buccal drug deliverry

Journal of Controlled Release 114 (2006) 15–40www.elsevier.com/locate/jconrel

Review

Buccal bioadhesive drug delivery — A promising optionfor orally less efficient drugs

Yajaman Sudhakar, Ketousetuo Kuotsu, A.K. Bandyopadhyay ⁎

Buccal Adhesive Research Laboratory, Division of Pharmaceutics, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India

Received 4 December 2005; accepted 26 April 2006Available online 7 July 2006

Abstract

Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs includingpeptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoidof untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensivepresystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parentral route of administration isthe only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly,have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the lastfew decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative toinjections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessiblesite for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth musclewhich is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells.Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to highbioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with theoptimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the rightdosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution andpermeation. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceuticalproperties of the drug and excipients. Advances in experimental and computational methodologies will be helpful in shortening the processingtime from formulation design to clinical use. This paper aims to review the developments in the buccal adhesive drug delivery systems to providebasic principles to the young scientists, which will be useful to circumvent the difficulties associated with the formulation design.© 2006 Elsevier B.V. All rights reserved.

Keywords: Buccal delivery; Bioadhesive; Polymers; Formulation; Permeation enhancers; Evaluation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161.1. Buccal mucosal structure and its suitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.2. Absorption pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171.3. Barriers to penetration across buccal mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

1.3.1. Membrane coating granules or cored granules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181.3.2. Basement membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181.3.3. Mucus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181.3.4. Saliva. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

⁎ Corresponding author. Tel.: +91 9831261813; fax: +91 033 30940712.E-mail addresses: [email protected] (Y. Sudhakar), [email protected] (A.K. Bandyopadhyay).

0168-3659/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.jconrel.2006.04.012

mailto:[email protected]

mailto:[email protected]

http://dx.doi.org/10.1016/j.jconrel.2006.04.012

16 Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40

2. Formulation design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192.1. Pharmaceutical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

2.1.1. Buccal adhesive polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.2. Physiological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242.3. Pharmacological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252.4. Permeation enhancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.4.1. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253. Muco/bioadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

3.1. Bio/mucoadhesive forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.1.1. Van der Waal's forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263.1.2. Hydrogen bonding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.1.3. Disulphide bridging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.1.4. Hydration forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.1.5. Electrostatic double-layer forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.1.6. Hydrophobic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.1.7. Steric forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283.1.8. Covalent bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

3.2. Methods for measuring mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283.2.1. Quantitative methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283.2.2. Qualitative methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

3.3. Factors affecting bio/mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314. Developments in buccal adhesive drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

4.1. Commercial buccal adhesive drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324.2. Research on buccal adhesive drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4.2.1. Solid buccal adhesive formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324.2.2. Semi-solid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324.2.3. Liquid dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.3. Delivery of proteins and peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335. Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

5.1. Determination of the residence time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.1.1. In vitro residence time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.1.2. In vivo residence time test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

5.2. Permeation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.2.1. In vitro methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.2.2. Ex vivo methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355.2.3. In vivo methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

1. Introduction

The main impediment to the use of many hydrophilic macro-molecular drugs as potential therapeutic agents is their inadequateand erratic oral absorption. The relatively recent evolution ofrecombinant DNA research and modern synthetic and biotech-nological methodologies allow the biochemist and chemist toproduce vast quantities of variety of peptides and proteins pos-sessing better pharmacological efficacy. However, therapeuticpotential of these compounds lies in our ability to design andachieve effective and stable delivery systems. The future chal-lenge of pharmaceutical scientists will not only be polypeptidecloning and synthesis, but also to develop effective nonparenteraldelivery of intact proteins and peptides to the systemic circulation.Based on our current understanding of biochemical and phy-siological aspects of absorption and metabolism of many bio-technologically-produced drugs, they cannot be deliveredeffectively through the conventional oral route. Because afteroral administration many drugs are subjected to presystemic

clearance extensive in liver, which often leads to a lack of sig-nificant correlation between membrane permeability, absorption,and bioavailability [1]. Difficulties associated with parenteraldelivery and poor oral availability provided the impetus for ex-ploring alternative routes for the delivery of such drugs. Theseinclude routes such as pulmonary, ocular, nasal, rectal, buccal,sublingual, vaginal, and transdermal. In absence of external sti-muli to facilitate absorption, use of these alternative routes has hadlimited success. Various strategies have been implemented topromote the bioavailability of these drugs, including supplemen-tal administration of enzyme inhibitors, use of absorption en-hancers, novel formulation strategies, and reversible chemicalmodifications [2].

Among the various transmucosal routes, buccal mucosa hasexcellent accessibility, an expanse of smooth muscle and relativelyimmobile mucosa, hence suitable for administration of retentivedosage forms. Direct access to the systemic circulation through theinternal jugular vein bypasses drugs from the hepatic first passmetabolism leading to high bioavailability. Other advantages such

Fig. 1. Cross-section of buccal mucosa.

17Y. Sudhakar et al. / Journal of Controlled Release 114 (2006) 15–40

as low enzymatic activity, suitability for drugs or excipients thatmildly and reversibly damages or irritates the mucosa, painlessadministration, easy drug withdrawal, facility to include perme-ation enhancer/enzyme inhibitor or pHmodifier in the formulationand versatility in designing as multidirectional or unidirectionalrelease systems for local or systemic actions etc, opts buccaladhesive drug delivery systems as promising option for continuedresearch [3].

However, the effect of salivary scavenging and accidentalswallowing of delivery system; barrier property of buccal mu-cosa stands as the major limitations in the development ofbuccal adhesive drug delivery systems.

Our intent, therefore, is to discuss the implication of variousapproaches for buccal adhesive delivery strategies applied forthe systemic delivery of orally less/in efficient drugs, in additionto the widely used local drug delivery.

1.1. Buccal mucosal structure and its suitability

Buccal region is that part of the mouth bounded anteriorly andlaterally by the lips and the cheeks, posteriorly and medially bythe teeth and/or gums, and above and below by the reflections ofthe mucosa from the lips and cheeks to the gums. Numerousracemose, mucous, or serous glands are present in the submucoustissue of the cheeks [4]. The buccal glands are placed between themucous membrane and buccinator muscle: they are similar instructure to the labial glands, but smaller. About five, of a largersize than the rest, are placed between the masseter and buccinatormuscles around the distal extremity of the parotid duct; their ductsopen in the mouth opposite the last molar tooth. They are calledmolar glands [5]. Maxillary artery supplies blood to buccal mu-cosa and blood flow is faster and richer (2.4ml/min/cm2) than thatin the sublingual, gingival and palatal regions, thus facilitatespassive diffusion of drug molecules across the mucosa. Thethickness of the buccal mucosa is measured to be 500–800 μmand is rough textured, hence suitable for retentive delivery sys-tems [6]. The turnover time for the buccal epithelium has beenestimated at 5–6 days [7].

Buccal mucosa composed of several layers of different cells asshown in Fig. 1. The epithelium is similar to stratified squamousepithelia found in rest of the body and is about 40–50 cell layersthick [5]. Lining epithelium of buccalmucosa is the nonkeratinizedstratified squamous epithelium that has thickness of approximately500–600 μ and surface area of 50.2 cm2. Basement membrane,lamina propria followed by the submucosa is present below theepithelial layer [8]. Lamina propria is rich with blood vessels andcapillaries that open to the internal jugular vein. Lipid analysis ofbuccal tissues shows the presence of phospholipid 76.3%, glu-cosphingolipid 23.0% and ceramide NS at 0.72%. Other lipidssuch as acyl glucosylated ceramide, and ceramides like Cer AH,CerAP,CerNH,CerAS, and EOHP/NP are completely absent [9].

The primary function of buccal epithelium is the protection ofthe underlying tissue. In nonkeratinized regions, lipid-basedpermeability barriers in the outer epithelial layers protect theunderlying tissues against fluid loss and entry of potentiallyharmful environmental agents such as antigens, carcinogens,microbial toxins and enzymes from foods and beverages [10].

1.2. Absorption pathways

Studies with microscopically visible tracers such as smallproteins [11] and dextrans [12] suggest that the major pathwayacross stratified epithelium of large molecules is via the inter-cellular spaces and that there is a barrier to penetration as a result ofmodifications to the intercellular substance in the superficiallayers. However, rate of penetration varies depending on thephysicochemical properties of the molecule and the type of tissuebeing traversed. This has led to the suggestion that materials usesone or more of the following routes simultaneously to cross thebarrier region in the process of absorption, but one route is pre-dominant over the other depending on the physicochemical pro-perties of the diffusant [13].

➢ Passive diffusion◦ Transcellular or intracellular route (crossing the cellmembrane and entering the cell)

◦ Paracellular or intercellular route (passing between thecells)

➢ Carrier mediated transport➢ Endocytosis

The flux of drug through the membrane under sink conditionfor paracellular route can be written as Eq. (1)

Jp ¼ Dpehp

Cd ð1Þ

Where, Dp is diffusion coefficient of the permeate in the inter-cellular spaces, hp is the path length of the paracellular route, ε is thearea fraction of the paracellular route and Cd is the donor drugconcentration.

Similarly, flux of drug through the membrane under sinkcondition for transcellular route can be written as Eq. (2).

Jc ¼ ð1−eÞDcKc

hcCd ð2Þ

http://en.wikipedia.org/wiki/


Where, Kc is partition coefficient between lipophilic cell mem-brane and the aqueous phase, Dc is the diffusion coefficient ofthe drug in the transcellular spaces and hc is the path length ofthe transcellular route [14].

In very few cases absorption also takes place by the process ofendocytosis where the drug molecules were engulfed by thecells. It is unlikely that active transport processes operate withinthe oral mucosa; however, it is believed that acidic stimulation ofthe salivary glands, with the accompanying vasodilatation, faci-litates absorption and uptake into the circulatory system [15].

The absorption potential of the buccal mucosa is influenced bythe lipid solubility and molecular weight of the diffusant. Ab-sorption of some drugs via the buccal mucosa is found to increasewhen carrier pH is lowered and decreased with an increase of pH[16]. However, the pH dependency that is evident in absorption ofionizable compounds reflects their partitioning into the epithelialcell membrane, so it is likely that such compounds will tend topenetrate transcellularly [17]. Weak acids and weak bases aresubjected to pH-dependent ionization. It is presumed that ionizedspecies penetrate poorly through the oral mucosa compared withnon-ionized species. An increase in the amount of non-ionizeddrug is likely to increase the permeability of the drug across anepithelial barrier, and thismay be achieved by a change of pHof thedrug delivery system. It has been reported that pH has effect on thebuccal permeation of drug through oral mucosa [18]. The diffusionof drugs across buccal mucosa was not related to their degree ofionization as calculated from theHenderson–Hasselbalch equationand thus it is not helpful in the prediction of membrane diffusion ofweak acidic and basic drugs [19].

In general, for peptide drugs, permeation across the buccalepithelium is thought to be through paracellular route by passivediffusion. Recently, it was reported that drugs that have a mono-carboxylic acid residue could be delivered into systemic circulationfrom the oral mucosa via its carrier [20]. The permeability of oralmucosa and the efficacy of penetration enhancers have been inves-tigated in numerous in vivo and in vitro models. Various kinds ofdiffusion cells, including continuous flow perfusion chambers,Ussing chambers, Franz cells andGrass–Sweetana, have been usedto determine the permeability of oral mucosa [21]. Cultured epi-thelial cell lines have also been developed as an in vitro model forstudying drug transport and metabolism at biological barriers aswell as to elucidate the possible mechanisms of action of pene-tration enhancers [22,23]. Recently, TR146 cell culture model wassuggested as a valuable in vitro model of human buccal mucosa forpermeability and metabolism studies with enzymatically labiledrugs, such as leu-enkefalin, intended for buccal drug delivery [24].

1.3. Barriers to penetration across buccal mucosa

The barriers such as saliva, mucus, membrane coating granules,basement membrane etc retard the rate and extent of drug ab-sorption through the buccal mucosa. The main penetration barrierexists in the outermost quarter to one third of the epithelium [8].

1.3.1. Membrane coating granules or cored granulesIn nonkeratinized epithelia, the accumulation of lipids and

cytokeratins in the keratinocytes is less evident and the change in

morphology is far less marked than in keratinized epithelia. Themature cells in the outer portion of nonkeratinized epithelia be-come large and flat, retain nuclei and other organelles and thecytokeratins do not aggregate to form bundles of filaments as seenin keratinizing epithelia. As cells reach the upper third to quarter ofthe epithelium, membrane-coating granules become evident at thesuperficial aspect of the cells and appear to fuse with the plasmamembrane so as to extrude their contents into the intercellularspace. The membrane-coating granules found in nonkeratinizingepithelia are spherical in shape, membrane-bounded and measureabout 0.2 μm in diameter [25]. Such granules have been observedin a variety of other human nonkeratinized epithelia, includinguterine cervix [26] and esophagus [27]. However, current studiesemploying ruthenium tetroxide as a post-fixative indicate that inaddition to cored granules, a small proportion of the granules innonkeratinized epithelium do contain lamellae, which may be thesource of short stacks of lamellar lipid scattered throughout theintercellular spaces in the outer portion of the epithelium. Incontrast to the intercellular spaces of stratum corneum, those of thesuperficial layer of nonkeratinizing epithelia contain electron lu-cent material, which may represent nonlamellar phase lipid, withonly occasional short stacks of lipid lamellae.

1.3.2. Basement membraneAlthough the superficial layers of the oral epithelium represent

the primary barrier to the entry of substances from the exterior, it isevident that the basement membrane also plays a role in limiting thepassage of materials across the junction between epithelium andconnective tissue. A similar mechanism appears to operate in theopposite direction. The charge on the constituents of the basallaminamay limit the rate of penetration of lipophilic compounds thatcan traverse the superficial epithelial barrier relatively easily [28].

1.3.3. MucusThe epithelial cells of buccal mucosa are surrounded by the

intercellular ground substance called mucus with the thicknessvaries from 40 μm to 300 μm [29]. Though the sublingual glandsand minor salivary glands contribute only about 10% of all saliva,together they produce the majority of mucus and are critical inmaintaining the mucin layer over the oral mucosa [30]. It serves asan effective delivery vehicle by acting as a lubricant allowing cellsto move relative to one another and is believed to play a major rolein adhesion ofmucoadhesive drugdelivery systems [31]. At buccalpH, mucus can form a strongly cohesive gel structure that binds tothe epithelial cell surface as a gelatinous layer [8]. Mucus mole-cules are able to join together to make polymers or an extendedthree-dimensional network.Different types ofmucus are produced,for example G, L, S, P and Fmucus, which form different networkof gels. Other substances such as ions, protein chains, and enzymesare also able to modify the interaction of themucus molecules and,as a consequence, their biophysical properties [32].

Mucus is composed chiefly of mucins and inorganic saltssuspended in water. Mucins are a family of large, heavily gly-cosylated proteins composed of oligosaccharide chains attachedto a protein core. Three quarters of the protein core are heavilyglycosylated and impart a gel like characteristic tomucus.Mucinscontain approximately 70–80% carbohydrate, 12–25% protein


and up to 5% ester sulphate [33]. The dense sugar coating ofmucins gives them considerable water-holding capacity and alsomakes them resistant to proteolysis, which may be important inmaintaining mucosal barriers [4].

Mucins are secreted as massive aggregates by prostaglandinswithmolecularmasses of roughly 1 to 10millionDa.Within theseaggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulphide bondsalso play a role in this process. Oligosaccharide side chains con-tain an average of about 8–10 monosaccharide residues of fivedifferent types namely L-fucose, D-galactose, N-acetyl-D-glucos-amine, N-acetyl-D-galactosamine and sialic acid. Amino acidspresent are serine, threonine and proline [34]. Because of thepresence of sialic acids and ester sulfates, mucus is negativelycharged at physiological salivary pH of 5.8–7.4 [8].

At least 19 human mucin genes have been distinguished bycDNA cloning-MUC1, 2, 3A, 3B, 4,5AC, 5B, 6–9, 11–13, and15–19.Mucin genes encodemucin monomers that are synthesizedas rod-shaped apomucin covers that are post translationally modi-fied by exceptionally abundant glycosylation. Two distinctly dif-ferent regions are found in mature genes. The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines,which are likely, involved in establishing disulfide linkages withinand among mucin monomers. A large central region formed ofmultiple tandems repeats of 10 to 80 residue sequences in which upto half of the amino acids are serine or threonine. This area becomessaturated with hundreds of O-linked oligosaccharides also foundon mucins, but much less abundantly [4].

Mucins are characterized not only by large molecular massesbut also by largemolecularmass distributions, as seen by analyticalultra centrifugation, and by the powerful technique of sizeexclusion chromatography coupled to multi-angle laser light sca-ttering [35,36]. In solution, mucins adopt a random-coil confor-mation [37], occupying a time averaged spheroidal domain asshown by hydrodynamics and critical-point-drying electron mi-croscopy. Mucins, which are different, are the submaxillary mu-cins, with a lower carbohydrate content and different structure [38].

