glands producemainly viscous saliva with limited enzymatic activity. The mainfunctions of saliva are to lubricate the oral cavity, facilitate swallowingand to prevent demineralization of the teeth. It also allows carbohydratedigestion and regulates oral microbial flora by maintaining the oral pHand enzyme activity [13,14]. The daily total salivary secretion volumeis between 0.5 and 2.0 l. However, the volume of saliva constantlypresent in themouth is around 1.1 ml, thus providing a relatively lowfluid volume available for drug release from delivery systemscompared to the GI tract. Compared to the GI fluid, saliva is relativelyless viscous containing 1% organic and inorganic materials. Inaddition, saliva is a weak buffer with a pH around 5.57.0. Ultimatelythe pH and salivary compositions are dependent on the flow rate ofsaliva which in turn depends upon three factors: the time of day, thetype of stimulus and the degree of stimulation [15]. For example, athigh flow rates, the sodium and bicarbonate concentrations increaseleading to an increase in the pH.

Saliva provides a water rich environment of the oral cavity whichcan be favorable for drug release from delivery systems especiallythose based on hydrophilic polymers. However, saliva flow decidesthe time span of the released drug at the delivery site. This flow canlead to premature swallowing of the drug before effective absorptionoccurs through the oral mucosa and is a well accepted concept knownas saliva wash out. However, there is little research on to whatextent this phenomenon affects the efficiency of oral transmucosal

image of Fig.2

Table 1Comparison of different mucosa [912].

Absorptivesite

EstimatedSurface area

Percenttotalsurfacearea

LocalpH

Meanfluidvolume(ml)

Relativeenzymeactivity

Relativedrugabsorptioncapacity

Oral cavity 100 cm2

(0.01 m2)0.01 5.87.6 0.9 Moderate Moderate

Stomach 0.10.2 m2 0.20 1.03.0 118 High ModerateSmallintestine

100 m2 98.76 5.07.0 212 High High

Largeintestine

0.51.0 m2 0.99 6.07.4 187 Moderate Low

Rectum 200400 cm2

(0.04 m2)0.04 7.07.4 Low Low

108 V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116delivery from different drug delivery systems and thus furtherresearch needs to be conducted to better understand this effect.

Drug permeability through the oral (e.g. buccal/sublingual)mucosa represents another major physiological barrier for oraltransmucosal drug delivery. The oral mucosal thickness variesdepending on the site as does the composition of the epithelium.The characteristics of the different regions of interest in the oral cavityare shown in Table 2. Themucosa of areas subject tomechanical stress(the gingiva and hard palate) is keratinized similar to the epidermis.Themucosa of the soft palate, sublingual, and buccal regions, however,are not keratinized. The keratinized epithelia contain neutral lipids likeceramides and acylceramides which have been associated with thebarrier function. These epithelia are relatively impermeable to water.In contrast, non-keratinized epithelia, such as the floor of the mouthand the buccal epithelia do not contain acylceramides and only havesmall amounts of ceramides [16]. They also contain small amounts ofneutral but polar lipids, mainly cholesterol sulfate and glucosylceramides. These epithelia have been found to be considerably morepermeable to water than keratinized epithelia [17,18].

Within the oral mucosa, the main penetration barrier exists in theoutermost quarter to one third of the epithelium [23,24]. The relativeimpermeability of the oralmucosa is predominantly due to intercellularmaterials derived from the so-called membrane coating granules Q(MCGs) [2]. MCGs are spherical or oval organelles that are 100300 nmin diameter and found in both keratinized andnon-keratinized epithelia[25]. They are found near the upper, distal, or superficial border of thecells, although a few occur near the opposite border [25]. Severalhypotheses have been suggested to describe the functions of MCGs,including membrane thickening, cell adhesion, production of a cellsurface coat, cell desquamation and as a permeability barrier. Hayward[25] summarized that the MCGs discharge their contents into theintercellular space to ensure epithelial cohesion in the superficial layers,and this discharge forms a barrier to the permeability of variouscompounds. Cultured oral epithelium devoid of MCGs has been shownto be permeable to compounds that do not typically penetrate the oralepithelium[26]. In addition, permeation studies conductedusing tracersof different sizes have demonstrated that these tracermolecules did notpenetrate any further than the top13 cell layers.When the same tracermolecules were introduced sub-epithelially, they penetrated throughTable 2Characteristics of oral mucosa.

Tissue Structure Thickness (m) [20] Turnover time (days) [22] Surface

Buccal NK 500600 57 50.22Sublingual NK 100200 20 26.54Gingival K 200 Palatal K 250 24 20.11

NK is nonkeratinized tissue, K is Keratinized tissue and * In rhesus monkeys (ml/min/100 gthe intercellular spaces. This limit of penetration coincideswith the levelwhere MCGs are observed. This same pattern is observed in bothkeratinized and non-keratinized epithelia [3], which indicates thatMCGs play a more significant role as a barrier to permeation comparedto the keratinization of the epithelia [27].

The cells of the oral epithelia are surrounded by an intercellularground substance called mucus, the principle components of whichare complexes made up of proteins and carbohydrates; its thicknessranges from 40 to 300 m [28]. In the oral mucosa, mucus is secretedby the major and minor salivary glands as part of saliva. Althoughmost of the mucus is water (9599% by weight) the keymacromolecular components are a class of glycoprotein known asmucins (15%). Mucins are large molecules with molecular massesranging from 0.5 to over 20 MDa and contain large amounts ofcarbohydrate. Mucins are made up of basic units (400500 kDa)linked together into linear arrays. These big molecules are able to jointogether to form an extended three-dimensional network [29] whichacts as a lubricant allowing cells to move relative to one another, andmay also contribute to cellcell adhesion [14]. At physiological pH, themucus network carries a negative charge due to the sialic acid andsulfate residues and forms a strongly cohesive gel structure that willbind to the epithelial cell surface as a gelatinous layer [3032]. This gellayer is believed to play a role in mucoadhesion for drug deliverysystems which work on the principle of adhesion to the mucosalmembrane and thus extend the dosage form retention time at thedelivery site.

Another factor of the buccal epithelium that can affect themucoadhesion of drug delivery systems is the turnover time. Theturnover time for the buccal epithelium has been estimated to be 38 days compared to about 30 days for the skin [2].

4. Physiological opportunities for oral transmucosal drug delivery

Despite the challenges, the oral mucosa, due to its uniquestructural and physiological properties, offers several opportunitiesfor systemic drug delivery. As the mucosa is highly vascularized anydrug diffusing across the oral mucosa membranes has direct access tothe systemic circulation via capillaries and venous drainage and willbypass hepatic metabolism. The rate of blood flow through the oralmucosa is substantial, and is generally not considered to be the rate-limiting factor in the absorption of drugs by this route (Table 2).

For oral delivery through the GI tract, the drug undergoes a ratherhostile environment before absorption. This includes a drastic change inGI pH (from pH 12 in the stomach to 77.4 in the distal intestine),unpredictable GI transit, the presence of numerous digestive enzymesand intestinal flora [33,34]. In contrast to this harsh environment of theGI tract, the oral cavity offers relatively consistent and friendlyphysiological conditions for drug delivery which are maintained bythe continuous secretionof saliva. Compared to secretionsof theGI tract,saliva is a relatively mobile fluid with less mucin, limited enzymaticactivity and virtually no proteases [35].

Enzyme degradation in the GI tract is a major concern for oral drugdelivery. In comparison, the buccal and sublingual regions have lessenzymes and lower enzyme activity, which is especially favorable toprotein and peptide delivery. The enzymes that are present in buccalmucosa are believed to include aminopeptidases, carboxypeptidases,area (cm2SD) [6] Permeability [19] Residence time [19] Blood flow* [21]

.9 Intermediate Intermediate 20.3

.2 Very good Poor 12.2Poor Intermediate 19.5

.9 Poor Very good 7.0

tissue).

Table 3Permeabilities of water for human skin and oral mucosa regions (Adapted from Squierand co-workers [38]).

Regiona Kp (107SEM cm/min)

Skin 444b

Oral mucosaHard palate 47027Buccal mucosa 57916Lateral border of tongue 77223Floor of mouth 97333

a Human (n=58).b Permeability constant (Kp) significantly different compared to oral mucosa at

pb0.05.

Table 4Regional difference in permeability expressed in terms of a uniform permeabilitybarrier (Adapted from Squier and Hall [39]).

Tissueregion

Thickness (m SEM) Mean Kp expressed in terms of auniform barrier of 100 m thick(SEM107)

Totalepithelium

Permeabilitybarrier

Water Horseradishperoxidise

Skin 694 161 21.14.3 9.41.8Gingiva 2089 354 98.316.0 79.511.4Buccalmucosa

77220 28217 173.224.6 99.110.6

Floor ofmouth

1927 231 1271.3203.1 331.651.9

Fig. 3. Schematic representation of different route of drug permeation.

109V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116dehydrogenases and esterases. Aminopeptidases may represent amajor metabolic barrier to the buccal delivery of peptide drugs.Proteolytic activity has been identified in buccal tissue homogenatesfrom various species and a number of peptides have been shown toundergo degradation [36]. Bernkop-Schnurch and co-workers [37]studied the peptidase activity on the surface of porcine buccal mucosaand found that no carboxypeptidase or dipeptidyl peptidase IVactivity was detected on the buccal mucosa, while aminopeptidaseN activity was detected using Leu-p-nitroanilide. However, this studyrepresents only the surface of procine mucosa and hence moreresearch will be required to fully characterize the levels and type ofdifferent enzymes presents especially in human buccal mucosa.