1.3.4. SalivaThe mucosal surface has a salivary coating estimated to be

70 μm thick [39], which act as unstirred layer. Within the salivathere is a high molecular weight mucin named MG1 [40] that canbind to the surface of the oral mucosa so as to maintain hydration,provide lubrication, concentrate protective molecules such assecretory immunoglobulins, and limit the attachment of micro-organisms. Several independent lines of evidence suggest thatsaliva and salivarymucin contribute to the barrier properties of oralmucosa [41]. The major salivary glands consist of lobules of cellsthat secrete saliva; parotids through salivary ducts near the upperteeth, submandibular under the tongue, and the sublingual throughmany ducts in the floor of the mouth. Besides these glands, thereare 600–1000 tiny glands called minor salivary glands located inthe lips, inner cheek area (buccal mucosa), and extensively in otherlinings of the mouth and throat [42]. Total output from the majorand minor salivary glands is termed as whole saliva, which atnormal conditions has flow rate of 1–2 ml/min [43]. Greatersalivary output avoids potential harm to acid-sensitive tooth enamel

by bathing the mouth in copious neutralizing fluid [44]. Withstimulation of salivary secretion, oxygen is consumed andvasodilator substances are produced; and the glandular bloodflow increases, due to increased glandular metabolism [45]. Salivais composed of 99.5% water in addition to proteins, glycoproteinsand electrolytes. It is high in potassium (7×plasma), bicarbonate(3×plasma), calcium, phosphorous, chloride, thiocyanate and ureaand low in sodium (1/10×plasma). The normal pH of saliva is 5.6–7. Saliva contains enzymes namely α-amylase (breaks 1–4glycosidic bonds), lysozyme (protective, digests bacterial cellwalls) and lingual lipase (break down the fats) [46].

Saliva serves multiple important functions. It moistens themouth, initiates digestion and protects the teeth from decay. It alsocontrols bacterial flora of the oral cavity. Because saliva is high incalcium and phosphate, it plays a role in mineralization of newteeth repair and precarious enamel lesions. It protects the teeth byforming “protective pellicle”. This signifies a saliva protein coat onthe teeth, which contains antibacterial compounds. Thus, problemswith the salivary glands generally result in rampant dental caries.Lysozyme, secretory IgA, and salivary peroxidase play importantroles in saliva's antibacterial actions. Lysozyme agglutinates bac-teria and activates autolysins. Ig A interferes with the adherence ofmicroorganisms to host tissue. Peroxidase breaks down salivarythiocyanate, which in turn, oxidizes the enzymes involved inbacterial glycolysis. However, salivary flow rate may play role inoral hygiene. Intraoral complications of salivary hypofunctionmaycause candidiasis, oral lichen planus, burning mouth syndrome,recurrent aphthous ulcers and dental caries. A constant flowingdown of saliva within the oral cavity makes it very difficult fordrugs to be retained for a significant amount of time in order tofacilitate absorption in this site [44,45]. The other important factorof great concern is the role of saliva in development of dentalcaries. Salivary enzymes act on natural polysaccharidic polymersthat hasten the growth of mutants of streptococci and other plaquebacteria leading to development of dental caries.

In general, intercellular spaces pose as the major barrier topermeation of lipophilic compounds, and the cell membranewhich is lipophilic in nature acts as the major transport barrier forhydrophilic compounds because it is difficult to permeate throughthe cell membrane due to a low partition coefficient [13].Permeabilities between different regions of the oral cavity varygreatly because of the diverse structures and functions. In general,the permeability is based on the relative thickness and degree ofkeratinization of these tissues in the order of sublingual>buc-cal>palatal. The permeability of the buccalmucosawas estimatedto be 4–4000 times greater than that of the skin [47].

2. Formulation design

Buccal adhesive drug delivery systems with the size 1–3 cm2

and a daily dose of 25 mg or less are preferable. The maximalduration of buccal delivery is approximately 4–6 h [3].

2.1. Pharmaceutical considerations

Great care needs to be exercised while developing a safeand effective buccal adhesive drug delivery device. Factors



Table 1Properties and characteristics of some representative bioadhesive polymers

Bioadhesives Properties Characteristics

Polycarbophil (polyacrylic acid crosslinked withdivinyl glycol)

• Mw 2.2×105 • Synthesized by lightly crosslinking of 0.5–1%w/w divinyl glycol• η 2000–22,500 cps (1% aq. soln.)• Swellable depending on pH and ionic strength.• κ 15–35 mL/g in acidic media (pH 1–3) 100 mL/g in

neutral and basic media • Swelling increases as pH increases.• φ viscous colloid in cold water • At pH 1–3, absorbs 15–35 ml of water per gram but

absorbs 100 ml per gram at neutral and alkaline pH.• Insoluble in water, but swell to varying degrees incommon organic solvents, strong mineral acids, andbases.

• Entangle the polymer with mucus on the surface ofthe tissue• Hydrogen bonding between the nonionizedcarboxylic acid and mucin.

Carbopol/carbomer (carboxy polymethylene)empirical formula: (C3H4O2)x (C3H5–Sucrose)y

• Pharmaceutical grades: 934 P, 940 P, 971 P and 974 P. • Synthesized by cross-linker of allyl sucrose orallyl pentaerythritol• Excellent thickening, emulsifying, suspending,gelling agent.

• Mw 1×106–4×106

• Common component in bioadhesive dosage forms.

• η 29,400–39,400 cps at 25 °C with 0.5% neutralizedaqueous solution.

• Gel looses viscosity on exposure to sunlight.• κ 5 g/cm3 in bulk, 1.4 g/cm3 tapped.

• Unaffected by temperature variations, hydrolysis,oxidation and resistant to bacterial growth.

• pH 2.5–3.0

• It contributes no off-taste and may mask theundesirable taste of the formulation.

• φ water, alcohol, glycerin

• Incompatible with Phenols, cationic polymers,high concentrations of electrolytes and resorcinol.

•White, fluffy, acidic, hygroscopic powder with a slightcharacteristic odour.

Sodium carboxymethyl cellulose SCMC (cellulosecarboxymethyl ether sodium salt) empiricalformula: [C6H7O2(OH)3x (OCH2–COONa)x]n

• It is an anionic polymer made by swelling cellulosewith NaOH and then reacting it with monochloroaceticacid.

• Emulsifying, gelling, binding agent

• Grades H, M, and L

• Sterilization in dry and solution form, irradiationof solution loses the viscosity.

• Mw 9×104–7×105• Stable on storage.

• η 1200 cps with 1.0% soln.• Incompatible with strongly acidic solutions

• ρ 0.75 g/cm3 in bulk• In general, stability with monovalent salts is verygood; with divalent salts good to marginal; withtrivalent and heavy metal salts poor, resulting ingelation or precipitation.

• pH 6.5–8.5

• CMC solutions offer good tolerance of watermiscible solvents, good viscosity stability over thepH 4 to pH 10 range, compatibility with most watersoluble nonionic gums, and synergism with HECand HPC.

• φ water

• Most CMC solutions are thixotropic; some arestrictly pseudoplastic.

•White to faint yellow, odorless, hygroscopic powder orgranular material having faint paper-like taste.

•All solutions showa reversible decrease in viscosity atelevated temperatures. CMC solutions lack yield value.• Solutions are susceptible to shear, heat, bacterial,enzyme, and UV degradation.• Good bioadhesive strength.• Cell immobilization via a combination of ionotropicgelation and polyelectrolyte complex formation (e.g.,with chitosan) in drug delivery systems and dialysismembranes.

Hydroxypropyl cellulose partially substitutedpolyhydroxy propylether of cellulose HPC(cellulose 2-hydroxypropyl ether) empiricalformula: (C15H28O8)n

• Grades: Klucel EF, LF, JF, GF, MF and HF • Best pH is between 6.0 and 8.0.• Mw 6×104–1×106 • Solutions of HPC are susceptible to shear, heat,

bacterial, enzymatic and bacterial degradation.• η 4–6500 cps with 2.0% aq. soln.• It is inert and showed no evidence of skin irritationor sensitization.• ρ 0.5 g/cm3 in bulk•Compatiblewithmostwater-soluble gums and resins.

• pH 5.0–8.0

• Synergistic with CMC and sodium alginate.• Soluble in water below 38 °C, ethanol, propyleneglycol, dioxane, methanol, isopropyl alcohol, dimethylsulphoxide, dimethyl formamide etc. • Not metabolized in the body.• Insoluble in hot water • It may not tolerate high concentrations of

dissolved materials and tend to be salting out.• White to slightly yellowish, odorless powder.• It is also incompatible with the substitutedphenolic derivatives such as methyl and propylparahydroxy benzoate.• Granulating and film coating agent for tablet• Thickening agent, emulsion• Stabilizer, suspending agent in oral and topicalsolution or suspension


ydroxypropylmethyl Cellulose HPMC (cellulose2-hydroxypropylmethyl ether) empirical formula:C8H15O6–(C10H18O6)n–C8H15O5

•Methocel E5, E15, E50, E4M, F50, F4M, K100, K4M,K15M, K100M.

• Mixed alkyl hydroxyalkyl cellulosic ether

• Mw 8.6×104• Suspending, viscosity-increasing and film-forming agent

• η E15–15 cps, E4M–400 cps and K4M–4000 cps(2% aqueous solution.)

• Tablet binder and adhesive ointment ingredient

• φ Cold water, mixtures of methylene chloride andisopropylalcohol.

• E grades are generally suitable as film formerswhile the K grades are used as thickeners.

• Insoluble in alcohol, chloroform and ether.• Stable when dry.

• Odorless, tasteless, white or creamy white fibrous orgranular powder.

• Solutions are stable at pH 3.0 to 11.0• Incompatible to extreme pH conditions andoxidizing materials.

ydroxyethyl Cellulose non-ionic polymer madeby swelling cellulose with NaOH and treating withethylene oxide.

•Available in grades ranging from2 to 8,00,000 cps at 2%. • Solutions are pseudoplastic and show a reversibledecrease in viscosity at elevated temperatures.• Light tan or cream to white powder, odorless and

tasteless. It may contain suitable anticaking agents. • HEC solutions lack yield value.• ρ 0.6 g/mL • Solutions show only a fair tolerance with water

miscible solvents (10 to 30% of solution weight).• pH 6–8.5•Compatible withmost water-soluble gums and resins.• φ in hot or cold water and gives a clear, colorless

solution. • Synergistic with CMC and sodium alginate.• Susceptible for bacterial and enzymatic degradation.• Polyvalent inorganic salts will salt out HEC atlower concentrations than monovalent salts.• Shows good viscosity stability over the pH 2 to pH12 ranges.• Used as suspending or viscosity builder• Binder, film former.

anthan gum xanthan gum is an anionicpolysaccharide derived from the fermentation ofthe plant bacteria Xanthamonas campestris

• It is soluble in hot or cold water and gives visuallyhazy, neutral pH solutions.

•Xanthan gum is more tolerant of electrolytes, acidsand bases than most other organic gums.

• It will dissolve in hot glycerin. • It can, nevertheless, be gelled or precipitated withcertain polyvalent metal cations under specificcircumstances.

• Solutions are typically in the 1500 to 2500 cps range at1%; they are pseudoplastic and especially shear-thinning.In the presence of small amounts of salt, solutions showsgood viscosity stability at elevated temperatures.

• Solutions show very good viscosity stability overthe pH 2 to 12 range and good tolerance of water-miscible solvents.• Solutions possess excellent yield value.• It is more compatible with most nonionic andanionic gums, featuring useful synergism withgalactomannans.• It is more resistant to shear, heat, bacterial,enzyme, and UV degradation than most gums.

uar gum (galactomannan polysaccharide) empiricalformula: (C6H12O6)n consists chiefly of a highmolecular weight hydrocolloid polysaccharidecomposed of galactan and mannan units combinedthrough glycosidic linkages

• Obtained from the ground endosperms of the seeds ofCyamposis tetyragonolobus (family leguminosae).

• Stable in solution over a pH range of 1.0–10.5.

• MW approx. 220,000• Prolonged heating degrades viscosity.Bacteriological stability can be improved by theaddition of mixture of 0.15% methyl paraben or0.1% benzoic acid.

• η 2000–22500 Cps (1% aqueous solution.)

• The FDA recognizes guar gum as a substanceadded directly to human food and has been affirmedas generally recognized as safe.

• Forms viscous colloidal solution when hydrated incold water. The optimum rate of hydration is between pH7.5 and 9.0.

• Incompatible with acetone, tannins, strong acids,and the alkalis. Borate ions, if present in thedispersing water, will prevent hydration of guar.• Used as thickener for lotions and creams, as tabletbinder, and as emulsion stabilizer.

ydroxypropyl Guar non-ionic derivative of guar.Prepared by reacting guar gum with propyleneoxide.

• Φ in hot and cold water • Compatible with high concentration of most salts.• Gives high viscosity, pseudoplastic solutions that showreversible decrease in viscosity at elevated temperatures.

• Shows good tolerance of water miscible solvents.

• Lacks yield value.• Better compatibility with minerals than guar gum.• Good viscosity stability in the pH range of 2 to 13.•More resistance to bacterial and enzymatic degradation.

hitosan a linear polysaccharide composed ofrandomly distributed β-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit).

• Prepared from chitin of crabs and lobsters by N-deacetylation with alkali.

• Mucoadhesive agent due to either secondarychemical bonds such as hydrogen bonds or ionicinteractions between the positively charged aminogroups of chitosan and the negatively charged sialicacid residues of mucus glycoproteins or mucins.

• Φ dilute acids to produce a linear polyelectrolyte witha high positive charge density and forms salts withinorganic and organic acids such as glutamic acid,hydrochloric acid, lactic acid, and acetic acid. • Possesses cell-binding activity due to polymer

cationic polyelectrolyte structure and to the negativecharge of the cell surface.

• The amino group in chitosan has a pKa value of ∼6.5,thus, chitosan is positively charged and soluble in acidicto neutral solution with a charge density dependent onpH and the %DA-value.

• Biocompatible and biodegradable.• Excellent gel forming and film forming ability.


Table 1 (continued )


H

H

X

G

H

C

(continued on next page)



•Widely used in controlled delivery systems such asgels, membranes, microspheres.• Chitosan enhance the transport of polar drugsacross epithelial surfaces. Purified qualities ofchitosans are available for biomedical applications.Chitosan and its derivatives such as trimethylchitosan(where the amino group has been trimethylated)have been used in non-viral gene delivery.Trimethylchitosan, or quaternised chitosan, hasbeen shown to transfect breast cancer cells. As thedegree of trimethylation increases the cytotoxicityof the derivative increases. At approximately 50%trimethylation the derivative is the most efficient atgene delivery. Oligomeric derivatives (3–6 kDa) arerelatively non-toxic and have good gene deliveryproperties.

Carrageenan an anionic polysaccharide, extractedfrom the red seaweed Chondrus crispus.

• Available in sodium, potassium, magnesium, calciumand mixed cation forms.

• All solutions are pseudoplastic with some degreeof yield value. Certain ca-Iota solutions arethixotropic. Lambda is non-gelling, Kappa canproduce brittle gels; Iota can produce elastic gels.All solutions show a reversible decrease in viscosityat elevated temperatures. Iota and Lambdacarrageenan have excellent electrolyte tolerance;kappa's being somewhat less. Electrolytes willhowever decreases solution viscosity. The bestsolution stability occurs in the pH 6 to 10. It iscompatible with most nonionic and anionic water-soluble thickeners. It is strongly synergistic withlocust bean gum and strongly interactive withproteins. Solutions are susceptible to shear andheat degradation.

• Three structural types exist: Iota, Kappa, andLambda, differing in solubility and rheology.

• Excellent thermoreversible properties.

• The sodium form of all three types is soluble in bothcold and hot water.

• Used also for microencapsulation.

• Other cation forms of kappa and Iota are soluble onlyin hot water.• All forms of lambda are soluble in cold water.

SodiumAlginate consists chiefly of the alginic acid,a polyuronic acid composed of β-D-mannuronicacid residues. empirical formula: (C6H7O6Na)nanionic polysaccharide extracted principally fromthe giant kelp Macrocystis Pyrifera as alginic acidand neutralized to sodium salt.

• Purified carbohydrate product extracted from brownseaweed by the use of dilute alkali.

• Safe and nonallergenic.

• Occurs as a white or buff powder, which is odorlessand tasteless.

• Incompatible with acridine derivatives, crystalviolet, phenyl mercuric nitrate and acetate, calciumsalts, alcohol in concentrations greater than 5%, andheavy metals.• pH 7.2• Stabilizer in emulsion, suspending agent, tabletdisintegrant, tablet binder.

• η 20–400 Cps (1% aqueous solution.)

• It is also used as haemostatic agent in surgicaldressings

• φ Water, forming a viscous, colloidal solution.

• Excellent gel formation properties

• Insoluble in other organic solvents and acids where thepH of the resulting solution and acids where the pH ofthe resulting solution falls below 3.0.

• Biocompatible• Microstructure and viscosity are dependent on thechemical composition.• Used as immobilization matrices for cellsand enzymes, controlled release of bioactivesubstances, injectable microcapsules for treatingneurodegenerative and hormone deficiencydiseases.• Lacks yield value.• Solutions show fair to good tolerance of watermiscible solvents (10–30% of volatile solvents; 40–70% of glycols)• Compatible with most water-soluble thickenersand resins.• Its solutions are more resistant to bacterial andenzymatic degradation than many other organicthickeners.

Poly (hydroxy butyrate), Poly (e-caprolactone)and copolymers

• Biodegradable • Used as a matrix for drug delivery systems, cellmicroencapsulation.• Properties can be changed by chemical modification,

copolymerization and blending.Poly (ortho esters) • Surface eroding polymers. • Application in sustained drug delivery and

ophthalmology.


Poly (cyano acrylates) • Biodegradable depending on the length of the alkylchain.

• Used as surgical adhesives and glues.• Potentially used in drug delivery.

Polyphosphazenes • Can be tailored with versatile side chain functionality • Can be made into films and hydrogels.• Applications in drug delivery.

Poly (vinyl alcohol) • Biocompatible • Gels and blended membranes are used in drugdelivery and cell immobilization.

Poly (ethylene oxide) • Highly biocompatible. • Its derivatives and copolymers are used in variousbiomedical applications.

Poly (hydroxytheyl methacrylate) • Biocompatible • Hydrogels have been used as soft contact lenses,for drug delivery, as skin coatings, and forimmunoisolation membranes.

Poly (ethylene oxide-b-propylene oxide) • Surfactants with amphiphilic properties. • Used in protein delivery and skin treatments.




influencing drug release and penetration through buccalmucosa, organoleptic factors, and effects of additives usedto improve drug release pattern and absorption, the effects oflocal drug irritation caused at the site of application are to beconsidered while designing a formulation.

2.1.1. Buccal adhesive polymersPolymer is a generic term used to describe a very long

molecule consisting of structural units and repeating unitsconnected by covalent chemical bonds. The term is derivedfrom the Greek words: polys meaning many, and merosmeaning parts [4]. The key feature that distinguishespolymers from other molecules is the repetition of manyidentical, similar, or complementary molecular subunits inthese chains. These subunits, the monomers, are smallmolecules of low to moderate molecular weight, and arelinked to each other during a chemical reaction calledpolymerization. Instead of being identical, similar monomerscan have varying chemical substituents. The differencesbetween monomers can affect properties such as solubility,flexibility, and strength. The term buccal adhesive polymercovers a large, diverse group of molecules, includingsubstances from natural origin to biodegradable grafted co-polymers and thiolated polymers.

Bioadhesive formulations use polymers as the adhesivecomponent. These formulations are often water soluble andwhen in a dry form attract water from the biological surfaceand this water transfer leads to a strong interaction. Thesepolymers also form viscous liquids when hydrated with waterthat increases their retention time over mucosal surfaces andmay lead to adhesive interactions. Bioadhesive polymersshould possess certain physicochemical features includinghydrophilicity, numerous hydrogen bond-forming groups,flexibility for interpenetration with mucus and epithelialtissue, and visco-elastic properties [48].

2.1.1.1. Ideal characteristics.

✓ Polymer and its degradation products should be non-toxic,non-irritant and free from leachable impurities.

✓ Should have good spreadability, wetting, swelling andsolubility and biodegradability properties.

✓ pH should be biocompatible and should possess goodviscoelastic properties.

✓ Should adhere quickly to buccal mucosa and shouldpossess sufficient mechanical strength.

✓ Should possess peel, tensile and shear strengths at thebioadhesive range.

✓ Polymer must be easily available and its cost should notbe high.

✓ Should show bioadhesive properties in both dry andliquid state.

✓ Should demonstrate local enzyme inhibition and penetra-tion enhancement properties.

✓ Should demonstrate acceptable shelf life.✓ Should have optimum molecular weight.✓ Should possess adhesively active groups.✓ Should have required spatial conformation.✓ Should be sufficiently cross-linked but not to the degree

of suppression of bond forming groups.✓ Should not aid in development of secondary infections

such as dental caries.

2.1.1.2. Some representative polymers:2.1.1.2.1. Hydrogels. Hydrogels, often called as “wet”

adhesives because they require moisture to exhibit theadhesive property. They are usually considered to be crosslinked water swollen polymers having water content rangingfrom 30% to 40% depending on the polymer used. These arehydrophilic matrices that absorb water when placed in anaqueous media. This may be supplied by the saliva, whichmay also act as the dissolution medium. They are structuredin such a manner that the crosslinking fibers present in theirmatrix effectively prevent them from being dissolved and thushelp them in retaining water. When drugs are loaded intothese hydrogels, as water is absorbed into the matrix, chainrelaxation occurs and drug molecules are released through thespaces or channels within the hydrogel network. Polymerssuch as polyacrylates (carbopol and polycarbophil), ethylenevinyl alcohol, polyethylene oxide, poly vinyl alcohol, poly(N-acryloylpyrrolidine), polyoxyethylenes, self cross linkedgelatin, sodium alginate, natural gums like guar gum, karayagum, xanthan gum, locust bean gum and cellulose ethers likemethyl cellulose, hydroxypropyl cellulose, hydroxy propyl



methyl cellulose, sodium carboxy methyl cellulose etc. formpart of the family of hydrogels [49].

2.1.1.2.2. Copolymers. Researchers are currently workingon carrier systems containing block copolymers rather thanusing single polymeric system. Copolymerization with two ormore different monomers results in chains with variedproperties. A block copolymer is formed when the reaction iscarried out in a stepwise manner, leading to a structure with longsequences or blocks of one monomer alternating with longsequences of the other. These networks when composed ofhydrophilic and hydrophobic monomers are called polymermicelle. These micelles are suitable for enclosing individualdrug molecules. Their hydrophilic outer shells help to protectthe cores and their contents from chemical attack by aqueousmedium. Most micelle-based systems are formed from poly(ethylene oxide)-b-polypropylene-b-poly (ethylene oxide) tri-block network.

There are also graft copolymers, in which entire chains of onekind (e.g., polystyrene) are made to grow out of the sides ofchains of another kind (e.g., polybutadiene), resulting in aproduct that is less brittle and more impact-resistant. Thus, blockand graft copolymers can combine the useful properties of bothconstituents and often behave as quasi-two-phase systems [50].

2.1.1.2.3. Multifunctional polymers. These are the bioad-hesive polymers having multiple functions. In addition to thepossession of bioadhesive properties, these polymers will alsoserve several other functions such as enzyme inhibition, per-meation enhancing effect etc. Examples are polyacrylates, po-lycarbophil, chitosan etc.

2.1.1.2.4. Thiolated polymers. These are the special classof multifunctional polymers also called thiomers. These arehydrophilic macromolecules exhibiting free thiol groups on thepolymeric backbone. Due to these functional groups variousfeatures of well established polymeric excipients such as poly(acrylic acid) and chitosan were strongly improved [51]. Thi-olated polymers designated thiomers are capable of formingdisulphide bonds with cysteine-rich subdomains of mucus gly-coproteins covering mucosal membranes [52]. Consequently, thebridging structure most commonly used in biological systems isutilized to bind drug delivery systems on themucosal membranes.By immobilization of thiol groups themucoadhesive properties ofpoly (acrylicacid) and chitosan, was improved to 100-fold to 250-fold [53,54].

Thiomers are capable of forming intra- and interchaindisulphide bonds within the polymeric network leading to stronglyimproved cohesive properties and stability of drug delivery sys-tems such asmatrix tablets. Due to the formation of strong covalentbonds with mucus glycoproteins, thiomers show the strongestmucoadhesive properties of all so far tested polymeric excipientsvia thioldisulphide exchange reaction and an oxidation process.Zinc dependent proteases such as aminopeptidases and carbox-ypeptidases are inhibited by thiomers. The underlying mechanismis based on the capability of thiomers to bind zinc ions and thisproperty is highly beneficial for oral administration of protein andpeptide drugs. They also exhibit permeation-enhancing effects forthe paracellular uptake of drugs based on a glutathione-mediatedopening process of the tight junctions [55,56].

2.1.1.2.5. Milk protein. A particular example is a milkprotein concentrate containing a minimum of 85% of proteinssuch as Prosobel L85, LR85F at concentration of 15% to 50%,preferably 20% to 30% in a bioadhesive tablet showed goodbioadhesive property [57].

2.1.1.2.6. In general.

➢ Cationic and anionic polymers bind more effectively thanneutral polymers.

➢ Anionic polymers with sulphate groups bind moreeffectively than those with carboxylic groups.

➢ Polyanions are better than polycations in terms of bindingpotential and toxicity.

➢ Water-insoluble polymers give greater flexibility indosage form design compared to rapidly or slowly dis-solving water-soluble polymers.

➢ Degree of binding is proportional to the charge density onthe polymer.

Some of the properties and characteristics of buccal adhesivepolymers are listed in Table 1.

2.1.1.3. Factors governing drug release from a polymer. Fora given drug the release kinetics from the polymer matrixcould be governed predominantly by the polymer morphologyand excipients present in the system. Drug release from apolymeric material takes place either by the diffusion or bypolymer degradation or by a combination of the both.Polymer degradation generally takes place by the enzymesor hydrolysis either in the form of bulk erosion or surfaceerosion [58].

2.1.1.3.1. Polymer morphology. The polymer matrixcould be formulated as macro or nanospheres, gel film or anextruded shape (cylinder, rod etc). Also the shape of the ex-truded polymer can be important to the drug release kinetics. Ithas been shown that zero order release kinetics can be achievedusing hemispherical polymer form.

2.1.1.3.2. Excipients. The main objective of incorporatingexcipients in the polymer matrix is to modulate polymer degra-dation kinetics. Studies carried out have shown that by in-corporating basic salts as excipients slow down the degradationand increases the stability of protein polymers. Similarly hydro-philic excipients can accelerate the release of drugs althoughthey may also increase the initial burst effect.

2.2. Physiological considerations

Physiological considerations such as texture of buccalmucosa, thickness of the mucus layer, its turn over time, effectof saliva and other environmental factors are to be considered indesigning the dosage forms [59]. Saliva contains moderatelevels of esterases, carbohydrases, and phosphatases that maydegrade certain drugs. Although saliva secretion facilitates thedissolution of drug, involuntary swallowing of saliva alsoaffects its bioavailability. Hence development of unidirectionalrelease systems with backing layer results high drug bioavail-ability [60].


2.3. Pharmacological considerations

Drug absorption depends on the partition coefficient of thedrugs. Generally lipophilic drugs absorb through the transcel-lular route, where as hydrophilic drugs absorb through theparacellular route. Chemical modification may increase drugpenetration through buccal mucosa. Increasing nonionizedfraction of ionizable drugs increases drug penetration throughtranscellular route. In weakly basic drugs, the decrease in pHincreases the ionic fraction of drug but decreases itspermeability through buccal mucosa [61]. Electrostaticinteractions of drugs such as tetracycline, hydrogen bondingwith drugs like urea and hydrophobic interactions with drugslike testosterone with mucin will decrease rate of absorption[62]. Residence time and local concentration of the drug inthe mucosa, the amount of drug transported across themucosa into the blood are the responsible factors for local orsystemic drug delivery. Optimization by a suitable formula-tion design hastens drug release from the dosage form andtaken up by the oral mucosa. Drugs such as buprenorphine,testosterone, fentanyl, nifedipine and several peptides such asinsulin, thyrotropin-releasing hormone, and oxytocin havebeen tried to deliver via the buccal route. However therelative bioavailabilities of peptides by the buccal route werestill low due to its poor permeation and enzymatic barrier ofbuccal mucosa but can be improved by the incorporation ofpenetration enhancers and/or enzyme inhibitors [63]. Previousdrug absorption studies have demonstrated that oral mucosalabsoption of amines and acids at constant concentration areproportional to their partition coefficients. Similar dependen-cies on partition coefficients were obtained from acyclovir, β-adrenoreceptor blocking agents, substituted acetanilide, andothers [18].

2.4. Permeation enhancers

Membrane permeation is the limiting factor for many drugsin the development of buccal adhesive delivery devices. Theepithelium that lines the buccal mucosa is a very effectivebarrier to the absorption of drugs. Substances that facilitate thepermeation through buccal mucosa are referred as permeationenhancers [64]. As most of the penetration enhancers wereoriginally designed for purposes other than absorptionenhancement, a systemic search for safe and effectivepenetration enhancers must be a priority in drug delivery. Thegoal of designing penetration enhancers, with improvedefficacy and reduced toxicity profile is possible by under-standing the relationship between enhancer structure and theeffect induced in the membrane and of course, the mechanismof action. However, the selection of enhancer and its efficacydepends on the physicochemical properties of the drug, site ofadministration, nature of the vehicle and other excipients. Insome cases usage of enhancers in combination has shownsynergistic effect than the individual enhancers. The efficacy ofenhancer in one site is not same in the other site because ofdifferences in cellular morphology, membrane thickness,enzymatic activity, lipid composition and potential protein

interactions are structural and functional properties. Penetrationenhancement to the buccal membrane is drug specific [65].Effective penetration enhancers for transdermal or intestinaldrug delivery may not have similar effects on buccal drugdelivery because of structural differences; however, enhancersused to improve drug permeation in other absorptive mucosaeimprove drug penetration through buccal mucosa. Thesepermeation enhancers should be safe and non-toxic, pharma-cologically and chemically inert, non-irritant, and non-aller-genic [66]. However, examination of penetration route fortransbuccal delivery is important because it is fundamental toselect the proper penetration enhancer to improve the drugpermeability. The different permeation enhancers available are[66–68].

➢ Chelators: EDTA, citric acid, sodium salicylate, methoxysalicylates.

➢ Surfactants: sodium lauryl sulphate, polyoxyethylene,Polyoxyethylene-9-laurylether, Polyoxythylene-20-cety-lether, Benzalkonium chloride, 23-lauryl ether, cetylpyr-idinium chloride, cetyltrimethyl ammonium bromide.

➢ Bile salts: sodium glycocholate, sodium deoxycholate,sodium taurocholate, sodium glycodeoxycholate, sodiumtaurodeoxycholate.

➢ Fatty acids: oleic acid, capric acid, lauric acid, lauric acid/propylene glycol, methyloleate, lysophosphatidylcholine,phosphatidylcholine.

➢ Non-surfactants: unsaturated cyclic ureas.➢ Inclusion complexes: cyclodextrins.➢ Others: aprotinin, azone, cyclodextrin, dextran sulfate,

menthol, polysorbate 80, sulfoxides and various alkylglycosides.

➢ Thiolated polymers: chitosan-4-thiobutylamide, chitosan-4-thiobutylamide/GSH, chitosan-cysteine, Poly (acrylicacid)-homocysteine, polycarbophil-cysteine, polycarbo-phil-cysteine/GSH, chitosan-4-thioethylamide/GSH, chit-osan-4-thioglycholic acid.

2.4.1. Mechanisms of actionMechanisms by which penetration enhancers are thought to

improve mucosal absorption are as follows [69,70]

➢ Changing mucus rheology: Mucus forms viscoelasticlayer of varying thickness that affects drug absorption.Further, saliva covering the mucus layers also hinders theabsorption. Some permeation enhancers' act by reducingthe viscosity of the mucus and saliva overcomes thisbarrier.

➢ Increasing the fluidity of lipid bilayer membrane: Themost accepted mechanism of drug absorption throughbuccal mucosa is intracellular route. Some enhancersdisturb the intracellular lipid packing by interaction witheither lipid packing by interaction with either lipid orprotein components.

➢ Acting on the components at tight junctions: Someenhancers act on desmosomes, a major component atthe tight junctions there by increases drug absorption.


➢ By overcoming the enzymatic barrier: These act byinhibiting the various peptidases and proteases presentwithin buccal mucosa, thereby overcoming the enzymaticbarrier. In addition, changes in membrane fluidity alsoalter the enzymatic activity indirectly.

➢ Increasing the thermodynamic activity of drugs: Someenhancers increase the solubility of drug there by altersthe partition coefficient. This leads to increased thermo-dynamic activity resulting better absorption.

Surfactants such as anionic, cationic, nonionic and bilesalts increases permeability of drugs by perturbation ofintercellular lipids whereas chelators act by interfering withthe calcium ions, fatty acids by increasing fluidity ofphospholipids and positively charged polymers by ionicinteraction with negative charge on the mucosal surface[71–76]. Chitosan exhibits several favorable properties suchas biodegradability, biocompatibility and antifungal/antimicro-bial properties in addition to its potential bioadhesion andabsorption enhancer [77,78].

3. Muco/bioadhesion

Bioadhesion is the phenomenon between two materials,which are held together for extended periods of time byinterfacial forces [79]. It is generally referred as bioadhesionwhen interaction occurs between polymer and epithelial surface;mucoadhesion when occurs with the mucus layer covering atissue. Generally bioadhesion is deeper than the mucoadhesion.However, these two terms seem to be used interchangeably. It isinteresting that the interaction between the layers adsorbed fromwhole saliva resembles the one previously reported betweenlayers of adsorbed gastric mucins, which points to a strongcontribution to the interaction of high molecular weightglycoproteins.

3.1. Bio/mucoadhesive forces

The common nature of all adhesive events, interfacialphenomena and forces that are involved in bioadhesion arestrongly related to those considered in classical colloid andsurface science. Intermolecular forces are electromagneticforces which act between molecules or between widelyseparated regions of a macromolecule. These are fundamen-tally electrostatic interactions or electrodynamic interactions.Such forces may be either attractive or repulsive in nature.They are conveniently divided into two classes: short-rangeforces, which operate when the centers of the molecules areseparated by 3 angstroms or less and long-range forces, whichoperate at greater distances. Generally, if molecules do not tendto interact chemically, the short-range forces between them arerepulsive. These forces arise from interactions of the electronsassociated with the molecules and are also known as exchangeforces. Molecules that interact chemically have attractiveexchange forces; these are also known as valence forces.Mechanical rigidity of molecules and effects such as limitedcompressibility of matter arise from repulsive exchange forces.

Long-range forces, or van der Waal's forces as they are alsocalled, are attractive and account for a wide range of physicalphenomena, such as friction, surface tension, adhesion andcohesion of liquids and solids, viscosity, and the discrepanciesbetween the actual behavior of gases and that predicted by theideal gas law [80].

Many theories have been proposed to explain the forces thatunderpin bioadhesion. They are

❖ Electronic theory❖ Adsorption theory❖ Wetting theory❖ Diffusion theory❖ Fracture theory, etc. [81].

However, there is yet to be a clear explanation. Asbioadhesion occurs between inherently different mucosalsurfaces and formulations that are solid, semisolid and liquid,it is unlikely that a single, universal theory will account for alltypes of adhesion observed. In biological systems it must berecognized that, owing to the amphiphilicity of many biologicalmacromolecules, orientation effects can often occur at inter-faces. These are crucially important and have in fact beenreported to be so dramatic as to change overall long-rangeinteractions from being purely repulsive to their becomingattractive [82]. For any type of charged surface, such asbiosurfaces, it is common to distinguish between pureelectrostatic repulsive forces, which oppose adhesion, andattractive forces, which, if the surfaces come close enough,will strive to bring the interacting bodies together. This balancedrelationship between repulsive and attractive interactions isexpressed in the DLVO theory [83]. In biological systems,interactions can be more complex, as they often take place inhigh ionic strength aqueous media and in the presence ofmacromolecules. Therefore electrostatic contributions may beless important, at least at long range, in favor of forcecomponents such as steric forces, hydrophobic interactions,and hydration forces.