The buccal and sublingual routes are the focus for drug delivery viathe oralmucosa because of the higher overall permeability compared tothe other mucosa of the mouth. The effective permeability coefficientvalues reported in the literature across the buccal mucosa for differentmolecules, range from a lower limit of 2.2109 cm/s for dextran 4000across rabbit buccal membrane to an upper limit of 1.5105 cm/s forboth benzylamine and amphetamine across rabbit and dog buccalmucosa, respectively [2]. The oralmucosa is believed to be44000 timesmore permeable than that of skin [24]. Squier and co-workers [38]revealed that the permeability of water through the buccal mucosa wasapproximately 10 times higher, whilst in floor of the mouth thepermeability was approximately 20 times higher than skin (Table 3). Inanother study by Squier and Hall [39], the permeability constant wascalculated for water and Horseradish peroxidase across skin and oralmucosal surface (Table 4).

Drugs can be transported across epithelial membranes by passivediffusion, carrier-mediated active transport or other specializedmechanisms. Most studies of buccal absorption indicate that thepredominant mechanism is passive diffusion across lipid membranesvia either the paracellular or transcellular pathways (Fig. 3) [4044];although these may actually be the same pathway. The hydrophilicnature of the paracellular spaces and cytoplasm provides a permeabilitybarrier to lipophilic drugs but can be favorable for hydrophilic drugs. Incontrast, the transcellular pathway involves drugs penetrating throughone cell and the next until entering the systemic circulation. Thelipophilic cell membrane offers a preferable route for lipophilic drugscompared to hydrophilic compounds [1]. Drugs can transverse bothpathways simultaneously although one route could be predominantdepending on the physicochemical properties of the drug [31].

Although passive diffusion is the predominant mechanism ofabsorption from the oral mucosa, specialized transport mechanismshave also been reported for a few drugs and nutrients. A study byKurosaki and co-workers [45] reported that the rate of absorption ofD-glucose from the dorsal and ventral surface of the tongue wassignificantly greater than that of L-glucose, which indicated theoccurrence of some specialized transport mechanism. In addition, theexistence of sodium-dependant D-glucose transport system wasreported across stratified cell layer of human oral mucosal cells [46].Table 5 provides examples of several drugs transported via differentmechanisms across the buccal mucosa.5. Oral transmucosal drug delivery technologies

Continuous research into the improvement of the oral transmucosaldelivery of drugs has resulted in the development of severalconventional and novel dosage forms like solutions, tablets/lozenges,chewing gums, sprays, patches and films, hydrogels, hollow fibers andmicrospheres. These dosage forms can be broadly classified into liquid,semi-solid, solid or spray formulations [54]. Oral transmucosal systemsfor systemic drug delivery are usually designed to deliver the drug foreither i) rapid drug release for immediate and quick action, ii) pulsatilerelease with rapid appearance of drug into systemic circulation andsubsequent maintenance of drug concentration within therapeuticprofile or iii) controlled release for extended period of time (as depictedin Fig. 4).

Several companies are currently engaged in development andcommercialization of drug delivery technologies based on oraltransmucosal systems. Table 6 shows a list of products commerciallyapproved for oral transmucosal administration. A list of companiescurrently engaged in developing technology platforms for oraltransmucosal drug delivery system is shown in Table 7. The majorityof the commercially available formulations are solid dosage formssuch as tablets and lozenges. A few companies have had successes indeveloping technology platforms for films or patches with mostaimed at achieving rapid drug release and clinical response. Thelimitations associated with such type of dosage forms includeuncontrolled swallowing of released drug intoGI tract and difficultiesin holding the dosage form at the site of absorption. These are theareas where more research focus is required, especially usingmucoadhesive systems.

5.1. Mucoadhesive systems

Other than the low surface area available for drug absorption in thebuccal cavity, the retention of the dosage form at the site of absorption isanother factor which determines the success or failure of buccal drugdelivery system. The utilization of mucoadhesive systems is essential tomaintain an intimate and prolonged contact of the formulationwith theoral mucosa allowing a longer duration for absorption. Some adhesivesystemsdeliver thedrug towards themucosaonlywith an impermeableproduct surface exposed to the oral cavity which prevents the drug

image of Fig.3

Table 5Examples of drugs transported via different mechanisms through buccal mucosa.

Name of Drug Transportmechanism

Path way Tissue References

5-Aza-2-deoxycytidine

Passive Not defined Buccal mucosa [40]

2, 3-dideoxycytidine

Passive Not defined Buccal mucosa [41]

Flecainide Passive Paracellular Buccal mucosa [42]Sotalol Passive Paracellular Buccal mucosa [42]Nicotine Passive Paracellular,

TranscellularTR146 Cell cultureand buccal mucosa

[43]

Lamotrigine Passive Transcellular Buccal mucosa [44]Galantamine Passive Not defined Human oral

epithelium andbuccal mucosa

[47]

Naltrexone Passive Not defined Buccal mucosa [48]Buspirone Passive Transcellular Buccal mucosa [49]OndansatronHCl

Passive Not defined Buccal mucosa [50]

Monocarboxylicacids

Carriermediated

Carriermediated

Primary culturedepithelial cells

[51,52]

Glucose Carriermediated

Carriermediated

Buccal, oral mucosalcells and dorsum oftongue

[53]

110 V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116release into oral cavity [76]. For example, Lopez and co-workers [77]designed bilaminatedfilms to provide unidirectional release of drug andavoid buccal leakage. They contained a bioadhesive layer made up ofchitosan, polycarbophil, sodium alginate and gellan gum while backinglayer made up of ethyl cellulose.0

10

20

30

40

50

60

70

80

90

100

-1 4 9 14 19 24Pre

sen

ce o

f d

rug

in s

yste

mic

cir

cula

tio

n

Time (hr)Quick release Pulsatile release Controlled release

Fig. 4. Schematic representation of different type of mucosal drug delivery system.5.1.1. Theories of mucoadhesionThemostwidely investigated groupofmucoadhesivesused in buccal

drug delivery systems are hydrophilic macromolecules containingnumerous hydrogen bond-forming groups [78]. The presence ofhydroxyl, carboxyl or amine groups on the molecules favors adhesion.They are called wet adhesives as they are activated by moistening andwill adhere non-specifically to many surfaces. Unless water uptake isrestricted, they may over hydrate to form slippery mucilage. For dry orpartially hydrated dosage forms two basic steps in mucoadhesion havebeen identified [79]. Step one is the contact stage where intimatecontact is formed between the mucoadhesive and mucous membrane.Within the buccal cavity the formulation can usually be readily placedinto contact with the required mucosa and held in place to allowadhesion to occur. Step two is the consolidation stage where variousphysicochemical interactions occur to consolidate and strengthen theadhesive joint, leading to prolonged adhesion.

Mucoadhesion is a complex process and numerous theories havebeen presented to explain the mechanisms involved. These theoriesinclude mechanical-interlocking, electrostatic, diffusioninterpenetra-tion, adsorption and fracture processes [80], whilst undoubtedly themost widely accepted theories are founded upon surface energythermodynamics and interpenetration/diffusion [81]. The wettabilitytheory is mainly applicable to liquid or low viscosity mucoadhesivesystems and is essentially a measure of the spreadability of the drugdelivery system across the biological substrate [82]. The electronictheory describes that adhesion occurs by means of electron transferbetween the mucus and the mucoadhesive system arising throughdifferences in their electronic structures. The electron transfer betweenthe mucus and the mucoadhesive results in the formation of a doublelayer of electrical charges at themucus andmucoadhesive interface. Thenet result of such a process is the formation of attractive forces withinthis double layer [83]. According to fracture theory, the adhesive bondbetween systems is related to the force required to separate bothsurfaces from one another. This fracture theory relates the force forpolymer detachment from the mucus to the strength of their adhesivebond. The work of fracture has been found to be greater when thepolymer network strands are longer or if the degree of cross-linkingwithin such a system is reduced [84]. According to the adhesion theory,adhesion is defined as being the result of various surface interactions(primary and secondary bonding) between the adhesive polymer andmucus substrate. Primary bonds due to chemisorption result in adhesiondue to ionic, covalent and metallic bonding, which is generallyundesirable due to their permanency [85]. The diffusioninterlockingtheory proposes the time-dependent diffusion of mucoadhesive poly-mer chains into the glycoprotein chain network of themucus layer. Thisis a two-way diffusion process with penetration rate being dependentupon the diffusion coefficients of both interacting polymers [78].

5.1.2. Polymers for mucoadhesive systemsThe polymeric attributes that are pertinent to high levels of

retention at applied and targeted sites via mucoadhesive bondsinclude hydrophilicity, negative charge potential and the presence ofhydrogen bond forming groups. Additionally, the surface free energyof the polymer should be adequate so that wetting with the mucosalsurface can be achieved. The polymer should also possess sufficientflexibility to penetrate the mucus network, be biocompatible, non-toxic and economically favorable [86]. According to the literaturemucoadhesive polymers are divided into first generation mucoadhe-sive polymers and second generation novel mucoadhesive polymers.The first generation polymers are divided into three major groupsaccording to their surface charges which include anionic, cationic andnon-ionic polymers. The anionic and cationic polymers exhibitstronger mucoadhesion [87].