3.1.1. Van der Waal's forcesThe attractive forces included in the DLVO theory are nor-

mally termed van der Waal's forces and will arise in a number ofways. These may be further divided into the following threecomponents [84,85]:

(i) London dispersion forces: These are also called as dis-persion forces. These originate out of the electronicmotions in paired molecules and give rise to attractiveinteractions. These forces involve the attraction betweentemporarily induced dipoles in nonpolar molecules (oftendisappear within a second) [86]. This polarization can beinduced either by a polar molecule or by the repulsion ofnegatively charged electron clouds in nonpolar molecules.These results when two atoms belonging to differentmolecules are brought sufficiently close together. Theseinteractions involve a force of about 0.5–1 K cal/mole.London Dispersion forces exist between all atoms [87].


(ii) Dipole–dipole interactions: These are also called Keesominteractions after Willem Hendrik Keesom who producedthe first mathematical description in 1921, are the forcesthat occur between two molecules with permanentdipoles. These work in a similar manner to ionic inter-actions, but are weaker because only partial charges areinvolved. These are due to attraction between polargroups. These have force of 1–7 K cal/mole. Dipole–dipole interactions also come from partial charges anotherorder of magnitude weaker [88].

(iii) Debye type forces: These are the interactions betweenpermanent and induced dipoles. Permanent dipoles caninduce a transient electric dipole in non-polar moleculesand produce dipole induced dipole interactions. Theseinteractions involve a force of about 1–3 K cal/mole [86].

The non-retarded van der Waal's force is inversely pro-portional to the square of the distance between two sphericalparticles, where the proportionality constant is the Hamakerconstant, which has the dimension of energy, can be used todescribe the strength of the van der Waal's interaction and isdependent on the properties of the involved particles and on themedium where the interaction takes place [89].

3.1.2. Hydrogen bondingHydrogen bonding is basically an electrostatic interaction

that arises when a hydrogen atom bound to an electronegativeatom, e.g., nitrogen, oxygen, or fluorine, interacts with anotherelectronegative atom [90]. The result is a dipolar molecule. Thehydrogen atom has a partial positive charge and hence caninteract with another highly electronegative atom in an adjacentmolecule. This results in a stabilizing interaction that binds thetwo molecules together. The force is short range and highlydirectional. In a more hydrophobic environment, hydrogenbonds become significant and are essential in the formation ofstable structures. Bond energy serves as a measure of strength ofbonds. Magnitude of bond energy for hydrogen bond is between10 and 20 kJ/mol [91]. Role of hydrogen bonding in interactionbetween mucoadhesive and mucin at gastric pH was studied byTobyn et al. [92]. The bonding is stronger and is directional. Thedirectional nature of hydrogen bonding requires the twomolecules to adopt a specific relative geometry [93].

3.1.3. Disulphide bridgingA disulfide bond (SS-bond), also called a disulfide bridge, is

a strong covalent bond between two sulfhydryl (–SH) groups.Oxidation of the thiol group yields a disulfide (S–S) bond [94].This bond is very important to the folding, structure, andfunction of proteins [95]. Due to the formation of strongcovalent bonds with mucus glycoproteins, thiomers show thestrongest mucoadhesive properties of all so far tested polymericexcipients via thioldisulphide exchange reaction and anoxidation process [96] as shown in Fig. 2.

3.1.4. Hydration forcesA type of short-range (<1 nm) repulsive interaction,

suggested as originating from the binding of water molecules

to polar surface sites, has been observed between phospholipids[97] and solid surfaces under certain conditions [98]. Thishydration force is believed to be particularly important inbiological systems, since it prevents contact even in the absenceof charge–charge repulsion.

3.1.5. Electrostatic double-layer forcesA charged surface is always surrounded by a cloud of counter

ions (double-layer), which balances the surface charge. Whentwo surfaces with the same charge approach each other, arepulsive force will arise due to the overlap of the double layers.This is the origin of the electrostatic double-layer forces, whichcan be described by the so-called Poisson–Bolzmann equation.These forces decay exponentially with the surface separation,with a decay length that decreases with increasing ionicstrength in the surrounding medium. It should be noted thatspecific dispersion force-induced ion adsorption could some-times dominate at charged interfaces, thereby making itvirtually impossible to distinguish between the contributionsof electrostatic and dispersion forces [89]. In biological fluids,which generally carry a large net negative charge, contributesignificantly to the decay length already at low concentrations[90]. Thus, the decay length in saliva is likely to be less thanthe value of approximately 1.0 nm calculated from its saltcomposition. Any increase in ionic strength, increasesadhesion to negatively charged surfaces; this was assigned toless repulsion between the surface and the adhering cells [91].

3.1.6. Hydrophobic interactionsHydrophobic effect is another particularly important phenom-

enon with respect to bioadhesion related to the presence of water.It is the property that nonpolar molecules like to self-associate inthe presence of aqueous solution. It has been assigned to thetendency of water molecules to form ordered structures inproximity to non-polar molecular domains and may give rise toattractive interactions between non-polar residues such ashydrocarbon side chains. The hydrophobic effect is usuallydescribed in the context of protein folding, protein–proteininteractions, nucleic acid structure, and protein–small moleculeinteractions. In the case of protein folding, it is used to explainwhy many proteins have a hydrophobic core which consists ofhydrophobic amino acids, such as alanine, valine, leucine,isoleucine, phenylalanine, and methionine grouped together;often coiled-coil structures form around a central hydrophobicaxis. The energetics of DNA tertiary structure assembly weredetermined by Eric Kool to be mostly caused by the hydrophobiceffect, as opposed to Watson–Crick base pairing [99].

The hydrophobic effect can be nullified to a certain extent bylowering the temperature of the solution to near zero degrees; atsuch temperatures, water prefers to be in an ordered structureand the order generated by hydrophobic patches is no longer asenergetically unfavorable. This is neatly demonstrated by theincreased solubility of benzene in water at temperatures lowerthan room temperature. On the macroscopic level, long-rangeattractive forces have been observed between hydrophobicsurfaces formed by adsorption or deposition of amphiphilicmolecules and are believed to be non-equilibrium forces

Fig. 2. Formation of covalent bonds between thiolated polymers and mucin glycoproteins.


[93,97]. It should be noted that the origin of the long-rangeattractive forces between hydrophobic surfaces is controversial,but their occurrence has been related to instability of thedeposited monolayer [100]. Strength of these interactions isabout 0.37 kcal/mol [86].

3.1.7. Steric forcesRepulsive steric interactions or steric forces appear as the

result of the increasing concentration of molecular segmentsthat occurs when surfaces bearing for example bound macro-molecules come close to each other and therefore considered tobe important in biological systems. The maximum possiblenumber of molecular contacts between an adhesive and itssubstrate may be greatly restricted by the steric aspects ofmolecular geometry [80].

3.1.8. Covalent bondsLike metallic bonds, covalent bonds are characterized by the

electrons that are shared between the engaged atoms. Covalentbonds operate only over short interatomic distances (1–2×10−1 nm). They tend to decrease in strength with increasingbond-length, and are oriented at well-defined angles. Unlesschemical reactions take place, based on the formation orbreakup of for example disulphide bridges, covalent bonds areunlikely to be important in bioadhesion processes underphysiological conditions.

On the basis of molecular interactions, the interaction betweentwo molecules is composed of attraction and repulsion. Attractiveinteractions arise fromweak forces such as van der Waal's forces,electrostatic attraction, hydrogen bonding, hydrophobic interac-tions and/or strong forces, which are covalent in nature. Repulsiveinteractions occur because of electrostatic and steric repulsion.For muco/bioadhesion to occur, the attractive interactions shouldbe larger than nonspecific repulsion [101].

Steps involved in the process of bio/mucoadhesion are

(i) Spreading, wetting, swelling and dissolution of bio/mucoadhesive polymer at the interface, initiates intimatemolecular contact at the interface between the polymerand the epithelial/mucus layer.

(ii) Interdiffusion and interpenetration between the chains ofthe adhesive polymer and the mucus/epithelial surfaceresulting physical cross links or mechanical interlocking.

(iii) Adsorption: The orientation of the polymers at the interfaceso that adhesive bonding across the interface is possible.

(iv) Formation of secondary chemical bonds between thepolymer chains and mucin molecules.

3.2. Methods for measuring mucoadhesion

These tests are important during the design and developmentof a mucoadhesive release system to study compatibility, sta-bility, surface analysis and bioadhesive bond strength. Thesetests are broadly classified in to qualitative methods and quan-titative methods.

3.2.1. Quantitative methodsThese are also called macroscopic methods. Themajority of the

quantitative bio and/or mucoadhesion measurement methodsfound in the literature are based on measuring the force requiredto break the adhesive bond between the model membrane and theadhesive. Depending on the direction in which the adhesive isbeing separated from the substrate, peel, shear, and tensile forcescan be measured.

3.2.1.1. Determination of peel strength. The peel adhesiontests are mainly used for buccal and transdermal patches [102].The test is based on the calculation of energy required to detachthe dosage form from the substrate material (usually excisedbuccal mucosa) attached through the bioadhesive material in thedirection as shown in Fig. 3.

Fracture Energy (G)

G ¼ Pð1−Cos hÞw

¼ W-ð1þ kÞ

Where P is the peel force;w is the peel width;W° is the intrinsic work of adhesion and k is the proportionality

constant that accounts for hysteretic losses.Peel work is the sum of the following components

➢ Surface energy that results from the creation of two freesurfaces (energy of dewetting) also referred to as theintrinsic work of adhesion (or cohesion)

➢ Bulk energy that dissipates into the stripping member➢ Strain energy in the newly detached strip

Intrinsic work of adhesion (or cohesion) is independent ofthe following:

◦ Peel rate (speed)◦ Peel angle◦ Thickness of the adhesive◦ Thickness of the stripping member


Values of intrinsicwork of adhesion vary from0.07 J/m squaredfor hydrocarbon van der Waal's interactions, 2 J/m squared for asystemwith covalent bonding as part of the adhesion. The work offracture can be several orders of magnitude greater than theintrinsic work of adhesion [4].

3.2.1.2. Determination of shear strength. Shear stress, τ isthe force acting tangentially to a surface divided by the area ofthe surface. It is the force per unit area required to sustain aconstant rate of fluid movement. Mathematically, shear stresscan be defined as:

s ¼ F=A

where,

τ shear stressF forceA area of the surface subjected to the force.

If a fluid is placed between two parallel plates spaced 1.0 cmapart, and a force of 1.0 dyn is applied to each square centimeter ofthe surface of the upper plate to keep it in motion, the shear stressin the fluid is 1 dyn/cm2 at any point between the two plates [4].

Shear stress measures the force that requires causing thebioadhesive to slide with respect to the mucus layer in a directionparallel to their plane of contact as shown in Fig. 3.

Sam et al. studied the mucoadhesiveness of Ca polycarbophil,sodium CMC, HPMC using homogenized mucus from pig in-testine as model substrate by modified wilhelmy plate surfacetension apparatus [103]. Similarly, Smart et al. studied mucoad-hesive strength of CP 934, Na CMC,HPMC, gelatin, PVP, acacia,PEG, pectin, tragacanth and sodium alginate wasmeasured by theforce required to pull the plate out of the solution is determinedunder constant experimental conditions by using mucus fromguinea pig intestine asmodel substrate byWilhelmy platemethod,where a glass plate suspended from a microbalance, which wasdipped in a temperature-controlled mucus sample [104]. Insteadof biological substrates, Ishida et al. [105] used glass plates asmodel substrate by shearing stickiness apparatus andGurney et al.[106] used polymethylmethacrylate to study shear stress ofcarbapol and sodium CMC by Instron model 1114, respectively.

3.2.1.3. Determination of tensile strength. Tensile stress is alsotermedMaximumStress orUltimate Tensile Stress. The resistance

Fig. 3. Representation of peel, shear and tensile forces.

of a material to a force tending to tear it apart, measured as themaximum tension the material can withstand without tearing.Tensile strength can be defined as the strength of materialexpressed as the greatest longitudinal stress it can bear withouttearing apart. As it is the maximum load applied in breaking atensile test piece divided by the original cross-sectional area of thetest piece, it is measured as Newtons/sq.m. Specifically, the tensilestrength of a material is the maximum amount of tensile stress thatit can be subjected to before failure. The definition of failure canvary according to material type and design methodology.

There are three typical definitions of tensile strength:

▪ Yield Strength — The stress a material can withstandwithout permanent deformation.

▪ Ultimate Strength — The maximum stress a material canwithstand.

▪ Breaking Strength — The stress coordinate on the stress–strain curve at the point of rupture.

Methods using the tensile strength usually measure the forcerequired to break the adhesive bond between a model membraneand the test polymers.

Lehr et al. [103] determined tensile strength of flat-facedbuccal adhesive tablets, with a diameter of 5.5 mm containing50 mg of the mucoadhesive material is to be tested for its shearstresses by clamping the model mucosal surface between twoplates, one having a U-shaped section cut away to expose the testsurface. The tablet was attached to a Perspex disc, and then placedinto contact with the exposed mucosa at the base of the U shapedcut. 1.5 g weight was used to consolidate the adhesive joint for2 min, and the plates were oriented from horizontal to vertical andPerspex disc attached to the underside of the balance, which waslinked to a microcomputer for data collection. A shear stress wasapplied by lowering the plates andmodelmucosa at a rate of 2mmmin−1 until adhesive joint failure occurred (Fig. 4).

Many researchers studied shear strength of polymers such aspolyacrylic acid, hydroxy propylcellulose, carbapol 934,HPMC etc. using buccal mucosa as substrate by using differentinstruments such as tensile tester, modified pan balance etc.

3.2.1.4. Colloidal gold staining method. Park [107] proposedthe colloidal gold staining technique for the study of bioadhesion.The technique employs red colloidal gold particles, which wereadsorbed on mucin molecules to form mucin–gold conjugates,which upon interaction with bioadhesive hydrogels developsa red color on the surface. This can be quantified by measuringat 525 nm either the intensity on the hydrogel surface or theconjugates.

3.2.1.5. Direct staining method. It is a novel technique toevaluate polymer adhesion to human buccal cells followingexposure to aqueous polymer dispersion, both in vitro and invivo. Adhering polymer was visualized by staining with 0.1%w/v of either Alcian blue or Eosin solution; and the uncomplexeddye was removed by washing with 0.25M sucrose. The extent ofpolymer adhesion was quantified by measuring the relativestaining intensity of control and polymer treated cells by image



Fig. 4. Schematic representation of apparatus for measuring tensile strength.


analysis. Carbopol 974 P, polycarbophil and chitosan were foundto adhere to human buccal cells from 0.10% w/w aqueous dis-persions of these polymers. Following in vivo administration as amouthwash, these polymers persisted upon the human buccalmucosa for at least one hour. This method is only suitable forassessing the liquid dosage forms, which are widely employed toenhance oral hygiene and to treat local disease conditions of themouth such as oral candidacies and dental caries [108].

3.2.2. Qualitative methodsThese methods are useful for preliminary screening of the

respective polymer for its bio or mucoadhesion, compatibilityand stability. However, these methods are not useful in mea-suring the actual bioadhesive strength of the polymers. They are

3.2.2.1. Viscometric method. Katarina Edsman [109] hasstudied the dynamic rheological measurements on gels containingfour different carbopol polymers and the corresponding mixtureswith porcine gastric mucin and bovine submaxillary mucin. Themethod does not give the same ranking order when two differentcomparison strategies were used. The results were contrast to theresults obtained with the tensile strength measurements.

Hassan [110] developed a simple viscometric method toquantify mucin–polymer bioadhesive bond strength. Viscositiesof 15% w/w porcine gastric mucin dispersion were measuredwith Brookfield's viscometer. In absence or presence of selectedneutral, anionic and cationic polymer, viscosity components andthe forces of bioadhesion were calculated. He observed apositive rheological synergism when chitosan solutions pre-pared in pH 5.5 acetate buffers and in 0.1 M Hcl, were mixedwith a fixed amount of porcine gastric mucin. The mixtures withmucin showed a viscosity greater than the sum of polymer andmucin viscosities.

Mortazavi and Smart [111] investigated the effect of carbopol934 P on rheological behavior of mucus gel and role of mucus andeffect of various factors such as ionic concentration, polymer mo-lecular weight, its concentration and the introduction of anionic,cationic and neutral polymers on mucoadhesive mucus interface.

Carla Caramella et al. [112] investigated the influence ofpolymer concentration and polymer: mucin weight ratio on

chitosan–mucin interaction, assessed by means of viscosimetricmeasurements. Two hydration media, distilled water and 0.1 MHcl were used. Chitosan solutions were prepared at concentra-tions greater than the characteristic entanglement concentrationand mixed with increasing amounts of porcine gastric mucin.Viscosity measurements were performed on the polymer–mucinmixtures and on polymer and mucin solutions having the sameconcentrations as in the mixtures. The formation of chitosan–mucin interaction products was determined on the basis of thechanges in low shear viscosity and high shear viscosity of themixtures as a function of polymer: mucin weight ratio. Rheo-logical synergism parameter was also calculated. The resultsobtained suggest that two different types of rheological interactionoccur between chitosan and mucin in both media, depending onpolymer concentration and polymer: mucin weight ratio.

3.2.2.2. Analytical ultracentrifuge criteria for mucoadhesion.These methods are useful in identifying the material that is able toform complexes with the mucin. The assay can be done for changein molecular mass using sedimentation equilibrium, but this has anupper limit of less than 50MDa. Since complexes can be very large,a more sensible assay procedure is to use sedimentation velocitywith change in sedimentation coefficient, s, as their marker formucoadhesion. Where mucin is available in only minisculeamounts, a special procedure known as Sedimentation Fingerprint-ing can be used for assay of the effect on the mucoadhesive. UVabsorption optics is used as the optical detection system. However,in this case the mucoadhesive is invisible, but the pig gastric mucinat the concentrations normally employed is visible. The sedimen-tation ratio (scomplex/smucin), the ratio of the sedimentation coef-ficient of any complex involving the mucin to that of pure mucinitself, is used as the measure for mucoadhesion [113].