Anionic polymers are the most widely employed mucoadhesivepolymers within pharmaceutical formulations due to their highmucoadhesive functionality and low toxicity. Such polymers arecharacterized by the presence of carboxyl and sulfate functionalgroups that give rise to a net overall negative charge at pH valuesexceeding the pKa of the polymer. Typical examples includepolyacrylic acid (PAA) and its weakly cross-linked derivatives andsodium carboxymethyl cellulose (Na CMC). PAA and Na CMC possessexcellent mucoadhesive characteristics due to the formation of stronghydrogen bonding interactions with mucin [88]. Among the cationicpolymer systems, undoubtedly chitosan is the most extensivelyinvestigated within the current scientific literature [89]. Chitosan isa cationic polysaccharide, produced by the deacetylation of chitin, themost abundant polysaccharide in the world, next to cellulose [89].Chitosan is a popular polymer to use due to its biocompatibility,biodegradability and favorable toxicological properties [90]. Chitosanhas been reported to bind via ionic interactions between primaryamino functional groups and the sialic acid and sulphonic acidsubstructures of mucus [91]. The major benefit of using chitosanwithin pharmaceutical applications has been the ease with which

image of Fig.4

Table 6Commercially available oral transmucosal drug delivery systems [35].

Drug Dosageform

Type ofrelease

ProductName

Manufacturer

Fentanyl citrate Lozenge Quick Actiq CephalonTablet Quick Fentora CephalonFilm Quick Onsolis Meda Pharmaceutical

Inc.BuprenorphineHCl

Tablet Quick Subutex Reckitt Benckiser

Buprenorphine HCland naloxone HCl

Tablet Quick Suboxane Reckitt Benckiser

Proclorperazine Tablet Controlled Buccastem Reckitt BenckiserTestosterone Tablet Controlled Striant SR Columbia

PharmaceuticalsNitroglycerine Tablet,

SprayQuick Nitrostat W LambertP Davis

Pfizer PharmaceuticalsGlyceryl trinitrate Spray Quick Nitromist NovaDelZolpidem Spray Quick Zolpimist NovaDel

Tablet Quick Suscard Forest LaboratoriesNicotine Chewing

gumQuick Nicorette GSK Consumer Health

Lozenge Quick Nicotinelle Novartis ConsumerHealth

Miconazole Tablet Quick Loramyc BioAlliance Pharma SACannabis-derived Spray Quick Sativex GW Pharmaceuticals,

PLCInsulin Spray Quick Oral-lyn Generex Biotechnology

Table 7List of companies with their technology platforms based on oral transmucosal system.

Company Technology References

IntelGenx VersaFilm (Quick release wafer technology) [55]Bioenvelop Thinsol (edible film technology) [56]HealthSport andInnoZen

Bilayer film-strip [57]

BioFilm Dissolvable thin film [58]Meldex XGel (Films), SoluLeaves (Films), WaferTab

(Film strip), OraDisc (disc)[59]

Uluru Inc OraDisc (disc) [6062]MonoSol Rx MonoSol Rx thin film [63]Passion for LifeHealthcare

Snoreeze Oral strips [64,65]

GW Pharma Sativex Buccal Spray [66]GenerexBiotechnology

Oral spray (RapidMist) technology [67]MetControl chewing gum [67]

NovaDel Novamist spray technology [68]Biodelivery SciencesInternational (BDSI)

BEMA technology [69,70]

TransceptPharmaceutical Inc.

Sublingual tablets [71]

Labtec Pharma RapidFilm technology [7274]MedPharm Ltd MedRo mucoadhesive spray technology [75]

111V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116various chemical groups may be added, in particular to the C-2position allowing for the formation of novel polymers with addedfunctionality. Using such modifications, the properties of chitosanmay be tailored to suit the requirements of specific pharmaceuticaltechnological challenges [92] although this often results in additionalregulatory requirements as it becomes a new excipient with all theadded problems of qualifying from a safety basis.

Unlike first-generation non-specific platforms, certain second-generation polymer platforms are less susceptible to mucus turnoverrates, with some species binding directly to mucosal surfaces; moreaccurately termed cytoadhesives. Furthermore as surface carbohydrateand protein composition at potential target sites vary regionally, moreaccurate drug delivery may be achievable [80]. Lectins are naturallyoccurring proteins that play a fundamental role in biological recognitionphenomena involving cells and proteins. After initial mucosal cell-binding, lectins can either remain on the cell surface or in the case ofreceptor-mediated adhesion possibly become internalized via endocy-tosis [93]. Although lectins offer significant advantages in relation to sitetargeting, many are toxic or immunogenic, and the effects of repeatedlectin exposure are largely unknown. It is also feasible that lectin-induced antibodies could block subsequent adhesive interactionsbetween mucosal epithelial cell surfaces and lectin delivery vehicles.Moreover, such antibodies may also render individuals susceptible tosystemic anaphylaxis on subsequent exposure [93].

Thiolated polymers (thiomers) are a type of second-generationmucoadhesive derived from hydrophilic polymers such as polyacry-lates, chitosan or deacetylated gellan gum [94]. The presence of thiolgroups allows the formation of covalent bonds with cysteine rich subdomains of the mucus gel layer leading to increased residence timeand improved bioavailability [95]. Whilst first-generation mucoadhe-sive platforms are facilitated via non-covalent secondary interactions,the covalent bonding mechanisms involved in second-generationsystems lead to interactions that are less susceptible to changes inionic strength and/or the pH [96].

5.2. Dosage forms

5.2.1. Liquid dosage formsLiquid dosage forms include solutions or suspensionsmade of drug

solubilized or suspended into suitable aqueous vehicles. Such types ofdosage forms are usually employed to exert local action into the oralcavity and several antibacterial mouthwashes and mouth-freshenerare commercially available for this purpose. The limitation associatedwith these liquid dosage forms are that they are not readily retainedor targeted to buccal mucosa and can deliver relatively uncontrolledamounts of drug throughout oral cavity. Patel and co-workers [97]found that polymers can be adsorbed from solution onto buccal cellsin vivo. From the wide range of polymer solutions screened, chitosangave the greatest binding, followed by methylcellulose, gelatin,carbopol and polycarbophil.

Drug present in the liquid dosage forms can also be delivered in amore controlled manner through the use of iontophoretic techniques,which are well known for the delivery of drugs through skin, but havealso been investigated for drug delivery across the buccal mucosa.Jacobsen [98] studied the iontophoretic drug delivery of atenololhydrochloride solution employing three-chamber permeation cell invitro. The delivery across porcine buccal mucosa increased propor-tionally to increased initial donor concentration, increased on timeof current on/ off ratio and increased current density. Microscopicalevaluation of hematoxyilin-eosin stained sections of porcine buccalmucosa showed only minute morphological alterations after con-ducting 8 h passive permeation whilst 8 h iontophoretic treatmentshowed disordering of the outer epithelial cell layers. Campisi and co-workers [99] reported that the iontophoretic buccal drug deliveryof naltrexone was a promising development as naltrexoneappeared in the plasma of pigs within 510 min of administrationand reached a peak around 90 min. After 6 h, the plasma level ofnaltrexone delivered via iontophoresis was higher compared tothat of naltrexone delivered intravenously. Such findings wereexplained by the presence of a drug reservoir within the buccal mucosaafter iontophoresis from which naltrexone released gradually and wassystemically available.5.2.2. Semisolid dosage formsSemisolid dosage forms usually include gels, creams and ointments,

which are applied topically into the mucosal surface for either local orsystemic effects. These typically contain a polymer and drug plus anyrequired excipient dissolved or suspended as afine powder in an aqueousor non-aqueous base. Hydrogels can also be used in semi-solids for drugdelivery to the oral cavity. These are formed from polymers and can behydrated in an aqueous environment without dissolution, acting as drugdelivery systems by physically entrapping molecules, which are then

Fig. 5. Schematic representation of different types of matrix tablets designed for buccaldrug delivery system (Adapted from Caramella and co-workers [106]).

Fig. 6.Mean salivarymiconazole concentration obtained in vivowithmucoadhesive patch(o) and Daktarin oral gel (). The insert represents correlation between in vitro/in vivocumulative miconazole concentration (g/ml) released from the mucoadhesive patch[Adapted from ref. [115]].

112 V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116slowly released by diffusion or erosion after gel hydration [100]. Semi-solid formulations can be applied using the finger to a target region andtend to bemore acceptable in terms ofmouth feel to patients relative to asolid dosage form. Semisolid systems also have the advantage of beingdeliverable with a syringe, with a consequent ease of placement to theperiodontal pockets [101] and easy dispersion throughout the mucosa ofthe oral cavity. However, they may deliver variable amounts of activeingredients in comparisonwith a unit dosage form [7]. Another drawbackof semi-solid dosage forms designed for use in the oral cavity is the poorretention at the site of application especially when the hydrogel polymerhas no adhesive properties. This drawback can be minimized oreliminated by the incorporation of a bioadhesive polymer into theformulation [102]. A mucoadhesive gel of risperidone containingPoloxamer 407 and Carbopol 974 was able to achieve a steady stateflux of 64.858.0 g/cm2/h in an in vitro permeation study, whichwas extrapolated to an in vivo plasma concentration of 11.256.1 g/l for mucosal application area between 2 and 10 cm2. As such andassuming that these predicted plasma concentrations are within thetherapeutic range of risperidone required in humans, delivery ofrisperidone via the buccal mucosa has potential for treatment ofschizophrenia [103]. In addition, Perioli and co-workers [104]proposed emulgels (gellified emulsion) made up of Pemulin 1621as a polymeric emulsifier and Compritol 888 ATO as an internal oilyphase for the buccal delivery of flurbiprofen and found that the drugreleasewas controlledwith 5080% of drug releasewithin 100 min ofapplication. In addition, the emulgels were reported to be retained onhuman buccal mucosa for an average period of one hour.5.2.3. Solid dosage forms

5.2.3.1. Tablets/lozenges. These are solid dosage forms prepared by thecompression of powder mixes that can be placed into contact with theoral mucosa and allowed to dissolve or adhere depending on the type ofexcipients incorporated into the dosage form. They can deliver drugmultidirectionally into the oral cavity or to the mucosal surface.Alternatively, the dosage form can contain an impermeable backinglayer to ensure that drug is delivered unidirectionally. Disadvantages ofbuccal tablets can include patient acceptability (mouth feel, taste andirritation) and the nonubiquitous distribution of drug within saliva forlocal therapy [7]. It is important to point out the possible problems thatchildren and the elderly may experience with the use of adhesive tabletswhich include the possible discomfort provoked by the material appliedto the mucosa and the possibility of the dosage form separating from themucosa, being swallowed, and then adhering to the wall of theesophagus. A typical bioadhesive formulation of this type consists of abioadhesive polymer (such as polyacrylic acids or a cellulose derivative),alone or in combination, incorporated into a matrix containing the activeagent and excipients, and perhaps a second impermeable layer to allowunidirectional drug delivery (Fig. 5) [105,106].

Amongst the different types of formulation available on the market,solid dosage forms have probably been developed most extensivelysuch as the nitroglycerin sublingual tablet, fentanyl lozenge on a stickand prochlorperazine buccal tablets. The limitation of these drugdelivery systems is the short residence time at the site of absorption;as depending on the size and type of formulation, they usually dissolvewithin 30 min, thus limiting the total amount of drug that can bedelivered. The dissolution or disintegration of lozenges is usuallycontrolled by the patient, i.e. how hard they suck the unit. Increasedsucking and saliva production causes uncontrolled swallowing and lossof drug down the GI tract. Thus, solid dosage forms generally have amuch higher inter- and intra-individual variations in absorption andbioavailability. Also such types of system are not able to provideunidirectional release of drug. Continuous secretion of saliva is anothermajor hurdle to the performance of such dosage forms.

Minghetti and co-workers [107] proposed the utilization ofclobetasol-17 propionate mucoadhesive tablets for the treatment oforal litchen planus. In this formulation, HPMC and MgCl2 were added

image of Fig.6

113V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116into a mucoadhesive polymer matrix, i.e. poly(sodium methacrylatemethylmethacrylate), to modify the tablet erosion rate and to obtaindrug release over a 6 h period. A double-blind, controlled study wasperformed using three groups of patients (n=16) who received threeapplications-a-day over 4 weeks of the developed clobetasol-17propionate tablets, placebo tablets or a commercial clobetasol-17propionate ointment for cutaneous application (123 g/application)combined with Orabase. The application of 24 g clobetasol-17propionate tablet three times a day appeared to be more effective andsafer than the semisolid preparation. The addition of HPMC andMgCl2 in the formulation was thought to effectively control tablethydration/erosion and, consequently drug release, without signifi-cantly modifying mucoadhesion.

Pillay and co-workers [108] reported the use of porosity enabledmatrix tablets for the sustained delivery of phenytoin sodium as amodel drug. The porosity (pore structure, interconnectors, pore widthor diameter, and pore volume of distribution) of the porosity enabledmatrix formulations had a significant impact on their physicochemicalproperties. Interphase, co-particulate, co-solvent, homogenizationcoupled with lyophilization, proved to be efficient methods forconstruction of the formulation. The optimized formulation displayedthe potential to consistently release drug in a steady state, controlledmanner over 8 h. Furthermore, the formulation showed the capabilityto consistently initiate and sustain the permeation of drug through themodel buccal mucosal tissue over the period of 8 h.

The work reported by Kramer and Flynn [109] on pH-solubilityprofile showed that it is possible to saturate simultaneously unionizedand ionized drug species at particular pH called pHmax which shouldlead to an increased transbuccal permeability compared to anyotherpH.Table 8Film type buccal drug delivery systems.

Drug Polymers Techniques DosageForm

Clinical outcomes References

Lidocaine HCl EC, HPC Solventcasting

Film Effect of drugobservedthroughoutadhesion ofdosage form

[114]

Miconazolenitrate

Na CMC,HEC,HPMC,PVP

Solventcasting

Film Uniform andeffective salivarylevels for at least6 h

[115]

Cetylpyridinumchloride

PVA,HEC,chitosan

Solventcasting

Patch Increase inresidence timeand decrease indrug release withstorage

[116]

Acyclovir ChitosanHCl, PAA

Solventcasting

Film Increasepermeationcompared tocream andsuspension

[118]

Calcitonin NoveonAA1,EudragitS100

Solventcasting

Bilayerfilm

Relativebioavailability of43.810.9% inrabbit

[119]

Clotrimazole HPC, PEO Hot meltextrusion

Film Excellent contentuniformity andpost processingdrug content of93.3%

[120]

Sumatriptansuccinate

Chitosan,gelatin,PVP

Solventcasting

Bilayerpatch

No mucosaldamageconfirmed byhistopathologicalstudy

[121]

EC is ethyl cellulose, HPC is hydroxypropyl cellulose, Na CMC is sodium carboxymethylcellulose, HEC is hydroxyethyl cellulose, HPMC is hydroxypropyl methylcellulose, PVPis polyvinyl pyrrolidone, PVA is polyvinyl alcohol, PAA is polyacrylic acid and PEO ispolyethylene oxide.Chowand co-workers [110] explored a pHmax concept for the sublingualdelivery of propanolol. A buffered sublingual propranolol tablet,designed to achieve its pHmax (when dissolved in saliva), was comparedto a marketed product (Inderal which could not achieve pHmax) in8 healthy human volunteers. Each subject received the productssublingually for 15 min followed by swallowing the remaining drug insaliva. The plasma propranolol AUC during the first 30 min from thebuffered tablet were significantly higher than that from the Inderaltablet (pb0.05). No significant differences in the remaining AUC wereobserved.

Disks are similar to tablets but are thinner andmore flat in shapeand can be developed into a different size and shape more suitableto be placed into the buccal cavity. An in vivo evaluation of a buccaldisk of cetylpyridinium chloride revealed adequate comfort, taste,non-irritancy and none of the volunteers reported severe drymouth/severe salivation or heaviness at the place of attachment.Salivary concentrations were maintained above the MIC for 8 h. Agood correlation was found between the drug concentration in situand concentration of drug in saliva collected from healthy humanvolunteers [111]. A buccal disk of oxycodone hydrochloride wasevaluated in healthy human volunteers. The Tmax data obtained wasgreater for the buccoadhesive disks compared to other oral tablets.The fact that the AUC and Cmax values were comparable toconventional tablets may have been due to the lack of a backinglayer for buccal disk [112]. Thiocochicoside has also been exploredfor use on the disk type delivery system. An in vivo thiocolchicosideabsorption experiment indicated that the fast dissolving sublingualform resulted in a quick uptake of drug within 15 min whereas forthe adhesive buccal form the same dose was absorbed over anextended period of time [113].

5.2.3.2. Patches/films/wafers. These dosage forms are usually preparedby casting a solution of the polymer, drug and any excipients (such asa plasticiser) on to a surface and allowing it to dry. Patches can bemade 1015 cm2 in size but are more usually 13 cm2 with perhapsan ellipsoid shape to fit comfortably into the centre of the buccalmucosa. In a similar fashion to buccal tablets, they can be mademultidirectional or unidirectional (e.g., by the application of animpermeable backing layer). They have many of the advantages anddisadvantages of buccal tablets, but by being thin and flexible, tend beless obtrusive and more acceptable to the patient. The relativethinness of the films, however, means that they are more susceptibleto overhydration and loss of the adhesive properties [7].

The major method of polymeric film manufacture is the solventevaporation process, in which the polymeric material, with or withoutplasticizer, is dissolved in a solvent or solvent mixture and into whichthe active constituent is dissolved or dispersed. This solution is thencast onto a suitable substrate and the solvent is allowed to evaporate,leaving a solid polymeric film containing the drug. These types ofdosage forms have also been prepared using other techniques such asdirect compression and hot-melt extrusion. The advantage associatedwith these types of techniques was the need of organic solvent isavoided and thus it proves to be environment friendly.

The oral cavity mucosa is an ideal surface for the placement ofretentive delivery systems such as patches, since it contains a largeexpanse of smooth and immobile tissue. Mucoadhesive patches foradministration to the mucosa of the oral cavity may have a number ofdifferent designs, depending on various considerations, such as thetherapeutic aim and the physicochemical and pharmacokineticproperties of the active ingredient. Two different rationales fordeveloping mucosal patches may be considered: patches can beintended to deliver a drug to the systemic circulation in a way that issuperior to other routes of administration, or their purpose may belocal therapy of the oral mucosa [105].