3.2.2.3. Atomic force microscopy. This method is based on thechanges in surface topography when the polymer bound on tobuccal cell surfaces. Unbound cells shows relatively smoothsurface characteristics with many small craters like pits andindentations spread over cell surfaces, while polymer boundcells will loose crater and indentation characteristics and gaineda higher surface roughness.


3.2.2.4. Electrical conductance. Bremakar used modifiedrotational viscometer to determine electrical conductance of varioussemi-solid mucoadhesive ointments and found that the electricalconductance was low in the presence of adhesive material.

3.2.2.5. Fluorescent probe method. In this method themembrane lipid bilayered and membrane proteins were labeledwith pyrene and fluorescein isothiocyanate, respectively. Thecells were mixed with the mucoadhesive agents and changes influorescence spectraweremonitored. This gave a direct indicationof polymer binding and its influence on polymer adhesion [114].

3.2.2.6. Lectin binding inhibition technique. The methodinvolves an avidin–biotin complex and a colorimetric detectionsystem to investigate the binding of bioadhesive polymers tobuccal epithelial cells without having to alter their physico-chemical properties by the addition of marker entities. Thelectin cancanavalian A has been shown to specifically bind tosugar groups present on the surface of buccal cells. If polymersbind to buccal cells, they will mask the surface glycoconjugates,thus reducing or inhibiting cancanavalian A binding [115].

3.2.2.7. Thumb test. This is a very simple test used for thequalitative determination of peel adhesive strength of thepolymer and is useful tool in the development of buccaladhesive delivery systems. The adhesiveness is measured by thedifficulty of pulling the thumb from the adhesive as a functionof the pressure and the contact time. Although the thumb testmay not be conclusive, it provides useful information on peelstrength of the polymer.

3.3. Factors affecting bio/mucoadhesion

Numerous studies have indicated that there is a certainmolecular weight at which bioadhesion is optimum. The optimummolecular weight for the maximum bioadhesion depends on thetype of polymers. It dictates the degree of swelling inwater, whichin turn determines interpenetration of polymer molecules withinthe mucus. It seems that the bioadhesive force increases with themolecular weight up to 100,000 and beyond this level there is notmuch effect [106]. For the best bioadhesion to occur, the con-centration of polymer must be at optimum. Flexibility of polymerchain is also important for interpenetration and entanglement[116,117]. As water-soluble polymers become cross-linked, themobility of the individual polymer chain decreases. As the crosslinking density increases, the effective length of the chain, whichcan penetrate into the mucus layer, decreases even further andmucoadhesive strength is reduced. Besides molecular weight orchain length, spatial conformation of amolecule is also important.Despite a high molecular weight of 19,500,000 for dextrans, theyhave similar adhesive strength to that of polyethylene glycol witha molecular weight of 200,000. The helical conformation ofdextran may shield many adhesively active groups, primarilyresponsible for adhesion, unlike PEG polymers, which have alinear conformation. Swelling is not only related to the polymeritself, and also to its environment. Interpenetration of chains iseasier as polymer chains are disentangled and free of interactions.

Swelling depends both on polymer concentration and thepresence of water. When swelling is too great, a decrease inbioadhesion occurs [116].

pH was found to have significant effect on mucoadhesion asobserved in studies of polyacrylic polymers cross-linked withcarboxyl groups. pH influences the charge on the surface of bothmucus and the polymers. Mucus will have a different chargedepending on pH because of differences in dissociation offunctional groups on the carbohydrate moiety and amino acids ofthe polypeptide backbone. It was observed that the pH of themedium was critical for the degree of hydration of highly crosslinked polyacrylic acid polymers, increasing between pH 4 and 5,continuing to increase slightly at pH 6 and 7 and decreasing atmore alkaline pH levels [118]. To place a solid bioadhesivesystem, it is necessary to apply a defined strength. Whatever thepolymer may be, the adhesion strength increases with the appliedstrength and duration of its application, up to an optimum [119].The initial contact time between mucoadhesive and the mucuslayer determine the extent of swelling and the interpenetration ofpolymer chains. Along with the initial pressure, the initial contacttime can dramatically affect the performance of a system. Themucoadhesive strength increases as the initial contact timeincreases [101]. Dehydration of the mucosa, causes by watermovement from themucosa to the dry powder, may have resultedin adhesion between the two surfaces [120]. A low interfacialtension value for the bioadhesive tissue increases the possibilityof obtaining adhesive bonds [121]. Addition of highly water-soluble additive reduces the water content when the materialdissolves, and thus makes the water unavailable for thebioadhesive material, and subsequently decreases bioadhesion[122]. The duration of adhesion depends on the amount of waterat the interface. Excessivewater reduces the duration of adhesion.However the magnitude of this change is not the same for all thematerials. It is believed that faster the rate of absorption of water,the shorter is the time required for the material to obtain initialadhesion and maximum adhesive strength. But rapid waterabsorbency may cause the shortening of the duration of adhesion[123]. Previous drug absorption studies have demonstrated thatbuccal absorption through oral mucosa for drugs such asmorphine sulphate, nicotine, flecainide, sotalol, propanolol andothers changed with changing pH [18].

4. Developments in buccal adhesive drug delivery

Retentive buccal mucoadhesive formulations may prove to bean alternative to the conventional oral medications as they can bereadily attached to the buccal cavity retained for a longer period oftime and removed at any time. Buccal adhesive drug deliverysystems using matrix tablets, films, layered systems, discs, microspheres, ointments and hydrogel systems has been studied andreported by several research groups. However, limited studies existon novel devices that are superior to those of conventional buccaladhesive systems for the delivery of therapeutic agents throughbuccal mucosa. A number of formulation and processing factorscan influence properties and release properties of the buccal ad-hesive system. There are numerous important considerations thatinclude biocompatibility (both the drug/device and device/

Table 2

Commercial name Bioadhesivepolymer

Company Dosageform

Buccastem PVP, Xanthum gum,Locust bean gum

RickittBenckiser

Tablet

Suscard HPMC Forest TabletGaviscon liquid Sodium alginate Rickitt

BenckiserOral liquid

Orabase Pectin, gelatin ConvaTech Oral pasteCorcodyl gel HPMC Glaxosmithkline Oromucosal

gelCorlan pellets Acacia Celltech Oromucosal

pelletsFentanyl Oralet™ Lexicomp LozengeMiconaczoleLauriad

Bioalliance Tablet

EmezineTM BDSI'sBEMA Fentanyl BDSI'sStraint™ SR ArdanaZilactin Zila Buccal filmLuborant Sodium CMC Antigen Artificial

salivaSaliveze Sodium CMC Wyvern Artificial

salivaTibozole Tibotec Tablet


environment interfaces), reliability, durability; environmental sta-bility, accuracy, delivery scalability and permeability are to beconsidered while developing such formulations. While biocom-patibility is always an important consideration, other considerationsvary in importance depending on the device application. Bioadhe-sive formulations designed for buccal application should exhibitsuitable rheological and mechanical properties, including pseudo-plastic or plastic flow with thixotrophy, ease of application, goodspreadability, appropriate hardness, and prolonged residence timein the oral cavity. These properties may affect the ultimate perfor-mance of the preparations and their acceptance by patients [124].

An ideal buccal adhesive system must have the followingproperties:

✓ Should adhere to the site of attachment for a few hours,✓ Should release the drug in a controlled fashion,✓ Should provide drug release in an unidirectional way

toward the mucosa,✓ Should facilitate the rate and extent of drug absorption,✓ Should not cause any irritation or inconvenience to the

patient and✓ Should not interfere with the normal functions such as

talking, drinking etc.

4.1. Commercial buccal adhesive drug delivery systems

Recent reports suggest that the market share of buccaladhesive drug delivery systems are increasing in the Americanand European market with the steady growth rate of above 10%.Some of the commercially available buccal adhesive formula-tions are listed in Table 2.

4.2. Research on buccal adhesive drug delivery systems

Several buccal adhesive delivery devices were developed atthe laboratory scale by many researchers either for local orsystemic actions. They are broadly classified in to

❖ Solid buccal adhesive dosage forms❖ Semi-solid buccal adhesive dosage forms❖ Liquid buccal adhesive dosage forms

4.2.1. Solid buccal adhesive formulationsDry formulations achieve bioadhesion via dehydration of the

local mucosal surface.

4.2.1.1. Tablets. Several bioadhesive tablet formulations weredeveloped in recent years either for local or systemic drugdelivery. Tablets that are placed directly onto the mucosalsurface have been demonstrated to be excellent bioadhesiveformulations. However, size is a limitation for tablets due to therequirement for the dosage form to have intimate contact withthe mucosal surface. These tablets adhere to the buccal mucosain presence of saliva. They are designed to release the drugeither unidirectionally targeting buccal mucosa or mutidirec-tionally in to the saliva. Table 3. represents some of the researchdone so far in the development of buccal adhesive tablets.

4.2.1.2. Microparticles. Bioadhesive microparticles offer thesame advantages as tablets but their physical properties enablethem to make intimate contact with a lager mucosal surfacearea. In addition, they can also be delivered to less accessiblesites including the GI tract and upper nasal cavity. The smallsize of microparticles compared with tablets means that they areless likely to cause local irritation at the site of adhesion and theuncomfortable sensation of a foreign object within the oralcavity is reduced.

4.2.1.3. Wafers. Bromberg et al. [160] described a conceptuallynovel periodontal drug delivery system that is intended for thetreatment of microbial infections associated with peridontitis. Thedelivery system is a composite wafer with surface layers posses-sing adhesive properties, while the bulk layer consists of anti-microbial agents, biodegradable polymers and matrix polymers.

4.2.1.4. Lozenges. Bioadhesive lozenges may be used for thedelivery of drugs that act topically within the mouth includingantimicrobials, corticosteroids, local anaesthetics, antibioticsand antifungals. Conventional lozenges produce a high initialrelease of drug in the oral cavity, which rapidly declines tosubtherapeutic levels, thus multiple daily dosing is required. Aslow release bioadhesive lozenge offers the potential for pro-longed drug release with improved patient compliance. Coddand Deasy investigated bioadhesive lozenges as a means todeliver antifungal agents to the oral cavity [161].

4.2.2. Semi-solid dosage forms

4.2.2.1. Gels. Gel forming bioadhesive polymers include cross-linked polyacrylic acid that has been used to adhere to mucosalsurfaces for extended periods of time and provide controlled release

Table 3Buccal adhesive tablets

Drug Bioadhesive polymer Excipients References

Ketoprofen Chitosan and sodiumalginate

[125]

Nifedipine Chitosan, polycarbophil,sodium alginate, gellan gum

[126]

Propranolol CP, HPMC, PC, SCMC,PAA

[127]

Propranolol HPMC, CP 934 [128]Propranolol HPMC, PC [129]Diltiazem CP, HPMC, PC, SCMC,

PAA[130]

Diltiazem CP 934 and PVP K-30 Citric acid andPEG 4000

[81]

Metaclopromide CP, HPMC, PC, SCMC,PAA

[127]

Nystatin Carbomer, HPMC Lactose [131]Verapamil HPC-M, CP 934 [132,133]Triamcilone HPC, CP-934 [134]Triamcilone HPMC, PADH [135]Lidocaine CP-934, HPC-H [136]Metronidazole CP-934, HPMC [137]Sodium fluoride Modified starch, PAA [138]Miconazole Modified starch, CP-934 [139]Pentazocine CP-934P, HPMC [140]Chlorpheneramine Hakea gum [141]Calcitonin Hakea gum [141]Omeprazole Sodium alginate,

HPMC, CP-934P, PCMagnesiumoxide

[142]

Nicotine HPC, CP-934P, PVP [143]Clotrimazole CP 974P, HPMC K4M [144]Nicotine hydrogen

tartrateAionic, cationic andnonionic

pH increasingadditive

[145]

Citrus oil andmagnesium salt

Cross linked PAA andHPC

[146]

Buspirone Hcl CP 974 HPMCK4M [147]Omeprazole Sodium alginate and

HPMCMgO andcroscaramellosesodium

[148]

Hydrocortisoneacetate

HPMC (methocelk4m),carbapol934P,polycarbiphyl

[149]

Ergotaminetartrate

PVA Witepsol W-35and cod liver oilextract

[150]

Hydralazine Hcl CP 934P and CMC [151]Prednisolone Polycarbophil and CP

934P[152]

Buprenorphine HEMA and Polymeg [153]Morphine

sulphateCarbomer and HPMC [154]

Piribedit [155]Nimesulide [156]Cetylpyridinium

chloride[157]

Thiocolchicoside [158]Propranolol CP-934P, HPMC K4M [159]

Abbrevations: CP: carbapol, HPMC: hydroxypropylmethylcellulose, PC:polycarbophil, SCMC: sodium carboxymethylcellulose, PAA: polyacrylicacid, HPC: hydroxypropyl cellulose, PVP: poly (vinylpyrrolidone), PADH:poly (acrylicacid-2-5-dimethyl 1-5 hexadiene).

Table 4Buccal adhesive patches/films

Drug Bioadhesive polymer Excipients Reference

Plasmid DNA Noveon, eudragit S-100 [163]B-galactosidase Noveon, eudragit S-100 [163]Ipriflavone PLGA, chitosan [164]Chlorhexidinegluconate

Chitosan [165]

Chlorpheneraminemaleate

Polyoxyethylene [166]

Protirelin HEC, HPC, PVP, PVA [167,168]Buprenorphine CP-934, PIB and PIP [169]Isosorbidedinitrate

HPC, HPMCP Glycerrhizinicacid

[170]

Lidocaine HPC, CP [171]Miconazole nitrate SCMC, chitosan,

PVA, HEC and HPMCPVP [172]

Nifedipine Sodium alginate Mannitol, PEG 6000 [173]Acyclovir [P (AA-co-PEG)] Sodium glycocholate [174]

Abbrevations: CP: carbapol, HPMC: hydroxypropylmethylcellulose, PC:polycarbophil, SCMC: sodium carboxymethylcellulose, PVP: poly (vinylpyrro-lidone), PLGA: poly (D,L-lactide co-glycolide), HPMCP: hydroxypropylmethylcellulosephthalate, PIB: polyisobutylene, PIP: polyisoprene, [P (AA-co-PEG)]:copolymers of polyacrylic acid and polyethylene glycol monomethylethermonomethacrylate, HPC: hydroxypropylcellulose, HEC: hydroxyethylcellulose,PVA: polyvinylalcohol.


of drugs. Gels have beenwidely used in the delivery of drugs to theoral cavity. Advantages of gel formulations include their ability toform intimate contact with the mucosal membrane and their rapid

release of drug at the absorption site. A limitation of gel formu-lations lies on their inability to deliver a measured dose of drug tothe site. They are therefore of limited use for drugs with narrowtherapeutic window. He et al. [162] designed a novel, hydrogel-based, bioadhesive, intelligent response system for controlled drugrelease. This system combined several desirable facets into a singleformulation; a poly (hydroxyethyl methacrylate) layer as barrier,poly (methacrylic acid-g-ethylene glycol) as a biosensor and poly(ethyleneoxide) to promote mucoadhesion.

4.2.2.2. Patches/films. Flexible films may be used to deliverdrugs directly to amucosalmembrane. They also offer advantagesover creams and ointments in that they provide ameasured dose ofdrug to the site. Buccal adhesive films are already in use com-mercially for example, Zilactin used for the therapy of cankersores, cold sores and lip sores. These were represented in Table 4.

4.2.3. Liquid dosage formsViscous liquids may be used to coat buccal surface either as

protectants or as drug vehicles for delivery to themucosal surface.Traditionally, pharmaceutically acceptable polymers were used toenhance the viscosity of products to aid their retention in the oralcavity. Dry mouth is treated with artificial saliva solutions that areretained on mucosal surfaces to provide lubrication. Thesesolutions contain sodium CMC as bioadhesive polymer.

4.3. Delivery of proteins and peptides

The buccal mucosa represents a potentially important site forcontrolled delivery of macromolecular therapeutic agents, suchas peptides and protein drugs with some unique advantages suchas the avoidance of hepatic first-pass metabolism, acidity andprotease activity encountered in the gastrointestinal tract.


Another interesting advantage is its tolerance (in comparisonwith the nasal mucosa and skin) to potential sensitizers. Avarietyof proteins/peptides with or without penetration enhancer werestudied by different scientists using different animal models likedogs, rabbits, rats, pigs and humans. Some of those develop-ments were represented in Table 5.

5. Evaluation

In addition to the routine evaluation tests such as weightvariation, friability, hardness, content uniformity, in vitro dis-solution for tablets; tensile strength, film endurance, hygroscop-icity etc for films and patches; viscosity, effect of aging etc for gelsand ointments; buccal adhesive drug delivery devices are also tobe evaluated specifically for their mucoadhesive strength andpermeability.

5.1. Determination of the residence time

5.1.1. In vitro residence timeIt was determined using a modified USP disintegration appa-

ratus as shown in Fig. 5. The disintegration medium composed of800 ml isotonic phosphate buffer pH 6.75 maintained at 37 °C. Asegment of rabbit intestinal mucosa, 3 cm long, was glued to thesurface of a glass slab, vertically attached to the apparatus. Themucoadhesive tablet was hydrated from one surface using 15 mlIPB and then the hydrated surface was brought into contact withthe mucosal membrane. The glass slab was vertically fixed to theapparatus and allowed tomove up and down so that the tablet wascompletely immersed in the buffer solution at the lowest point andwas out at the highest point. The time necessary for completeerosion or detachment of the tablet from the mucosal surface wasrecorded [189].