Mucoadhesive buccal patches of lidocaine produced anesthesiathroughout the adhesion period of 60120 min and the patch was not

114 V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116detached from the buccal mucosa [114]. In a study by Ismail and co-workers [115], it was found that the in vivo release of miconazole wasquick but transient from the commercial oral gel Daktarin, whichdiminished sharply after thefirst hour of application, compared to buccalpatches of miconazole (Fig. 6). The optimum patch formulationcomprised PVA and PVP and exhibited sustained release over 5 h.Although high drug levels were observed for both formulations duringthe first 30 min of the experiment, a remarkable drug concentrationwasreleased from thepatch after 4 h compared to traces of thedrug obtainedfromthecommercial gel. Detectabledrug concentrationswerepresent insaliva even after the complete erosion of the patch (44.5 h). Theminimuminhibitory concentrations (MIC) formiconazolenitrate againstC. albicans is 5 g/ml; TNMIC is the time where the last salivaryconcentration is above the MIC. The recorded values of TNMIC were 1.3and 6.1 h for Daktarin oral gel and for mucoadhesive patch,respectively. It is clear that themucoadhesive patch had a greater abilityto sustain an elevated drug concentration in saliva despite theadministration of a smaller dose (10 mg) compared with the gel(25 mg). In another study in human volunteers by Ismail and co-workers [116], a cetylpyridinum chloride patchmade up of chitosanwasshown to be superior to a patch made up of hydroxyethyl cellulose andpolyvinyl alcohol in termsof in vivobuccal residence time thoughnoneofthe polymeric patcheswere detached from themucosa during the study.

Bilayer films have been evaluated for the mucosal immunization ofrabbit via the buccal route [117]. The film consists of two layers andamong them one made up of an impermeable backing layer whileanother layer consists of a drug facing towards the mucosa. Efficacy ofimmunization has been compared by administering the proteininjection by subcutaneous route. Postloaded plasmid DNA and -lactosidase proteins remained stable after being released from bilayerfilms. Buccal immunization using novel bilayerfilms containing plasmidDNA led to comparable antigen-specific IgG titer to that of subcutaneousprotein injection. All rabbits immunized with plasmid DNA via thebuccal route but none by the subcutaneous route with protein antigen,demonstrated splenocyte proliferative immune responses. The authorsconcluded that the vaccination without the use of needles wouldprovide a distinct advantage in terms of both cost and safety overconventional vaccines that must be given with needles [117].

The current literature shows that the research is more focusedtowards the mucoadhesive type of films or patches which containdifferent mucoadhesive components to extend the residence time ofdosage forms at the site of application. Table 8 shows list of the drugsexplored in such mucoadhesive systems.

5.2.3.3. Micro/nano-particulates. These are typically delivered as anaqueous suspension but can also be applied by aerosol or incorporatedinto a paste or ointment. Particulates have the advantage of beingrelatively small and, therefore, more likely to be acceptable to the patient.However, the dose of drug retained on the buccal mucosa and, therefore,deliveredmay not be consistent relative to a single-unit dosage form suchas a patch or buccal tablet. Polymeric microparticles (2338 m) ofCarbopol, polycarbophil, chitosan or Gantrezwere found to be capableof adhering to porcine esophageal mucosa, with particles prepared fromthe polyacrylic acids exhibiting greater mucoadhesive strength duringtensile testing studies.Whereas, in elution studies, particles of chitosanorGantrez were seen to persist onmucosal tissue for longer periods of time[122,123]. Holpuch and co-workers [124] explored the use of nanopar-ticles for local delivery to the oral mucosa. Two types of nanoparticles,solid lipidnanoparticles incorporatingeither idarubicinorBODIPYFLC12as model fluorescent probes and polystyrene nanoparticles (Fluo-Spheres), were investigated using monolayer-cultured human oralsquamous cell carcinoma (OSCC) cell lines and normal human oralmucosal explants in a proof of concept study. The results demonstratedthat OSCC cells internalized solid lipid nanoparticles. The observedpenetration of nanoparticles through the epithelium and basementmembrane into the underlying connective tissue suggested the possibilityof oral transmucosal nanoparticle delivery for systemic therapy. Montiand co-workers [125] produced an atenolol containing microsphereusing Poloxamer 407 and evaluated the formulation in vivo in rabbitsagainst a marketed tablet formulation as a reference. After admin-istration of themicrosphere formulations, the atenolol concentrationremained higher than the reference tablet during the entireelimination phase showing a sustained release profile from themicrospheres; the concentrations at 24 h were 0.750.1 g/ml vs0.20.1 g/ml for the microspheres and marketed tablet, respec-tively. Moreover, the absolute bioavailability of microsphere for-mulations was higher than that of reference tablets in spite of a lowerdrug dose in the former, suggesting a possible dose reduction byatenolol microparticles via oral transmucosal administration.

Intra-orally fast-dissolving particles of perphenazine (PPZ) werereported by Laitinen and co-workers [126]. Freeze-drying of solutionsof a poorly water soluble drug PPZ with 0%, 20%, 80% or 95% of apolyethylene glycol (PEG) led to an improved PPZ solubility andextremely fast dissolution rate in a small liquid (pH 6.8) volumecompared to crystalline or micronized PPZ. The most remarkableimprovement in the dissolution rate was seenwith the 1:5 ratio of PPZto PEG, which was dissolved within one minute without precipitationof the supersaturated PPZ. A solid dispersion of PPZ with -CDprepared by spray drying and with PEG 8000 prepared by freezedrying were compared with micronized PPZ for pharmacokineticparameters in the rabbit after sublingual administration [127]. Thevalue for area under the curve from 0 to 360 min (AUC0360 min) ofperphenazine after per oral administration was only 8% compared tothe AUC0360 min value obtained after intravenous administration,while the corresponding values for the sublingually administeredformulations were 53% (perphenazine/PEG 8000 solid dispersion),41% (perphenazine/-CD complex) and 64% (micronized perphena-zine). These results revealed that the micronized PPZ despite havinglower solubility compared to its solid dispersion showed improvedplasma concentration. This may have been due to PEG increasing theviscosity of the fluid at site of absorption or it may be that theabsorption was not solubility or dissolution rate limited.

Liposomes are one of the alternatives for drugs which are poorlysoluble and hence are not efficiently delivered from a solid dosageform. For example, silamyrin liposomal buccal delivery showed steadystate permeation through a chicken buccal pouch for 6 h and washigher compared to free drug powder [128].

5.2.4. SpraysAn aerosol spray is one of the suitable alternatives to the solid

dosage forms and can deliver the drug into the salivary fluid or ontothemucosal surface and thus is readily available for the absorption. Asthe spray delivers the dose in fine particulates or droplets, the lag timefor the drug to be available for the site of the absorption is reduced.For example, a pharmacokinetic study of buccal insulin spray inpatient with Type I diabetes revealed no statistical difference inglucose, insulin and C-peptide plasma level compared to insulinadministered subcutaneously [129]. In a study by Xu and co-workers[130], insulin delivered through a novel insulin buccal spray waspassed through the buccal mucosa promoted by the soybean lecithinand propanediol. Results of rabbit and rat experiments revealed thatinsulin delivered through the buccal spray is an effective therapeuticalternative to the current medication system for treating diabetes.Generex's Oral-lyn is an oral spray for insulin for the treatment ofdiabetes I and II which is based on the RapidMist technologyplatform. Generex Oral-lyn is reported to be a safe, simple, fast,effective, and pain-free alternative to subcutaneous injections ofprandial insulin and is conveniently delivered to the membranes ofthe oral cavity by a simple asthma-like device with no pulmonarydeposition [131]. Fentanyl citrate, morphine and low molecularweight heparin are also in clinical development based on RapidMisttechnology by Generex [67].

115V.F. Patel et al. / Journal of Controlled Release 153 (2011) 1061166. Conclusion

Due to the ease of access and avoidance of the hepatic metabolism,oral transmucosal drug delivery offers a promising alternative toovercome the limitations of conventional oral drug delivery andparental administration. The buccal and sublingual routes, inparticular, present favorable opportunities and many formulationapproaches have been explored for such an application; although thecurrent commercially available formulations are mostly limited totablets and films. Oral mucoadhesive dosage forms will continue to bean exciting research focus for improving drug absorption especiallyfor the new generation of the so called biologics, although, thepalatability and irritancy and formulation retention at the site ofapplication need to be considered in the design of such medicines.

References

[1] A.H. Shojaei, Buccal mucosa as a route for systemic drug delivery: a review, JPharm. Pharmaceut. Sci. 1 (1998) 1530.

[2] R.B. Gandhi, J.R. Robinson, Oral cavity as a site for bioadhesive drug delivery, Adv.Drug Deliv. Rev. 13 (1994) 4374.

[3] N. Salamat-Miller, M. Chittchang, T.P. Johnston, The use of mucoadhesivepolymers in buccal drug delivery, Adv. Drug Deliv. Rev. 57 (2005) 16661691.

[4] M.E. Dowty, K.E. Knuth, B.K. Irons, J.R. Robinson, Transport of thyrotropin releasinghormone in rabbit buccal mucosa in vitro, Pharm. Res. 9 (1992) 11131122.

[5] J.D. Smart, Lectin-mediated drug delivery in the oral cavity, Adv. Drug Deliv. Rev.56 (2004) 481489.

[6] L.M.C. Collins, C. Dawes, The surface area of adult human mouth and thickness ofsalivaryfilm covering the teeth and oralmucosa, J. Dent. Res. 66 (1987)13001302.

[7] C.A. Squier, M.J. Kremer, Biology of oral mucosa and esophagus, J. Natl CancerInst. Monogr. 29 (2001) 715.

[8] J.D. Smart, Buccal drug delivery, Expert Opin. Drug Deliv. 2 (2005) 507517.[9] M.R. DeFelippis, Overcoming the challenges of noninvasive proteins and

peptides delivery, Am. Pharm. Rev. 6 (2003) 2130.[10] E.M. Martn del Valle, M.A. Galan, R.G. Carbonell, Drug delivery technologies: the

way forward in the new decade, Ind. Eng. Chem. Res. 48 (2009) 24752486.[11] F. Gotch, J. Nadell, I.S. Edelman, Gastrointestinal water and electrolytes. IV. The

equilibration of deuterium oxide (D2O) in gastrointestinal contents and theproportion of total body water (T.B.W) in the gastrointestinal tract, J. Clin. Invest.36 (1957) 289296.

[12] J.H. Cummings, J.G. Banwell, I. Segal, N. Coleman, H.N. Englyst, G.T. Macfarlane,The amount and composition of large bowel contents in man, Gastroenterology98 (1990) A408.

[13] J.L. Herrera, M.F. Lyons, L.F. Johnson, Saliva: its role in health and disease, J. Clin.Gastroenterol. 10 (1988) 569578.

[14] B.L. Slomiany, V.L. Murty, J. Piotrowski, A. Slomiany, Salivary mucins in oralmucosal defence, Gen. Pharmac. 27 (1996) 761771.

[15] P. Gilles, F.A. Ghazali, J. Rathbone, Systemic oral mucosal drug delivery systemsand delivery systems, in: M.J. Rathbone (Ed.), Oral Mucosal Drug Delivery, Vol.74, Marcel Dekker Inc, New York, 1996, pp. 241285.

[16] C.A. Squier, P.W. Wertz, Structure and function of the oral mucosa andimplications for drug delivery, in: M.J. Rathbone (Ed.), Oral Mucosal DrugDelivery, Vol. 74, Marcel Dekker, Inc., New York, 1996, pp. 126.

[17] I.D. Consuelo, Y. Jacques, G. Pizzolato, R.H. Guy, F. Falson, Comparison of the lipidcomposition of porcine buccal and esophageal permeability barriers, Arch. OralBiol. 50 (2005) 981987.

[18] S.P. Humphrey, R.T. Williamson, A review of saliva: normal composition, flowand function, J. Prosthet. Den. 85 (2001) 162169.

[19] M.E. de Vries, H.E. Bodde, J.C. Verhoef, H.E. Junginger, Developments in buccaldrug delivery, Crit. Rev. Ther. Drug Carrier Syst. 8 (1991) 271303.

[20] B. Li, J.R. Robinson, Preclinical assessment of oral mucosal drug delivery systems,in: T.K. Ghosh, W.R. Pfister (Eds.), Drug delivery to the Oral Cavity: Molecules toMarket, CRC Press, Boca Raton, FL, 2005, pp. 4166.

[21] C.A. Squier, D. Nanny, Measurement of blood flow in the oral mucosa and skin ofthe rhesus monkey using radiolabelled microspheres, Arch. Oral Biol. 30 (1985)313318.

[22] H. Sohi, A. Ahuja, F.J. Ahmad, R.K. Khar, Critical evaluation of permeation enhancersfor oral mucosal drug delivery, Drug Dev. Ind. Pharm. 36 (2010) 254282.

[23] D. Harris, J.R. Robinson, Drug delivery via the mucous membranes of the oralcavity, J. Pharm. Sci. 81 (1992) 110.

[24] W.R.Galey,H.K. Lonsdale, S.Nacht, The invitropermeabilityof skinandbuccalmucosato selected drugs and tritiated water, J. Invest. Dermatol. 67 (1976) 713717.

[25] A.F. Hayward, Membrane-coating granules, Int. Rev. Cyt. 59 (1979) 97127.[26] C.A. Squier, R.A. Eady, R.M. Hopps, The permeability of epidermis lacking normal

membrane-coating granules: an ultrastructural tracer study of KyrleFlegeldisease, J. Invest. Dermatol. 70 (1978) 361364.

[27] C.A. Squier, B.K. Hall, The permeability of mammalian nonkeratinized oral epithelia tohorseradish peroxidise applied in vivo and in vitro, Arch. Oral Biol. 29 (1984) 4550.

[28] A. Allen, The gastrointestinal physiology. Salivary, gastric and hepatobiliarysecretions, in: J.G. Forte (Ed.), Handbook of Physiology, Vol. III Section 6,American Physiological Society, Bethesda, MD, 1989, pp. 359382.[29] D.A. Norris, N. Puri, P.J. Sinko, The effect of physical barriers and properties on theoral absorption of particulates, Adv. Drug Deliv. Rev. 34 (1998) 135154.

[30] P. Bures, Y. Huang, E. Oral, N.A. Peppas, Surface modifications and molecularimprinting of polymers in medical and pharmaceutical applications, J. Control.Release 72 (2001) 2533.

[31] M. Rathbone, B. Drummond, I. Tucker, Oral cavity as a site for systemic drugdelivery, Adv. Drug Delivery Rev. 13 (1994) 122.

[32] M.R. Castellanos, H. Zia, C.T. Rhodes, Mucoadhesive drug delivery systems, DrugDev. Ind. Pharm. 19 (1993) 143194.

[33] E.L. McConnell, H.M. Fadda, A.W. Basit, Gut instincts: explorations in intestinalphysiology and drug delivery, Int. J. Pharm. 364 (2008) 213226.

[34] E.L. McConnell, F. Lui, A.W. Basit, Colonic treatment and targets: issues andopportunities, J. Drug Target. 17 (2009) 335363.

[35] S.I. Pather, M.J. Rathbone, S. Senel, Current status and the future of buccal drugdelivery systems, Expert Opin. Drug Deliv. 5 (2008) 531542.

[36] H.M. Nielsen,M.R. Rassing, TR146 cells grownonfilters as amodel of humanbuccalepithelium: V. Enzyme activity of the TR146 cell culture model, human buccalepithelium and porcine buccal epithelium, and permeability of leu-enkephalin, Int.J. Pharm. 200 (2000) 261270.

[37] G.F. Walker, N. Langoth, A. Bernkop-Schnurch, Peptidase activity on the surfaceof the porcine buccal mucosa, Int. J. Pharm. 233 (2002) 141147.

[38] C.A. Lesch, C.A. Squier, A. Cruchley, D.M.Williams, P. Speight, The permeability ofhuman oral mucosa and skin to water, J. Dent. Res. 68 (1989) 13451349.

[39] C.A. Squier, B.K. Hall, The permeability of the skin and oral mucosa to water andhorseradish peroxidise as related to the thickness of the permeability barrier, J.Inv. Dermat. 84 (1985) 176179.

[40] R. Mahalingam, H. Ravivarapu, S. Redkar, X. Li, B.R. Jasti, Transbuccal delivery of5-Aza-2-Deoxycytidine: effects of drug concentration, buffer solution and bilesalts on permeation, AAPS PharmSciTech 8 (2007) E1E68 Article 55.

[41] J. Xiang, X. Fang, X. Li, Transbuccal delivery of 2, 3-dideoxycytidine: in vitropermeation study and histological investigation, Int. J. Pharm. 231 (2002) 5766.

[42] V.H.M. Deneer, G.B. Drese, P.E.H. Roemele, J.C. Verhoef, L. Lie-A-Huen, J.H.Kingma, J.R.B.J. Brouwers, H.E. Junginger, Buccal transport of flecainide andsotalol: effect of a bile salt and ionization state, Int. J. Pharm. 241 (2002)127134.

[43] H.M. Nielsen, M.R. Rassing, Nicotine permeability across the buccal TR146 cellculture model and porcine buccal mucosa in vitro: effect of pH andconcentration, Eur. J. Pharm. Sci. 16 (2002) 151157.

[44] R. Mashru, V. Sutariya, M. Sankalia, J. Sankalia, Transbuccal delivery oflamotrigine across porcine buccal mucosa: in vitro determination of routes ofbuccal transport, J. Pharm. Pharmaceut. Sci. 8 (2005) 5462.

[45] Y. Kurosaki, K. Yano, T. Kimura, Perfusion cells for studying regional variation inoral mucosal permeability in humans. 2. A specialized transport mechanism inD-glucose absorption across cultured dorsum of tongue, J. Pharm. Sci. 87 (1998)613615.

[46] T. Kimura, H. Yamano, A. Tanaka, T. Matsumara, M. Ueda, K. Ogawara, Transportof D-glucose across cultured stratified cell layer of human oral mucosal cells, J.Pharm. Pharmacol. 54 (2002) 213219.

[47] V. De Caro, G. Giandalia, M.G. Siragusa, C. Paderni, G. Campisi, L.I. Giannola,Evaluation of galantamine transbuccal absorption by reconstituted human oralepithelium and porcine tissue as buccal mucosa models: part I, Eur. J. Pharm.Biopharm. 70 (2008) 869873.

[48] L.I. Giannola, V. De Caro, G. Giandalia, M.G. Siragusa, C. Tripodo, A.D. Florena, G.Campisi, Release of naltrexone on buccal mucosa: permeation studies,histological aspects and matrix system design, Eur. J. Pharm. Biopharm. 67(2007) 425433.