5.1.2. In vivo residence time testThe experiment was conducted on four human healthy

volunteers of 25–50 years old. Plain bioadhesive tablets with

Table 5Buccal adhesive formulations for proteins/peptides

Protein/peptide drug Dosage form Enhancer

Buserelin Patch SGDCCalcitonin Tablet No enhancCaptopril Tablet SGDCColony stimulating factor (G-SCF) Patch No enhanc

Enalapril Solution No enhancGlucagon like peptide Tablet STCGonadotropin releasing hormone Tablet SC, SDC,Interferon Solution No enhancInsulin Liposomes No enhancLisinopril Solution No enhancLutinizing hormone releasing hormone Tablet SDC 5%Octreotide acetate Azone, SCOxytocin Patch No enhancProtrelin (TRH) Patch Citric acid

5-methoxyRecombinant human interferon alpha B/D hybrid Solution No enhanc

optimized properties were selected for the in vivo evaluation. Thebioadhesive tablet was placed on the buccal mucosa between thecheek and gingiva in the region of the upper canine and gentlypressed onto the mucosa for about 30 s. The tablet and the innerupper lip were carefully moistened with saliva to prevent thesticking of the tablet to the lip. The volunteers were asked tomonitor the easewithwhich the systemwas retained on themucosaand note any tendency for detachment. The time necessary forcomplete erosion of the tablet was simultaneously monitored bycarefully observing for residual polymer on the mucosa. In ad-dition, any complaints such as discomfort, bad taste, dry mouth orincrease of salivary flux, difficulty in speaking, irritation ormucosallesions were carefully recorded. Repeated application of the bio-adhesive tablets was allowed after a two days period for the samevolunteer [189].

5.2. Permeation studies

During the preformulation studies, buccal absorption/perme-ation studies must be conducted to determine the feasibility of thisroute of administration for the candidate drug and to determine thetype of enhancer and its concentration required to control the rateof permeation of drugs. These studies involvemethods that wouldexamine in vitro, ex vivo and/or in vivo buccal permeation profileand absorption kinetics of the drug.

5.2.1. In vitro methodsDeasy [157] used an apparatus consisting of a water jacket and

an internal compartment containing 50 ml of simulated saliva asdissolution medium to study the release of cetylpyridinium chlo-ride tablet by placing in the metal die sealed at the lower end byparaffin wax to ensure the drug release from one end alone. Themedium was stirred with a rotating stirrer at 250 rpm. Ishida [171]conducted dissolution studies with similar apparatus with slightmodification of providing a water jacket for the maintenanceof temperature for dosage forms of lidocaine. Nagai [190] usedToyamp-Sangyo TR-553 dissolution tester to measure the

Animal model % increase in bioavailability Ref.

Pig, rat 12.7% [175]er Rabbits 37% [176]

Humans [177]er Dogs Two fold increase in

pharmacological action.[178]

er Human No significant increase [179]Human 4–23% [180]

STC, STDC Dog SDC>SC>STC>STDC [181]er Mice Marked increase [182]er Rat No significant increase [183]er Human No significant increase [179]

Dog 237% [184], EDTA, STC Dog Azone>SC>EDTA>STC [185]er Rabbit Slight increase [186], Sodium-salicylate

Human, rats Increase in plasmathyrotropin concentration

[187]

er Rabbit, rat 0.005% [188]

Fig. 5. Schematic diagram of the apparatus used for the determination ofresidence time. S: glass slab; D: disintegration apparatus; B: glass beaker; M:mucosal membrane; T: mucoadhesive tablet; IBP: Isotonic phosphate buffer.


dissolution rate of disk like dosage forms by keeping in a rotatingbasket at 100 rpm in 900 ml of purified water. The same apparatuswas used for the evaluation of oral mucosal dosage forms ofinsulin. Hughes and Gehris [191] described a novel dissolutiontesting system that is capable of characterizing buccal dissolution.It comprises of a single, stirred, continuous flow-through filtrationcell that includes a dip tube designed to remove finely divided solidparticles. Filtered solution is removed continuously and used toanalyze for dissolved drug.

5.2.2. Ex vivo methodsMost of the ex vivo studies examining drug transport across

buccal mucosa uses buccal tissues from animal models. Im-mediately after sacrificing the animals the buccal mucosal tissueis surgically removed from the oral cavity. The membranes arestored in Krebs buffer at 4 °C until mounted in the diffusion cellsfor the ex vivo permeation experiments. Preservation of thedissected tissue is an important issue that will affect the studies.There is no standard means by which the viability or the integrityof the dissected tissue can be assessed. The most meaningfulmethod to assess tissue viability is the actual permeation experi-ment itself, if the drug permeability does not change during thetime course of the study under the specific experimental con-ditions of pH and temperature, then the tissue is consideredviable.

Dowty [192] studied tissue viability by using ATP levels inrabbit buccal mucosa. He reported a 50% drop in the tissueATP concentration during the initial 6 h of the experimentwithout a corresponding drop in tissue permeability. Despitecertain gradual changes, the buccal tissue seems to remainviable for a rather long period of time. Hence, a decrease inATP levels does not assure a drop in permeability character-istics of the tissue.

Buccal cell cultures have also been suggested as useful invitro models for buccal drug permeation and metabolism.However, to utilize these culture cells for buccal drug transport,the number of differentiated cell layers and the lipid compositionof the barrier layers must be well characterized and controlled[193–195].

5.2.3. In vivo methods

5.2.3.1. Selection of animal species. Apart from the specificmethodology used to study buccal drug permeation characteristics,special attention is warranted to the selection of experimentalanimal species for such experiments. Many researchers have usedsmall animals including rats and hamsters for permeability studies[196,197].But unlike humans,most laboratory animals have totallykeratinized oral lining, hence not suitable. The rat has a buccalmucosawith a very thick, keratinized surface layer. The rabbit is theonly laboratory rodent that has non-keratinized mucosal liningsimilar to human tissue. But, the sudden transition to keratinizedtissue at the mucosal margins makes it hard to isolate the desirednon-keratinized region [198].

Among the larger experimental animals monkeys are practicalmodels because of the difficulties associated with its mainte-nance. Dogs [199,200] are easy to maintain and less expensivethan monkeys [201] and their buccal mucosa is non-keratinizedand has a close similarity to that of the human buccal mucosa.Pigs also have non-keratinized buccal mucosa similar to that ofhuman and their inexpensive handling and maintenance costsmake them a highly suitable animal model for buccal drugdelivery studies. In fact, the oral mucosa of pigs resembles that ofhuman more closely than any other animal in terms of structureand composition [202].

5.2.3.2. Buccal absorption test. Beckett and Triggs [203]developed a method to measure the kinetics of drug absorption.It is carried out by swirling of a 25 ml sample of the test solutionfor 15min by human volunteers followed by the expulsion of thesolution. The amount of drug remaining in the expelled volumeis then determined to assess the amount of drug absorbed. Thedrawbacks of this method are inability to localize the drugsolution within a specific site of the oral cavity, accidentalswallowing of a portion of the sample solution and the salivarydilution of the drug.

5.2.3.3. Modified buccal absorption test. Gonzalez-Younes etal. [204] developed this method by correcting for salivarydilution and accidental swallowing, but these modifications alsosuffer from the inability of site localization.

5.2.3.4. Perfusion system. A circulating perfusion chamberattached to the upper lip of anesthetized dogs by cyanoacrylatecement and the drug solution is circulated through the device fora predetermined period of time. Sample fractions are collectedfrom the perfusion chamber and blood samples are drawn atregular intervals [205].

5.2.3.5. Buccal perfusion cell apparatus. Rathbone [206]developed an apparatus that provides continuous monitoring ofdrug loss as a function of time offers larger area for drug transferand has no leakage problem.He used several methods to study therate and extent of drug loss from human oral cavity. These includethe buccal absorption test, disk methods and perfusion cells.These methods have provided information on the mechanism bywhich drugs are transported across oral cavity membranes and


suggest that passive diffusion or carrier mediated transportsystems may be involved.

In vivo buccal permeation of FITC labeled dextran 4400 andthe peptide drug buserelin was investigated in pigs. The deliverydevice consisted of an application chamber with a solution ofFD4 or buserelin, and was attached to the buccal mucosa forfour hours using an adhesive patch. The randomized crossoverstudy including intravenous administration and buccal deliverywithout and with 10 mM sodium glycodeoxycholate as anabsorption enhancer was performed in pigs [207].

Tanaka et al. [208] studied the absorption of salicylic acidthrough the hamster cheek pouch. Ointments containing salicylicacid were applied to the cheek pouch of hamster and the influenceof the type of base on drug absorption was examined.

6. Conclusion

The need for research into drug delivery systems extendsbeyond ways to administer new pharmaceutical therapies. Thesafety and efficacy of current treatments may be improved if theirdelivery rates, biodegradation, and site specific targeting can bepredicted, monitored and controlled. From both a financial andglobal healthcare perspective, finding ways to administerinjectable medications is costly and some time leads to serioushazardous effects. Hence inexpensive multiple dose formulationswith better bioavailabilities are needed. Improved methods ofdrug release through transmucosal and transdermal methodswould be of great significance, as by such routes, the pain factorassociated with parenteral routes of drug administration can betotally eliminated. Buccal adhesive systems offer innumerableadvantages in terms of accessibility, administration and with-drawal, retentivity, low enzymatic activity, economy and highpatient compliance. Since the introduction of Orabase in 1947,when gum tragacanth was mixed with dental adhesive powder toapply penicillin to the oral mucosa; the market share of bioad-hesive drug delivery systems is increasing. The growth rate fortransmucosal drug delivery systems is expected to increase 11%annually through 2007. Worldwide market revenues are at $3Bwith the U.S. at 55%, Europe at 30% and Japan at 10%.

Adhesion of buccal adhesive drug delivery devices tomucosal membranes leads to an increased drug concentrationgradient at the absorption site and therefore improved bioavail-ability of systemically delivered drugs. In addition, buccaladhesive dosage forms have been used to target local disorders atthe mucosal surface (e.g., mouth ulcers) to reduce the overalldosage required and minimize side effects that may be caused bysystemic administration of drugs. Researchers are now lookingbeyond traditional polymer networks to find other innovativedrug transport systems. Much of the development of novelmaterials in controlled release buccal adhesive drug delivery isfocusing on the preparation and use of responsive polymericsystem using copolymer with desirable hydrophilic/hydrophobicinteraction, block or graft copolymers, complexation networksresponding via hydrogen or ionic bonding and new biodegradablepolymers especially from natural edible sources. At the currentglobal scenario, scientists are finding ways to develop buccaladhesive systems through various approaches to improve the

bioavailability of orally less/inefficient drugs by manipulating theformulation strategies like inclusion of pH modifiers, enzymeinhibitors, permeation enhances etc. Novel buccal adhesivedelivery systems, where the drug delivery is directed towardsbuccal mucosa by protecting the local environment is also gaininginterest. Currently solid dosage forms, liquids and gels applied tooral cavity are commercially successful. The future direction ofbuccal adhesive drug delivery lies in vaccine formulations anddelivery of small proteins/peptides. Microparticulate bioadhesivesystems are particularly interesting as they offer protection totherapeutic entities as well as the enhanced absorption that resultfrom increased contact time provided by the bioadhesivecomponent. Exciting challenges remain to influence the bioavail-ability of drugs across the buccal mucosa. Many issues are yet tobe resolved before the safe and effective delivery through buccalmucosa. Successfully developing these novel formulationsrequires assimilation of a great deal of emerging informationabout the chemical nature and physical structure of these newmaterials.

References

[1] L.M. Sanders, Drug delivery system and routes of administration ofpeptide and protein drugs, Eur. J. Drug Metab. Pharmacokinet. 15 (1990)95–102.

[2] Y.J. Wang, R. Pearlman, Stability and characterization of protein andpeptide drugs, case histories, in Pharmaceutical Technology, New York/London, vol. 5.

[3] H.H. Alur, T.P. Johnston, A.K. Mitra, Encyclopedia of PharmaceuticalTechnology, in: J. Superbrick, J.C. Boylan (Eds.), Peptides and Proteins:Buccal Absorption, vol. 20 (3), Marcel Dekker Inc., New York,2001, pp. 193–218.

[4] Wikipedia, The free encyclopedia, http://en.wikipedia.org/wiki/.[5] The mouth (cavum oris; oral or buccal cavity). XI. Splanchnology, Gray's

Anatomy of the Human Body.[6] M.J. Rathbone, G. Ponchel, F.A. Ghazali, Systemic and oral mucosal

drug delivery and delivery systems, in: M.J. Rathbone (Ed.), OralMucosal Drug Delivery, vol. 74, Marcel Dekker Inc., New York, 1996,pp. 241–284.

[7] D. Harris, J.R. Robinson, Drug delivery via the mucous membranes of theoral cavity, J. Pharm. Sci. 81 (1992) 1–10.

[8] R.B. Gandhi, J.R. Robinson, Bioadhesion in drug delivery, Ind. J. Pharm.Sci. 50 (3) (1988) 145–152.

[9] P.C. Fox, Acquired salivary dysfunction: drugs and radiation, Ann. N.Y.Acad. Sci. 842 (1998) 132–137.

[10] C.A. Squier, M.W. Finkelstein, in: A.R. Ten Cate (Ed.), Oral Histology,Development, Structure and Function, C.V. Mosby, St. Louis, 1989,pp. 345–385.

[11] C.A. Squier, The permeability of keratinized and nonkeratinized oralepithelium to horseradish. Peroxidase, J. Ultrastruct. Res. 43 (1973) 160–177.

[12] A.J. Hoogstraate, S. Senel, C. Cullander, J. Verhoef, H.E. Junginger, H.E.Bodde, Effects of bile salts on transport rates and routes of FTIC-labelledcompounds across porcine buccal epithelium in vitro, J. Control. Release40 (1996) 211–221.

[13] J. Hao, P.W.S. Heng, Buccal delivery systems, Drug Dev. Ind. Pharm. 29(8) (2003) 821–832.

[14] A.H. Shojaei, X. Li, Determination of transport route of acyclovir acrossbuccal mucosa, Proc. Int. Symp. Control. Release Bioact. Mater. 24(1997) 427–428.

[15] L. Chen, X. Hui-Nan, L. Xiao-Ling, In vitro permeation of tetramethyl-pyrazine across porcine buccal mucosa, Acta Pharmacol. Sin. 23 (2002)792–796.

[16] H.M. Nielsen, M.R. Rassing, TR146 cells grown on filters as a model ofhuman buccal epithelium. III. Permeability enhancement by different pH


value, different osmolarity value, and bile salts, Int. J. Pharm. 185 (1999)215–225.

[17] H. Zhang, J.R. Robinson, In vitro methods for measuring permeabilityof the oral mucosa, in: J. Swarbrick, J.C. Boylan (Eds.), Oral MucosalDrug Delivery, 1st edition, vol. 74, Marcel Dekker, INC, New York,1996, pp. 85–100.

[18] R. Mashru, V. Sutariya, M. Sankalia, J. Sankalia, Transbuccal delivery oflamotrigine across porcine buccal mucosa: in vitro determination ofroutes of buccal transport, J. Pharm. Pharmaceut. Sci. 8 (1) (2005) 54–62.

[19] M.A. Randhawa, S.A. Malik, M. Javed, Buccal absorption of weak acidicdrugs is not related to their degree of ionization as estimated from theHenderson–Hasselbalch equation, Pak. J. Med. Res. 42 (2) (2003).

[20] N. Utoguchi, Y. Watanabe, T. Suzuki, J. Maeharai, Y. Matsumoto,M. Matsumoto, Pharm. Res. 14 (1997) 320–324.

[21] C.A. Squier, M.J. Kremer, P.W. Wertz, J. Pharm. Sci. 86 (1997) 82–84.[22] P.P.H.L. Brun, P.L.A. Fox, M.E.D. Vries, H.E. Bodde, In vitro penetration

of some β-adrenoreceptor blocking drugs through porcine buccalmucosa, Int. J. Pharm. 49 (1989) 141–145.

[23] K.L. Audus, Oral mucosal drug delivery, in: M.J. Rathbone (Ed.), MarcelDekker, New York, pp 101–119.

[24] H.M. Nielsen, M.R. Rassing, TR146 cells grown on filters as a model ofhuman buccal epithelium. III. Permeability enhancement by different pHvalue, different osmolarity value, and bile salts, Int. J. Pharm. 185 (1999)215–225.

[25] C.A. Squier, J. Ultrastruct. Res. 60 (1977) 212–220.[26] C. Grubb, M. Hackemann, K.R. Hill, J. Ultrastruct. Res. 22 (1968)

458–468.[27] D. Hopwood, K.R. Logan, I.A. Bouchier, D. Virchows, Arch. B. Cell

Path. 26 (1978) 345–358.[28] K. Wolff, H.J. Honigsmann, J. Ultrastruct. Res. 36 (1971) 176–190.[29] A. Allen, in: J.G. Forte (Ed.), Handbook of Physiology — the

Gastrointestinal Physiology, Salivary, Gastric and Hepatobiliary Secre-tions, vol. III(6), American Physiological Society, Bethesda, MD, 1989,pp. 359–382.

[30] F.S. Rosen, B.J. Bailey, Anatomy and physiology of salivary glands,Grand Rounds presentation, UTMB, Department of Otolaryngology.

[31] N.A. Peppas, P.A. Buri, Surface, interfacial and molecular aspectsof polymer bioadhesion on soft tissues, J. Control. Release 2 (1985)257–275.

[32] E. Odeblad, The discovery of different types of cervical mucus, Bull.Ovul. Method Res. Ref. Cent. Aust. 21 (1994) 3–35.

[33] S.E. Harding, J.M. Creeth, A.J. Rowe, in: A. Chester, D. Heinegard, A.Lundblad, S. Svenssion (Eds.), Proceedings of the 7th InternationalGlucoconjugates Conference Olsson Reklambyra, Sweden, 1983,pp. 558–559.

[34] M.R. Jimmenez-Castellanos, H. Zia, C.T. Rhodes, Mucoadhesive drugdelivery systems, Drug Dev. Ind. Pharm. 19 (1 and 2) (1993) 143–194.

[35] S.E. Harding, An analysis of the heterogeneity of mucins: no evidence fora self-association, Biochem. J. 219 (1984) 1061–1064.

[36] S.E. Harding, Mucoadhesive interactions, Adv. Carbohydr. Chem.Biochem. 47 (1989) 345–381.

[37] S. Dodd, G.A. Place, R.L. Hall, S.E. Harding, Hydrodynamic propertiesof mucins secreted by primary cultures of Guinea pig trachealepithelial cells: determination of diffusion coefficients by analyticalultracentrifugation and kinetic analysis of mucus gel hydration anddissolution, Eur. Biophys. J. 28 (1998) 38–47.

[38] P. Hallet, A.J. Rowe, S.E. Harding, A highly expanded spheroidal modelfor a mucus glycoprotein from a cystic fibrosis patient: new evidencefrom electron microscopy, Biochem. Soc. Trans. 12 (1984) 878–879.

[39] L.M.C. Collins, C. Dawes, J. Dent. Res. 66 (1987) 1300–1302.[40] M.J. Levine, P.C. Jones, R.E. Looms, M.S. Reddy, I. Al-Hashimi, E.J.

Bergey, in: I.C. Mackenzie, C.A. Squierv, Dablesteen (Eds.), OralMucosal Diseases: Biology, Etiology and Therapy, Laege-foreningensFolag, Copenhagen, 1987, pp. 7–9.

[41] L. Schenkels, T.L. Gururaja, M.J. Levine, in: M.J. Rathbone (Ed.), OralMucosal Drug Delivery, Marcel Dekker, New York, 1996, pp. 191–220.

[42] T.C. Kontis, M.E. Johns, Anatomy and physiology of salivary glands,in: Byron J. Bailey (Ed.), Head and Neck surgery–Otolaryngology,

second edition, Lippincott_raven publishers, Philadelphia, PA, 1998,pp. 531–539.

[43] R.D. Mattes, Physiologic responses to sensory stimulation by food:nutritional implications, J. Am. Diet. Assoc. 97 (1997) 406–410.

[44] K.L. Moore, Clinically Oriented Anatomy, Third edition, Williams andWilkins, MD, Baltimore, 1992, pp. 751–752.

[45] U.K. Sinha, M. Ng, Surgery of the salivary glands, Otolaryngol. Clin.North Am. 32 (5) (1999) 887–918.

[46] A.R. Silvers, P.M. Som, Salivary glands, Head Neck Imag. 36 (1998)941–966.

[47] W.R. Galey, H.K. Lonsdale, S. Nacht, The in vitro permeability of skinand buccal mucosa to selected drugs and tritiated water, J. Invest. Dermat.67 (1976) 713–717.

[48] H. Batchelor, Novel bioadhesive formulations in drug delivery, The DrugDelivery Companies Report Autumn/Winter, Pharma Ventures Ltd, 2004.

[49] P.R. Mishra, A. Namdeo, S. Jain, N.K. Jain, Hydrogels as drug deliverysystem, Indian Drugs 33 (5) (1996) 181–186.

[50] A. Lowman, N.A. Peppas, Complexation graft copolymers as oral drugdelivery systems, Polym. Prepr. 38 (2) (1997) 566–567.

[51] M.D. Hornof, W. Weyenberg, A. Ludwig, A. Bernkop-Schnurch,J. Control. Release 89 (2003) 419–428.

[52] P.L. Soo, L. Luo, D. Maysinger, A. Eisenberg, Incorporation and releaseof hydrophobic probes in biocompatible polycaprolactone-block-poly(ethylene oxide) micelles: implications for drug delivery, Langmuir 18(2002) 9996–10004.

[53] R. Saviae, L.L.A. Eisenberg,D.Maysinger,Micellar nanocontainers distributeto defined cytoplasmic organelles, Science 300 (2003) 615–618.

[54] C. Allen, D. Maysinger, A. Eisenberg, Nano-engineering blockcopolymer aggregates for drug delivery, Colloids Surf., B. BiointerfacesSpec. Issue, Polym. Micelles Biol. Pharma. 16 (1999) 3–27.

[55] C.E. Kast, D. Guggi, N. Langoth, A. Bernkop-Schnürch, Pharm. Res. 20(2003) 931–936.

[56] V.M. Leitner, D. Guggi, A. Bernkop-Schnürch, 5th Central Eur. Symp.Pharm. Technology, Ljubljana, Slovenia, 2003.

[57] United States Patent: 6,916,485 Title: Prolonged release bioadhesivetherapeutic systems. Inventors: Aiache; Jean-Marc (Paris, FR); Costan-tini; Dominique (Paris, FR); Chaumont; Christine (Paris, FR) Issued: July12, 2005 Assignee: Bioalliance Pharma (Paris, FR).

[58] J. Heller, D.C.Washington, D.W.H. Penhale, Use of bioerodible polymers inself-regulated drug delivery systems, in: P.I. Lee, W.R. Good (Eds.),Controlled Release Technology, Pharmaceutical Applications, Washing-ton DC, ACS Symposium Series, vol. 76, 1997, pp. 281–282.

[59] J.R. Robinson, X. Yang, Absorption enhancers, in: J. Swarbrick, J.C.Boylan (Eds.), Encyclopedia of Technology, vol. 18, Marcel Dekker Inc,New York, 1999, pp. 1–27.

[60] J.A. Weathercell, C. Robinson, M.J. Rathbone, Site-specific differencesin the salivary concentrations of substances in the oral cavity —implications for the etiology of oral-disease and local drug delivery, Adv.Drug Del. Rev. 130 (1–2) (1994) 24–42.

[61] F. Veuillez, Y.N. Kalia, Y. Jacques, J. Deshusses, P. Buri, Factors andstrategies for improving buccal absorption of peptides, Eur. J. Pharm.Biopharm. 51 (2) (2001) 93–109.

[62] K. Khanvilkar, M.D. Donovan, D.R. Flanagan, Drug transfer throughmucus, Adv. Drug Del. Rev. 48 (2–3) (2001) 173–193.

[63] S. Jay, W. Fountain, Z. Cui, R.J. Mumper, Transmucosal delivery oftestosterone in rabbits using novel bi-layer mucoadhesive wax-filmcomposite disks, J. Pharm. Sci. 91 (9) (2002) 2016–2025.

[64] S.C. Chattarajee, R.B. Walker, Penetration enhancer classification, in:E.W. Smith, H.I. Maibach (Eds.), Percutaneous Penetration Enhance-ment, CRC Press, Boca Raton, FL, 1995, pp. 1–4.

[65] A.H. Shojaei, Buccal mucosa as a route for systemic drug delivery: areview, J. Pharm. Pharmaceut. Sci. 1 (1) (1998) 15–30.

[66] A. Aungst, Permeability and metabolism as barriers to transmucosal deliveryof peptides and proteins. in:D.S. Hsieh (Ed.) , DrugPermeationEnhancement.Theory and Applications, Marcel Dekker, New York, (1994) 323-343.

[67] Y. Kurosaki, S. Hisaichi, L. Hong, T. Nakayana, Int. J. Pharm. 51 (1889)47–52.

[68] V. Lee, Crit. Rev. Ther. Drug Carr. Syst. 8 (1991) 91–92.


[69] A. Ganem, R. Falson, P. Buri, Eur. J. Drug Metab. Pharmacokinet. 111(1996) 112–123.

[70] J.A. Siegel, H.P. Gordon, Toxicol. Lett. 26 (1985) 153–157.[71] C.K. Oh, W.A. Ritschel, Biopharmaceutic aspects of buccal absorption of

insulin, Methods Find. Exp. Clin. Pharmacol. 12 (1990) 205–212.[72] I.A. Siegel, H.P. Gordon, Effects of surfactants on the permeability of

canine oral mucosa in-vitro, Toxicol. Lett. 26 (1985) 153–157.[73] G.J.M. Wolany, J. Munzer, A. Rummelt, H.P. Merkle, Buccal absorption

of Sandostatin (octreotide) in conscious beagle dogs, Proc. Int. Symp.Control. Release Bioact. Mater. 17 (1990) 224–225.

[74] A. Steward, D.L. Bayley, C. Howes, The effect of enhancers on thebuccal absorption of hybrid (BDBB) alpha interferon, Int. J. Pharm. 104(1994) 145–149.

[75] A.M. Manganaro, P.W. Wertz, The effects of permeabilizers on the invitro penetration of propranolol through porcine buccal epithelium, Mil.Med. 161 (1996) 669–672.

[76] S. Senel, M.J. Kremer, S.H. Ka, P.W. Wertz, A.A. Hıncal, C.A. Squier,in: M.G. Peter, R.A.A. Muzzarelli, A. Domard (Eds.), Effect of Chitosanin Enhancing Drug Delivery Across Buccal Mucosa, Advances inChitin Science, University of Potsdam, vol. 4, 2000, pp. 254–258.

[77] S. Senel, M.J. Kremer, S.H. Ka, P.W. Wertz, A.A. Hıncal, C.A. Squier,Enhancing effect of chitosan on peptide drug delivery across buccalmucosa, Biomaterials 21 (2000) 2067–2071.

[78] N.G.M. Schipper, K.M. Varum, P. Artursson, Chitosans as absorptionenhancers for poorly absorbable drugs: influence of the molecularweight and degree of acetylation on drug transport across humanintestinal epithelium (Caco-2) cells, Pharm. Res. 21 (2004) 344–353.

[79] M.A. Longer, J.R. Robinson, Fundamental aspects of bioadhesion,Pharm. Int. 7 (1986) 114–117.

[80] P. J. Glantz, T. Arnebrant, T. Nylander, R.E. Baier, Bioadhesion—aphenomenon with multiple dimensions, Acta Odontol. Scand. 57 (1999)238–241.

[81] A. Ahuja, R.K. Khar, J. Ali, Mucoadhesive drug delivery systems, DrugDev. Ind. Pharm. 23 (5) (1997) 489–517.

[82] T. Nylander, N.M. Wahlgren, Forces between adsorbed layers of β-casein, Langmuir 13 (1997) 6219–6225.

[83] H. Elwing, B. Nilson, K.E. Svensson, A. Askendahl, U.R. Nilson, L.Lundstrom,Conformational changes ofmodel protein (complement factor 3)adsorbed on hydrophilic and hydrophobic solid surface, J. Colloid InterfaceSci. 125 (1988) 139–145.

[84] P.C. Hiemenz, Principles of Colloid and Surface Chemistry, MarcelDekker, New York, 1986.

[85] J.N. Israelachvili, Intermolecular and Surface Forces, London academicpress, 1991.

[86] A. Martin, P. Bustamante, P. chun, (eds), BI Waverly Pvt ltd. New Delhi,4th edition. 1995.

[87] G.M. Whitesides, J.P. Mathias, C.T. Seto, Science 254 (1991) 1312.[88] E.A. Rawlins (Ed.), Bentley's Textbook of Pharmaceutics, 8th edition,

ELBS publishers, 1984, pp. 32–33.[89] B.W. Ninham, V. Yaminsky, Ion binding and ion specificity: the

Hofmeister effect, Onsager and Lifshitz theories, Langmuir 13 (1997)2097–2108.

[90] T. Nylander, P. Kekicheff, B.W. Ninham, The effect of solution behaviorof insulin on interactions between adsorbed layers of insulin, J. Colloidinterface Sci. 164 (1994) 136–150.

[91] K. Larsson, P.O. Glantz, Microbial adhesion to surfaces with differentcharges, Acta Odontol. Scand. 39 (1981) 79–82.

[92] M.J Tobyn, J.R. Johnson, S.A.W. Gibson, J. Pharm. Pharmacol. 44(1992) 1048 (suppl).

[93] H.K. Christensson, P.M. Claesson, Cavitation and the interaction betweenmicroscopic hydroscopic surfaces, Science 239 (1988) 390–392.

[94] V.M. Leitner, G.F. Walker, A. Bernkop-Schnurch, Eur. J. Pharm.Biopharm. 56 (2) (2003) 207–214.

[95] K. Kafedjiiski, Multifunctional Polymeric Excipients in Non-InvasiveDelivery of Hydrophilic Macromolecular Drugs, The Drug DeliveryCompanies Report Autumn/Winter, Pharm Ventures Ltd, 2004.

[96] D. Guggi, M.K. Marschutz, A. Bernkop-Schnurch, Int. J. Pharm. 274(2004) 97–105.

[97] P.M. Claesson, H.K. Christensson, Very long-range attractive forcesbetween uncharged hydrocarbon and fluorocarbon surface in water,J. Phys. Chem. 92 (1988) 1650–1655.

[98] L.G.T. Erikson, P.M. Claesson, S. Ohnishi, H. Masakatsu, Stability ofdimethyldioctadecyl-ammonium bromide LB films on mica in aqueoussalt solutions, Thin Solid Films 300 (1997) 240–255.

[99] K.A. Dill, Science 250 (1990) 297.[100] R. Baldwin, Proc. Natl. Acad. Sci. U. S. A. 83 (1986) 8069.[101] K.R. Kamath, K. Park, Mucosal adhesive preparations, in: J. Swabrick,

J.C. Boylan (Eds.), Encyclopedia of Pharmaceutical Technology,vol. 10, Marcel Dekker, New York, 1994, pp. 133–163.

[102] J.W. Lee, J.H. Park, J.R. Robinson, Bioadhesive based dosage forms: thenext generation, J. Pharm. Sci. 89 (7) (2000) 850–866.

[103] C.M. Lehr, F.G.J. Poelma, H.E. Junginger, J.J. Tucker, An estimate ofturnover time of intestinal mucus gel layer in the rat intestinal in situ loop,Int. J. Pharm. 70 (1991) 235–240.

[104] J.D. Smart, M.E. Johnson, A new technique for assessing mucoadhesionby application of tensile and shear stresses, Eur. J. Pharm. Sci. 4 (1996)S65–S65.

[105] M. Ishida, Y. Machida, N. Nambu, T. Nagai, Chem. Pharm. Bull. 29 (1981)810–816.

[106] R. Gurney, J.M. Meyer, N.A. Peppas, Bioadhesive intraoral releasesystems: design, testing and analysis, Biomaterials 5 (1984) 336–340.

[107] K. Park, H. Park, Test methods of bioadhesion, Int. J. Pharm. 52 (1989)265–270.

[108] S. Koclkisch, G.D. Rees, S.A. Young, J. Tsibouklis, J.D. Smart, A directstaining method to evaluate the mucoadhesion of polymers from aqueousdispersion, J. Control. Release 77 (1–2) (2001) 1–6.

[109] H. Hagerstorm, K. Edsman, Limitations of the rheological method: theeffect of the choice of conditions and the rheological synergism parameter,Eur. J. Pharm. Sci. 18 (5) (2003) 349–357.

[110] E.E. Hassan, J.M. Gallo, Pharm. Res. 7 (1990) 491.[111] S.A. Mortzavi, J.D. Smart, An investigation of some factors influencing the

in vitro assessment of mucoadhesion, Int. J. Pharm. 116 (1995) 223–230.[112] C. Carmella, S. Rossi, M.C. Bonferoni, F. Ferrari, Characterization of

chitosan hydrochloride–mucin rheological interaction: influence of polymerconcentration and polymer:mucinweight ratio, Eur. J. Pharm. Sci. 12 (2001)479–485.

[113] S.E. Harding, Mucoadhesive interactions, Biochem. Soc. Trans. 31 (5)(2003) 1036–1041.

[114] K. Park, J.R. Robinson, Bioadhesive polymers as platforms for oralcontrolled drug delivery, Int. J. Pharm. 19 (1984) 107–127.

[115] P.K. Nanti, D.J. Cook, D.J. Rogers, J.D. Smart, Lectins for drug deliverywithin the oral cavity — investigation of lectin binding to oral mucosa,J. Drug Target 5 (1997) 45–55.

[116] H. Park, On the mechanism of bioadhesion. Ph.D. Thesis, Pharmaceutics,School of Pharmacy, University of Wisconsin-Madison, 1986.

[117] R.M. Barrer, J.A. Barrie, P.S.L. Wong, The diffusion and solution ofgases in highly cross-linked copolymers, Polymer 9 (1968) 609–627.

[118] H.S. Ch'ng, H. Park, P. Kelly, J.R. Robinson, Bioadhesive polymers asplatforms for oral controlled drug delivery. II. Synthesis and evaluation ofsome swelling, water-insoluble bioadhesive polymers, J. Pharm. Sci. 74(1985) 399–405.

[119] D. Duchene, F. Touchard, N.A. Peppas, Pharmaceutical and medicalaspects of bioadhesive systems for drug administration, Drug Dev. Ind.Pharm. 14 (1988) 283–318.

[120] E. Mathiwitz, D.E. Chickering, C.M. Lehr, Bioadhesive Drug DeliverySystems: Fundamentals, Novel Approaches and Development, MarcelDekker, Inc., New York, 1999.

[121] M.J. Tobyn, J.N. Staniforth, E. Jorgensen, D. Bhagwat, Use of gelstrength analysis to characterize a polysaccharide controlled releasematrix, Controlled Release of Bioactive Materials Conference Paper,1997.

[122] J.L. Chen, G.N. Cyr, in: R.S. Manly (Ed.), Composition ProducingAdhesion Through Hydration, Adhesion in Biological System, Academicpress, New York, 1970, pp. 163–181.

[123] C.M. Lehr, J.A. Bouwstra, J.J. Tucker, H.E. Junginger, Intestinal transitof bioadhesive microspheres in an in situ loop in the rat— a comparative


study with copolymers and blends bases on poly (acrylic acid), J. Control.Release 13 (1990) 51–62.