[49] R. Birudaraj, B. Berner, S. Shen, X. Li, Buccal permeation of buspirone:mechanistic studies on transport pathways, J. Pharm. Sci. 94 (2005) 7078.

[50] R.C. Mashru, V.B. Sutariya, M.G. Sankalia, J.M. Sankalia, Effect of pH on in vitropermeation of ondansetron hydrochloride across porcine buccal mucosa, Pharm.Dev. Tech. 10 (2005) 241247.

[51] N. Utoguchi, Y. Watanabe, T. Suzuki, J. Maehara, Y. Matsumoto, M. Matsumoto,Carrier-mediated transport of monocarboxylic acids in primary culturedepithelial cells from rabbit oral mucosa, Pharm. Res. 14 (1997) 320324.

[52] N. Utoguchi, Y. Watanabe, T. Suzuki, J. Maehara, Y. Matsumoto, M. Matsumoto,Carrier-mediated absorption of salicylic acid from hamster cheek pouch mucosa,J. Pharm. Sci. 88 (1999) 142146.

[53] Y. Oyama, H. Yamano, A. Ohkuma, K. Ogawara, K. Higaki, T. Kimura, Carrier-mediated transport systems for glucose in mucosal cells of the human oralcavity, J. Pharm. Sci. 88 (1999) 830834.

[54] Y. Sudhakar, K. Kuotsu, A.K. Bandyopadhyay, Buccal bioadhesive drug delivery - apromisingoption for orally less efficient drugs, J. Control. Release 114(2006)1540.

[55] http://www.intelgenx.com/technologies/quickreleasewafer.html, accessed on02/03/2010.

[56] http://www.bioenvelop.com/english/prd_technology.html, accessed on02/03/2010.

[57] http://www.innozen.com, accessed on 02/03/2010.[58] http://www.biofilm.co.uk/cms/index.php?option=com_content&view=arti-

cle&id=23&Itemid=69, accessed on 02/03/2010.[59] http://www.meldexinternational.com/technology_platforms.asp, accessed on

02/03/2010.[60] http://www.meldexinternational.com/pages/content/index.asp?PageID=50,

accessed on 02/03/2010.[61] http://www.meldexinternational.com/pages/content/index.asp?PageID=48,

accessed on 02/03/2010.[62] http://www.uluruinc.com/oradisc_a.htm, accessed on 02/03/2010.

http://www.intelgenx.com/technologies/quickreleasewafer.htmlhttp://www.bioenvelop.com/english/prd_technology.htmlhttp://www.innozen.comhttp://www.biofilm.co.uk/cms/index.php?option=com_content&view=article&id=23&Itemid=69http://www.biofilm.co.uk/cms/index.php?option=com_content&view=article&id=23&Itemid=69http://www.meldexinternational.com/technology_platforms.asphttp://www.meldexinternational.com/pages/content/index.asp?PageID=50http://www.meldexinternational.com/pages/content/index.asp?PageID=48http://www.uluruinc.com/oradisc_a.htm

116 V.F. Patel et al. / Journal of Controlled Release 153 (2011) 106116[63] http://www.monosolrx.com/technology_thinfilm.html, accessed on02/03/2010.

[64] http://www.monosolrx.com/rx_develop.html, accessed on 02/03/2010.[65] http://www.snoreeze.com/the-snoreeze-range/snoreeze-oral-strips, accessed

on 03/03/2010.[66] http://www.gwpharm.com/Sativex.aspx, accessed on 03/03/2010.[67] http://www.generex.com/technology.php, accessed on 30/03/2010.[68] http://www.novadel.com/pipeline/index.htm, accessed on 30/03/2010.[69] http://www.biodeliverysciences.com/BEMA.php, accessed on 03/03/2010.[70] http://www.biodeliverysciences.com/pipeline.php, accessed on 30/03/2010.[71] http://www.transcept.com/content/view/39/95/, accessed on 30/03/2010.[72] http://www.biodeliverysciences.com/BEMA_Buprenorphine.php, accessed on

03/03/2010.[73] http://www.biodeliverysciences.com/pipeline.php, accessed on 03/03/2010.[74] http://www.labtec-pharma.com/index.php?article_id=24, accessed on

03/03/2010.[75] http://www.medpharm.co.uk.[76] H.H. Alur, J.D. Beal, S.I. Pather, A.K. Mitra, T.P. Johnston, Evaluation of a novel,

natural oligosaccharide gum as a sustained-release and mucoadhesive compo-nent of calcitonin buccal tablets, J. Pharm. Sci. 88 (1999) 13131319.

[77] C.R. Lopez, A. Portero, J.L. Vila-Jato, M.J. Alonso, Design and evaluation ofchitosan/ethylcellulose mucoadhsive bilayered devices for buccal drug delivery,J. Control. Release 55 (1998) 143152.

[78] J.W. Lee, J.H. Park, J.R. Robinson, Bioadhesive-based dosage forms: the nextgeneration, J. Pharm. Sci. 89 (2000) 850866.

[79] J.D. Smart, The basics and underlying mechanisms of mucoadhesion, Adv. DrugDeliv. Rev. 57 (2005) 15561568.

[80] G.P. Andrews, T.P. Laverty, D.S. Jones, Mucoadhesive polymeric platforms forcontrolled drug delivery, Eur. J. Pharm. Biopharm. 71 (2009) 505518.

[81] F. Madsen, K. Eberth, J. Smart, A rheological assessment of the nature ofinteractions between mucoadhesive polymers and a homogenised mucus gel,Biomaterials 19 (1998) 10831092.

[82] M.I. Ugwoke, R.U. Agu, N. Verbeke, R. Kinget, Nasal mucoadhesive drug delivery:background, applications, trends and future perspectives, Adv. Drug Deliv. Rev.57 (2005) 16401665.

[83] D. Dodou, P. Breedveld, P. Wieringa, Mucoadhesives in the gastrointestinal tract:revisiting the literature for novel applications, Eur. J. Pharm. Biopharm. 60(2005) 116.

[84] A. Ahagon, A.N. Gent, Effect of interfacial bonding on the strength of adhesion, J.Polym. Sci., Part B: Polym. Phys. 13 (1975) 12851300.

[85] M.R. Jimnez-Castellanos, H. Zia, C.T. Rhodes, Mucoadhesive drug deliverysystems, Drug Dev. Ind. Pharm. 19 (1993) 143194.

[86] A. Shojaei, X. Li, Mechanisms of buccal mucoadhesion of novel copolymers ofacrylic acid and polyethylene glycol monomethylether monomethacrylate, J.Control. Release 47 (1997) 151161.

[87] A. Ludwig, The use of mucoadhesive polymers in ocular drug delivery, Adv. DrugDeliv. Rev. 57 (2005) 15951639.

[88] N. Fefelova, Z. Nurkeeva, G. Mun, V. Khutoryanskiy, Mucoadhesive interactions ofamphiphilic cationic copolymers based on [2- (methacryloyloxy) ethyl]trimethyl ammonium chloride, Int. J. Pharm. 339 (2007) 2532.

[89] P. He, S. Davis, L. Illum, In vitro evaluation of the mucoadhesive properties ofchitosan microspheres, Int. J. Pharm. 166 (1998) 7588.

[90] A. Portero, D. Teijeiro-Osorio, M. Alonso, C. Remun-Lpez, Development ofchitosan sponges for buccal administration of insulin, Carbohydr. Polym. 68(2007) 617625.

[91] S. Rossi, F. Ferrari, M. Bonferoni, C. Caramella, Characterization of chitosanhydrochloride-mucin interaction by means of viscosimetric and turbidimetricmeasurements, Eur. J. Pharm. Sci. 10 (2000) 251257.

[92] A. Bernkop-Schnrch, Chitosan, its derivatives: potential excipients for peroralpeptide delivery systems, Int. J. Pharm. 194 (2000) 113.

[93] M.A. Clark, B. Hirst, M. Jepson, Lectin-mediated mucosal delivery of drugs andmicroparticles, Adv. Drug Deliv. Rev. 43 (2000) 207223.

[94] V. Leitner, G.Walker, A. Bernkop-Schnrch, Thiolated polymers: evidence for theformation of disulphide bonds with mucus glycoproteins, Eur. J. Pharm.Biopharm. 56 (2003) 207214.

[95] K. Albrecht, M. Greindl, C. Kremser, C. Wolf, P. Debbage, A. Bernkop-Schnrch,Comparative in vivo mucoadhesion studies of thiomer formulations usingmagnetic resonance imaging and fluorescence detection, J. Control. Release 115(2006) 7884.

[96] M. Roldo, M. Hornof, P. Caliceti, A. Bernkop-Schnrch, Mucoadhesive thiolatedchitosans as platforms for oral controlled drug delivery: synthesis and in vitroevaluation, Eur. J. Pharm. Biopharm. 57 (2004) 115121.

[97] D. Patel, A.W. Smith, N. Grist, P. Barnett, J.D. Smart, In-vitro mucosal modelpredictive of bioadhesive agents in the oral cavity, J. Control. Release 61 (1999)175183.

[98] J. Jacobsen, Buccal iontophoretic delivery of atenolol HCl employing a new invitro three-chamber permeation cell, J. Control. Release 70 (2001) 8395.

[99] G. Campisi, L.I. Giannola, A.M. Florena, V. De Caro, A. Schumacher, T. Gttsche, C.Paderni, A. Wolff, Bioavailability in vivo of naltrexone following transbuccaladministration by an electronically-controlled intraoral device: a trial on pigs, J.Control. Release 145 (2010) 214220.

[100] L. Martin, C.G. Wilson, F. Koosha, I.F. Uchegbu, Sustained buccal delivery of thehydrophobic drug denbufylline using physically cross-linked palmitoyl glycolchitosan hydrogels, Eur. J. Pharm. Biopharm. 55 (2003) 3545.[101] I.G. Needleman, Controlled drug release in periodontics: a review of newtherapies, Bri. Dent. J. 170 (1991) 405408.

[102] D.S. Jones, A.D. Woolfson, J. Djokic, W.A. Coulter, Development and mechanicalcharacterization of bioadhesive semi-solid, polymeric systems containingtetracycline for the treatment of periodontal diseases, Pharm. Res. 13 (1996)17341738.

[103] L.B. Heemstra, B.C. Finnin, J.A. Nicolazzo, The buccal mucosa as an alternativeroute for the systemic delivery of risperidone, J. Pharm. Sci. 99 (2010) 45844592.

[104] L. Perioli, C. Pagano, S. Mazzitelli, C. Rossi, C. Nastruzzi, Rheological andfunctional characterization of new anti-inflammatory delivery systems designedfor buccal administration, Int. J. Pharm. 356 (2008) 1928.

[105] M.L. Bruschi, O. de Freitas, Oral bioadhesive drug delivery systems, Drug Dev. Ind.Pharm. 31 (2005) 293310.

[106] S. Rossi, G. Sandri, C.M. Caramella, Buccal drug delivery: a challenge alreadywon? Drug Discovery Today 2 (2005) 5965.

[107] F. Cilurzo, C.G.M. Gennari, F. Selmin, J.B. Epstein, G.M. Gaeta, G. Colella, P.Minghetti,A new mucoadhesive dosage form for the management of oral lichen planus:formulation study and clinical study, Eur. J. Pharm. Biopharm. 76 (2010) 437442.

[108] O.A. Adeleke, V. Pillay, L.C. du Toit, Y.E. Choonara, Construction and in vitrocharacterization of an optimized porosity-enabled amalgamated matrix forsustained transbuccal drug delivery, Int. J. Pharm. 391 (2010) 7989.

[109] S.F. Kramer, G.L. Flynn, Solubility of organic hydrochlorides, Pharm. Res. 61(1972) 18961904.

[110] Y. Wang, Z. Zuo, X. Chen, B. Tomlinson, M.S.S. Chow, Improving sublingualdelivery of weak base compounds using pHmax concept: application topropranolol, Eur. J. Pharm. Sci. 39 (2010) 272278.

[111] J. Ali, R. Khar, A. Ahuja, R. Kalra, Buccoadhesive erodible disk for treatment of oro-dental infections: design and characterisation, Int. J. Pharm. 283 (2002) 93103.

[112] B. Parodi, E. Russo, G. Caviglioli, M. Vallarino, F. Fusco, F. Henriquet, Buccoadhesiveoxycodone hydrochloride disks: plasma pharmacokinetics in healthy volunteersand clinical study, Eur. J. Pharm. Biopharm. 44 (1997) 137142.

[113] M. Artusi, P. Santi, P. Colombo, H.E. Junginger, Buccal delivery of thiocolchicoside: invitro and in vivo permeation studies, Int. J. Pharm. 250 (2003) 203213.

[114] Y. Kohda, H. Kobayashi, Y. Baba, H. Yuasa, T. Ozeki, Y. Kanaya, E. Sagara,Controlled release of lidocaine hydrochloride from buccal mucosa-adhesivefilms with solid dispersion, Int. J. Pharm. 158 (1997) 147155.

[115] N.A. Nafee, F.A. Ismail, N.A. Boraie, L.M. Mortada, Mucoadhesive buccal patches ofmiconazole nitrate: in vitro/in vivo performance and effect of ageing, Int. J.Pharm. 264 (2003) 114.

[116] N.A. Nafee, F.A. Ismail, N.A. Boraie, L.M. Mortada, Design and characterization ofmucoadhesive buccal patches containing cetylpyridinium chloride, Acta Pharm. 53(2003) 199212.

[117] Z. Cui, R.J. Mumper, Bilayer films for mucosal (genetic) immunization via thebuccal route in rabbits, Pharm. Res. 19 (2002) 947953.

[118] S. Rossi, G. Sandri, F. Ferrari, M.C. Bonferoni, C. Caramella, Buccal delivery ofacyclovir from films based on chitosan and polyacrylic acid, Pharm. Dev. Tech.8 (2003) 199208.

[119] Z. Cui, R.J. Mumper, Buccal transmucosal delivery of calcitonin in rabbits usingthin-film composites, Pharm. Res. 19 (2002) 19011906.

[120] M.A. Repka, S. Prodduturi, S.P. Stodghill, Production and characterization of hot-meltextruded films containing clotrimazole, Drug Dev. Ind. Pharm. 29 (2003) 757765.

[121] S.S. Shidhaye, N.S. Saindane, S. Sutar, V. Kadam,Mucoadhesive bilayeredpatches foradministration of sumatriptan succinate, AAPS PharmSciTech 9 (2008) 909916.

[122] S. Kockisch, G.D. Rees, S.A. Young, J. Tsibouklis, J.D. Smart, Polymeric microspheresfor drug delivery to the oral cavity: an in vitro evaluation of mucoadhesivepotential, J. Pharm. Sci. 92 (2003) 16141623.

[123] S. Kockisch, G.D. Rees, S.A. Young, J. Tsibouklis, J.D. Smart, In-situ evaluation ofdrug-loaded microspheres on a mucosal surface under dynamic test conditions,Int. J. Pharm. 276 (2004) 5158.

[124] A.S. Holpuch, G.J. Hummel, M. Tong, G.A. Seghi, P. Pei, P. Ma, R.J. Mumper, S.R.Mallery, Nanoparticles for local drug delivery to the oral mucosa: proof ofprinciple studies, Pharm. Res. 27 (2010) 12241236.

[125] D. Monti, S. Burgalassi, M.S. Rossato, B. Albertini, N. Passerini, L. Rodriguez, P.Chetoni, Poloxamer 407 microspheres for orotransmucosal drug delivery. Part II:in vitro/in vivo evaluation, Int. J. Pharm. 400 (2010) 3236.

[126] R. Laitinen, E. Suihko, K. Toukola, M. Bjrkqvist, J. Riikonen, V. Lehto, K. Jrvinen,J. Ketolainen, Intraorally fast-dissolving particles of a poorly soluble drug:preparation and in vitro characterization, Eur. J. Pharm. Biopharm. 71 (2009)271281.

[127] E. Turunen, J. Mannila, R. Laitinen, J. Riikonen, V. Lehto, T. Jrvinen, J. Ketolainen,K. Jrvinen, P. Jarho, Fast-dissolving sublingual solid dispersion and cyclodextrincomplex increase the absorption of perphenazine in rabbits, J. Pharm.Pharmacol. (Nov. 16 2010), doi:10.1111/j.2042-7158.2010.01173.x.

[128] M.S. El-Samaligy, N.N. Afifi, E.A. Mahmoud, Increasing bioavailability of silymarinusing a buccal liposomal delivery system: preparation and experimental designinvestigation, Int. J. Pharm. 308 (2006) 140148.

[129] P. Pozzilli, S. Manfrini, F. Costanza, G. Coppolino, M.G. Cavallo, E. Fioriti, P. Modi,Biokinetics of buccal spray insulin in patients with type 1 diabetes, Metabol. Clin.Exp. 54 (2005) 930934.

[130] H. Xu, K. Huang, Y. Zhu, Q. Gao, Q. Wu, W. Tian, X. Sheng, Z. Chen, Z. Gao,Hypoglycaemic effect of a novel insulin buccal formulation on rabbits,Pharmacol. Res. 46 (2002) 459467.

[131] http://www.generex.com/products.php?prod_id=Nzk=, accessed on23/11/2010.

http://www.monosolrx.com/technology_thinfilm.htmlhttp://www.monosolrx.com/rx_develop.htmlhttp://www.snoreeze.com/the-snoreeze-range/snoreeze-oral-stripshttp://www.gwpharm.com/Sativex.aspxhttp://www.generex.com/technology.phphttp://www.novadel.com/pipeline/index.htmhttp://www.biodeliverysciences.com/BEMA.phphttp://www.biodeliverysciences.com/pipeline.phphttp://www.transcept.com/content/view/39/95/http://www.biodeliverysciences.com/BEMA_Buprenorphine.phphttp://www.biodeliverysciences.com/pipeline.phphttp://www.labtec-pharma.com/index.php?article_id=24http://www.medpharm.co.ukhttp://dx.doi.org/10.1111/j.20422010.01173.xhttp://www.generex.com/products.php?prod_id=Nzk=

Advances in oral transmucosal drug deliveryIntroductionOverview of the oral mucosaPhysiological barriers for oral transmucosal drug deliveryPhysiological opportunities for oral transmucosal drug deliveryOral transmucosal drug delivery technologiesMucoadhesive systemsTheories of mucoadhesionPolymers for mucoadhesive systems

Dosage formsLiquid dosage formsSemisolid dosage formsSolid dosage formsTablets/lozengesPatches/films/wafersMicro/nano-particulates

Sprays

ConclusionReferences