[124] D.S. Jones, A.D. Woolfson, A.F. Brown, Textural analysis and flowrheometry of novel bioadhesive antimicrobial oral gels, Pharm. Res. 114(4) (1997) 450–457.

[125] S. Miyazaki, A. Nakayama, M. Oda, M. Takada, D. Attwood, Chitosanand sodium alginate based bioadhesive tablets for intraoral drug delivery,Biol. Pharm. Bull. 17 (1994) 745–747.

[126] C. Remunan-Lopez, A. Portero, J.L. Vila-Jato, M.J. Alonso, Design andevaluation of chitosan/ethylcellulose mucoadhesive bilayered devices forbuccal drug delivery, J. Control. Release 55 (1998) 143–152.

[127] B. Taylan, Y. Capan, O. Guven, S. Kes, A.A. Hincal, Design andevaluation of sustained release and buccal adhesive propronololhydrochloride tablets, J. Control. Release 38 (1) (1996) 11–20.

[128] K.G.H. Desai, T.M.P. Kumar, Preparation and evaluation of a novelbuccal adhesive system, AAPS PharmSciTech 5 (2004) 1–9.

[129] B. Taylan, Y. Capan, O. Güven, S. Kes, A.A. Hincal, Design andevaluation of sustained-release and buccal adhesive propranolol hydro-chloride tablets, J. Control. Release 38 (1996) 11–20.

[130] N.A. Nafee, F.A. Ismail, N.A. Boraie, L.M. Mortada, Mucoadhesivedelivery systems. II. Formulation and in-vitro/in-vivo evaluation ofbuccal mucoadhesive tablets containing water-soluble drugs, Drug Dev.Ind. Pharm. 30 (2004) 995–1004.

[131] J.M. Labot, R.H. Manzo, A. Allemandi, Double layered mucoadhesivetablets containing nystatin, AAPS PharmSciTech 3 (3) (2002) 22.

[132] S. Bouckaert, H. Schautteet, R.A. Lefebvre, J.P. Remon, R.V. Clooster,Double-layered mucoadhesive tablets containing nystatin, Eur. J. Clin.Pharmacol. 43 (1992) 137.

[133] A. Gupta, S. Garg, R.K. Khar, Interpolymer complexation and its effecton bioadhesion strength and dissolution characteristics of buccal drugdelivery systems, Drug Dev. Ind. Pharm. 20 (1994) 315–325.

[134] T. Nagai, Adhesive topical drug delivery system, J. Control. Release 2(1985) 121–134.

[135] T. Nagai, R. Konishi, Buccal/gingival drug delivery systems, J. Control.Release 6 (1987) 353–360.

[136] T. Nagai, Y. Machida, Buccal delivery systems using hydrogels, Adv.Drug Del. Rev. 11 (1993) 179–191.

[137] G. Ponchel, F. Touchard, D. Wouessidjewe, D. Duchëne, N.A. Peppas,Bioadhesive analysis of controlled release systems. III. Bioadhesive andrelease behaviour of metronidazole containing poly (acrylic acid)-hydoxypropyl methylcellulose systems, Int. J. Pharm. 38 (1987) 65–70.

[138] P. Bottenberg, R. Cleymaet, C.D. Mynck, J.P. Remenn, D. Coomans, Y.Michotte, D. Slop, Comparison of salivary fluoride concentration afteradministration of a bioadhesive slow-release tablet and a conventionalfluoride tablet, J. Pharm. Pharmacol. 43 (1991) 457.

[139] S. Bouckaert, H. Schautteet, R.A. Lefebvre, J.P. Remon, R. Van Clooster,Comparison of salivary miconazole concentrations after administration ofa bioadhesive slow-release buccal tablet and an oral gel, Eur. J. Clin.Pharmacol. 43 (1992) 137–140.

[140] V. Agarwal, B. Mishra, Design, development, and biopharmaceuticalproperties of buccoadhesive compacts of pentazocine, Drug Dev. Ind.Pharm. 25 (1999) 701–709.

[141] H.H. Alur, S.I. Pather, A.K. Mitra, T.P. Johnston, Transmucosalsustained-delivery of chlorpheniramine maleate in rabbits using a novelnatural mucoadhesive gum as an excipient in buccal tablets, Int. J. Pharm.188 (1999) 1–10.

[142] H.G. Choi, C.K. Kim, Development of omeprazole buccal adhesivetablets with stability enhancement in human saliva, J. Control. Release 68(2000) 397–404.

[143] C.R. Park, D.L. Munday, Development and evaluation of a biphasicbuccal adhesive tablet for nicotine replacement therapy, Int. J. Pharm. 237(2002) 215–226.

[144] K. Rajesh, S.P. Agarwal, A. Ahuja, Buccoadhesive erodible carriers forlocal drug delivery: design and standardization, Int. J. Pharm. 138 (1996)68–73.

[145] G. İkinci, S. Senel, C.G. Wilson, M. Şumnu, Development of buccalbioadhesive nicotine tablet formulation for smoking cessation, Int. J. Pharm.277 (1–2) (2004) 173–178.

[146] B. Mizrahi, J. Golenser, J.S. Wolnerman, A.J. Dombi, Adhesive tableteffective for treating canker sores in humans, Assoc. J. Pharm. Sci. 93(2004) 2927–2935.

[147] Q. Du, Q.N. Ping, G.J. Liu, Preparation of Buspirone hydrochloridebuccal adhesive tablet and study on its drug release mechanism, Yao XueXue Bao 37 (8) (2002) 653–656.

[148] H. Choi, J. Jung, C.S. Yong, C. Rhee, M. Lee, J. Han, K. Park, C. Kim,Formulation and in vivo evaluation of Omeprazole buccal adhesivetablet, J. Control. Release 68 (3) (2000) 405–412.

[149] G.C. Ceschel, P. Maffei, S.L. Borgia, C. Ronchi, Design and evaluation ofbuccal adhesive hydrocortisone acetate tablets, Int. J. Pharm. 238 (2002)161–170.

[150] K. Tsutsumi, Y. Obata, T. Nagai, T. Loftsson, K. Takayama, Buccalabsorption of ergotamine tartrate using the bioadhesive tablet system inguinea-pigs, Int. J. Pharm. 238 (1–2) (2002) 161–170.

[151] Dinsheet, S.P. Agarwal, A. Ahuja, Preparation and evaluation of buccaladhesive tablets of Hydralazine hydrochloride, Indian J. Pharm. Sci. 59(3) (1997) 135–141.

[152] M. Rafiee-Tehrani, G. Jazayeri, T. Toliyat, K. Bayati, K. Khalkhali, K.Shamimi, A. Miremadi, F.A. Dorkoosh, Development and in-vitroevaluation of novel buccoadhesive tablet formulation of prednisolone,Acta Pharm. 52 (2002) 123–130.

[153] J.P. Cassidy, N.M. Landzert, E. Quadros, Controlled buccal delivery ofbuprenorphine, J. Control. Release 25 (1993) 21–29.

[154] S. Anlar, Y. Capan, O. Guven, A. Gogus, T. Dlakara, A.A. Hincal,Formulation and in vitro and in vivo evaluation of buccoadhesivemorphine sulphate tablets, Pharm. Res. 11 (2) (1994) 231–236.

[155] E. Beyssac, J.M. Aiche, C. Chezaubernarul, H. Caplin, M.J. Douin, A.Renoux, Proc. Int. Symp. Control. Rel. Biact. Mater., Contr. Rel. Soc. 21(1984).

[156] G.C. Ceschel, P. Maffei, S.L. Borgia, Design and evaluation of a newmucoadhesive bilayered tablet containing nimesulide for buccal admin-istration, Drug Deliv. 11 (2004) 225–230.

[157] A.E. Collins, P.B. Deasy, Bioadhesive lozenge for the improved deliveryof cetylpyridinium chloride, J. Pharm. Sci. 79 (2) (1990) 116.

[158] M. Artusi, P. Santi, P. Colombo, H.E. Junginger, Buccal delivery ofthiocolchicoside: in vitro and in vivo permeation studies, Int. J. Pharm.250 (1) (2003) 203–213.

[159] H.K. Goud, T.M.P. Kumar, Preparation and evaluation of a novel buccaladhesive systems, AAPS PharmSciTech 5 (3) (2004) 35.

[160] L.E. Bromberg, D.K. Buxton, P.M. Friden, J. Control. Release 71 (2001)251–259.

[161] J.E. Codd, P.B. Deasy, Int. J. Pharm. 173 (1998) 13–24.[162] H. He, X. Cao, I.J. Lee, J. Control. Release 95 (2004) 391–402.[163] Z. Cui, R.J. Mumper, Bilayer films for mucosal (genetic) immunization

via the buccal route in rabbits, Pharm. Res. 19 (2002) 947–953.[164] P. Perugini, I. Genta, B. Conti, T. Modena, F. Pavanetto, Periodontal

delivery of ipriflavone: new chitosan/PLGA film delivery system for alipophilic drug, Int. J. Pharm. 18 (2003) 1–9.

[165] S. Senel, G. Ikinci, S. Kas, A. Yousefi-Rad, M.F. Sargon, A.A. Hıncal,Chitosan films and hydrogels of chlorhexidine gluconate for oral mucosaldelivery, Int. J. Pharm. 193 (2000) 197–203.

[166] D. Tiwari, D. Goldman, R. Sause, P.L. Madan, Evaluation ofpolyoxyethylene homopolymers for buccal bioadhesive drug deliverydevice formulations, AAPS PharmSci 1 (1999) 1–8.

[167] R. Anders, H. Merckle, Evaluation of laminated mucoadhesive patchesfor buccal drug delivery, Int. J. Pharm. 49 (1989) 231–240.

[168] R. Anders, H.P. Merckle, W. Schurr, R. Ziegler, Buccal absorption ofProtirelin: an effective way to stimulate Thyrotropin and Prolactin,J. Pharm. Sci. 72 (1983) 1481–1483.

[169] J.H. Guo, Investigating the surface properties and bioadhesion of buccalpatches, J. Pharm. Pharmacol. 46 (1994) 647–650.

[170] K. Danjo, H. Kato, A. Otsuka, K. Ushimaru, Fundamental study on theevaluation of strength of granular particles, Chem. Pharm. Bull. 42 (1994)2598–2603.

[171] M. Ishida, N. Nambu, T. Nagai, Mucosal dosage form of lidocaine fortoothache using hydroxypropyl cellulose and carbopol, Chem. Pharm.Bull. 30 (1982) 980–984.


[172] N.A. Nafee, F.A. Ismail, A. Nabila, L.M. Boraie, Mucoadhesive buccalpatches of miconazole nitrate: in vitro/in vivo performance and effect ofageing, Int. J. Pharm. 264 (2003) 1–14.

[173] T. Save, U.M. Shah, A.R. Ghamande, P. Venkatachalam, Comparativestudy of buccoadhesive formulations and sublingual capsules ofnifedipine, J. Pharm. Pharmacol. 46 (3) (1994) 192–195.

[174] A.H. Shojaei, X. Li, Mechanisms of buccal mucoadhesion of novelcopolymers of acrylic acid and polyethylene glycol monomethylethermonomethacrylate, J. Control. Release 47 (1997) 151–161.

[175] A.J. Hoogstraate, J.C. Verhoef, A. Pijpers, L.A.V. Leengoed, J.H.Verheijden, H.E. Junginger, H.E. Bodde, In vivo buccal delivery of thepeptide drug buserelin with glycodeoxycholate as an absorption enhancerin pigs, Pharm. Res. 13 (1996) 1233–1237.

[176] H. Alur, J.D. Beal, S.I. Pather, A.K. Mitra, T.P. Johnston, J. Pharm. Sci.88 (12) (1999) 1313–1319.

[177] Y. Yaziksiz-Iscan, Y. Capan, S. Senel,M.F. Sahin, S.Kes, D. Duchêne,A.A.Hincal, S.T.P. Pharma, Pharm. Sci. 8 (1998) 357–363.

[178] Y. Ito, Z. Hu, M. Yoshikawa, M. Murakami, K. Takada, Proc. Int. Symp.Control. Release Bioact. Mater. 26 (1999) 6303–6304.

[179] J.C. Mcelnay, T.A. Furaih, C.M. Hughes, M.G. Scott, J.S. Elborn, D.P.Nicholls, Eur. J. Clin. Pharmacol. 54 (1998) 609–614.

[180] M.K. Gutniak, H. Larsson, S.J. Heiber, O.T. Juneskans, J.J. Holst, B.Ahren, Diabetes Care 19 (1996) 843–848.

[181] Y. Chien, S. Nakane, Y. Lee, M. Kakumoto, K. Yukimatsu, Proc. 1stWorld Meeting APGI/APV, Budapest, 1995, pp. 813–814.

[182] M.G. Towey, C. Maury, J. Interferon Cytokine Res. 19 (2) (1999)145–155.

[183] J. Zhang, S. Nui, C. Ebert, T.H. Stanley, Int. J. Pharm. 101 (1994) 15–22.[184] S. Nakane, M. Kakumoto, K. Yukimatsu, Y.W. Chien, Pharm. Dev.

Technol. 1 (1996) 251–259.[185] H.P. Merkle, G.J.M. Wolany, J. Control. Release 21 (1992) 155–164.[186] C. Li, P.B. Padmanabh, T.P. Johnston, Pharm. Dev. Technol. 2 (3) (1997)

265–274.[187] R. Anders, H.P. Merkle, W. Schurr, R. Ziegler, J. Pharm. Sci. 72 (1983)

1481–1483.[188] D. Bayley, C. Temple, V. Clay, A. Steward, N. Lowther, J. Pharm.

Pharmacol. 47 (1995) 721–724.[189] N.A. Nafee, F.A. Ismail, N.A. Boraie, L.M. Mortada, Mucoadhesive

delivery systems. I. Evaluation of mucoadhesive polymers for buccaltablet formulation, Drug Dev. Ind. Pharm. 30 (9) (2004) 985–993.

[190] Y. Machida, H. Masuda, N. Fujiyama, S. Ito, M. Iwata, T. Nagai, Chem.Pharm. Bull. 27 (2) (1990) 116.

[191] D.L. Hughes, A. Gehris, A new method for characterizing the buccaldissolution of drugs, Rohm and Haas Research laboratories, Springhouse, PA, USA.

[192] M.E. Dowty, K.E. Knuth, B.K. Irons, J.R. Robinson, Transport ofthyrotropin releasing hormone in rabbit buccal mucosa in vitro, Pharm.Res. 9 (1992) 1113–1122.

[193] M.W. Hill, C.A. Squier, The permeability of oral palatal mucosamaintained in organ cell cultures, J. Anat. 128 (1979) 169–178.

[194] M.R. Tavakoli-Saberi, K.L. Andus, Cultured buccal epithelium: an invitro model derived from the hamster pouch for studying transport andmetabolism, Pharm. Res. 6 (1989) 160–162.

[195] H.R. Leipold, E. Quadros, Nicotine permeation through buccal cultures,Proc. Int. Symp. Control. Release Bioact. Mater. 20 (1993) 242–243.

[196] B.J. Angust, N.J. Rogers, Comparison of the effects of varioustransmucosal absorption promoters on buccal insulin delivery, Int. JPharm. 53 (1989) 227–235.

[197] I.A. Siegel, H.P. Gordon, Surfactant — induced increase of permeabilityof rat oral mucosa to non-electrolytes in vivo, Arch. Oral Biol. 30 (1985)43–47.

[198] C.A. Squier, P.W. Wertz, in: M.J. Rathbone (Ed.), Structure and Functionof the Oral Mucosa and Implications for Drug Delivery, Oral MucosalDrug Delivery, Marcel Dekker Inc., New York, 1996, pp. 1–26.

[199] M. Ishida, Y. Machida, N. Nambu, T. Nagai, New mucosal dosage formsof insulin, Chem. Pharm. Bull. 84 (1981) 810–816.

[200] C.L. Barsuchn, L.S. Olanoff, D.D. Gleason, E.L. Olanoff, D.D. Gleason,E.L. Adkins, N.F.H. Ho, Human buccal absorption of flubiprofen, Clin.Pharmacol. Ther. 44 (1988) 225–231.

[201] M. Mehta, B.W. Kemppainen, R.G. Stafford, In vitro penetration oftritium labeled water (THO) and [3H] Pb Tx-3 (a red tide toxin) throughmonkey buccal mucosa and skin, Toxicol. Lett. 55 (1991) 185–194.

[202] C.A. Squier, P. Cox, P.W. Wertz, Lipid content and water permeability ofskin and oral mucosa, J. Invest. Dermat. 96 (1991) 123–126.

[203] A.H. Beckett, E.J. Triggs, Buccal absorption of basic drugs and itsapplication as an in vivo model of passive drug transfer through lipidmembranes, J. Pharm. Pharmacol. 19 (1967) 31S–41S.

[204] I. Gonzalez-Younes, J.G. Wagner, D.A. Gaines, Absorption of flubripro-fen through human buccal mucosa, J. Pharm. Sci. 80 (1991) 820–823.

[205] H. Yamahara, V.H. Lee, Drug metabolism in the oral cavity, Adv. DrugDel. Rev. 12 (1993) 25–39.

[206] M.J. Rathbone, J. Hadgraft, Absorption of drugs from human oral cavity,Int. J. Pharm. 74 (1991) 9–24.

[207] H.E. Junginger, J.A. Hoogstate, J.C. Verhoef, Recent advances in buccaldrug delivery and absorption — in vitro and in vivo studies, J. Control.Release 62 (1–2) (1999) 149–159.

[208] M. Tanaka, N. Yanagibashi, H. Fukuda, T. Nagai, Absorption of salicylicacid through the oral mucous membrane of hamster cheek pouch, Chem.Pharm. Bull. 28 (1980) 1056–1061.

buccal drug deliverry

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