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INTRODUCTION: Oral trans-mucosal drug delivery concerned with the systemic delivery of the drug moiety via mucous membrane of the oral cavity . Oral trans-mucosal drug delivery can be subdivided into : sublingual drug delivery : via the mucosa of the ventral surface of the tongue and the floor of the mouth under the tongue. E g . Sublingual tablet, patches etc. buccal drug delivery : via the buccal mucosa—the epithelial lining of the cheeks, the gums and also the upper and lower lips . Eg . Buccal tablets, patches, wafers etc. 5/27/2011 SNDCOP 3



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ORAL EPITHELIUM : The epithelium of the mouth consists of stratified, squamous epithelium, which can be keratinized, or nonkeratinized . It contains following layers: Stratum distendum Stratum filamentosum Stratum suprabasale Stratum basale 5/27/2011 SNDCOP 5

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LAMINA PROPRIA : Constitutes of a continuous sheet of connective tissue containing collagen, elastic fibres and cellular components in a hydrated ground substance . It also carries blood capillaries and nerve fibres that serve the mucosa. It is through the blood vessels in the lamina propria that drug moieties can gain entry to the systemic circulation . SUBMUCOSA : This is a layer of loose connective tissue that supports the epithelium and also contains blood vessels, lymphatics and nerves. 5/27/2011 SNDCOP 6


IMPORTANT TERM : BIOADHESION : The adhesion between two biological materials or adhesion between some biological material and an artificial substrate. Bioadhesion is necessary: to maximize the intimacy of contact of the patch with the mucosa; to retain the delivery system in the oral cavity.. 5/27/2011 SNDCOP 7

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MECHANISM OF BIOADHESION : Step 1 : wetting and swelling of polymer to permit intimate contact with biological tissue. Step 2 : inter-penetration of bioadhesive polymer(BP) chains and entanglement of polymer and mucin chains. 5/27/2011 SNDCOP 8

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Step 3 : Formation of chemical bonds between the entangled chains. Chemical bonds can include strong primary bonds (i.e., covalent bonds) as well as weaker secondary forces such as ionic bonds, Van der Waals' interactions, and hydrogen bonds. 5/27/2011 SNDCOP 9

Transport routes and mechanisms::

Transport routes and mechanisms: 5/27/2011 SNDCOP 10

The paracellular route-:

The paracellular route- Low molecular weight, water-soluble compounds may traverse the mucosa via the paracellular route, moving between the junctions of the epithelial cells . Tight junctions are rare in oral epithelia. Thus in the majority of cases, drug absorption for small hydrophilic moieties is thought to occur via paracellular penetration. Intercellular space of the epithelial cells contains lipidic material. Lipidic moieties may be able to permeate through this lipidic environment between the cells, thereby being absorbed via the paracellular route. 5/27/2011 SNDCOP 11

The transcellular route:

The transcellular route Transcellular passive diffusion- Low molecular weight, lipophilic drugs may be absorbed transcellularly , by passive diffusion across the cells of the epithelium. Again, movement occurs down a concentration gradient, according to Fick’s Law. The stratified nature of the epithelium means that lipophilic moieties must permeate across several layers of cells to reach the underlying blood capillaries. Carrier-mediated processes- Endocytic processes- 5/27/2011 SNDCOP 12


FORMULATION DESIGN- Pharmaceutical considerations: Great care needs to be exercised while developing a safe and effective buccal adhesive drug delivery device . Factors influencing drug release and penetration through buccal mucosa are organoleptic factors and effects of additives used to improve drug release pattern and absorption, the effects of local drug irritation caused at the site of application are to be considered while designing a formulation. 5/27/2011 SNDCOP 13

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Physiological considerations- Physiological considerations such as texture of buccal mucosa , thickness of the mucus layer, its turn over time, effect of saliva and other environmental factors are to be considered in designing the dosage forms Eg . Saliva contains moderate levels of esterases , carbohydrases , and phosphatases that may degrade certain drugs. Although saliva secretion facilitates the dissolution of drug, involuntary swallowing of saliva also affects its bioavailability 5/27/2011 SNDCOP 14

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Pharmacological considerations- Drug absorption depends on the partition coefficient of the drugs . Generally lipophilic drugs absorb through the transcellular route , where as hydrophilic drugs absorb through the paracellular route . Chemical modification may increase drug penetration through buccal mucosa. Residence time and local concentration of the drug in the mucosa, the amount of drug transported across the mucosa into the blood are the responsible factors for local or systemic drug delivery. Optimization by a suitable formulation design f astens drug release from the dosage form and taken up by the oral mucosa. 5/27/2011 SNDCOP 15


BASIC COMPONENTS FOR BDDS : Buccal adhesive drug delivery systems with the size 1–3 sq.cm and a daily dose of 25 mg or less are preferable. The maximal duration of buccal delivery is approximately 4–6 hrs. To make such dosage form following components are required: BIOADHESIVE POLYMERS DRUG(API) PERMEATION ENHANCERS OTHER EXCIPIENTS 5/27/2011 SNDCOP 16


` BIOADHESIVE POLYMERS: Bioadhesive formulations use polymers as the adhesive component. These formulations are often water soluble and when in a dry form attract water from the biological surface and this water transfer leads to a strong interaction . It also form viscous liquids when hydrated with water that increases their retention time over mucosal surfaces and may lead to adhesive interactions. They should possess certain physicochemical features including hydrophilicity , numerous hydrogen bond-forming groups, flexibility for interpenetration with mucus and epithelial tissue , and visco -elastic properties. 5/27/2011 SNDCOP 17


IDEAL CHARACTERISTICS non-toxic, non-irritant and free from leachable impurities . good spreadability , wetting, swelling and solubility and biodegradability properties . Should adhere quickly to buccal mucosa and should possess sufficient mechanical strength Should show bioadhesive properties in both dry and liquid state. Should possess peel, tensile and shear strengths at the bioadhesive range. 5/27/2011 SNDCOP 18


EXAMPLES HYDROGELS:- WET ADHESIVES P olyacrylates ( carbopol and polycarbophil ) P oly vinyl alcohol, Ethylene vinyl alcohol sodium alginate Natural gums like guar gum, karaya gum , xantham gum HPC, HPMC etc. Multifunctional polymers:- polyacrylates , polycarbophil , chitosan etc . 5/27/2011 SNDCOP 19

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Thiolated polymers :- THIOMERS hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone Eg : thiomers of chitosan and polyacrylic acid etc. 5/27/2011 SNDCOP 20

Permeation enhancers-:

Permeation enhancers- Membrane permeation is the limiting factor for many drugs in the development of buccal adhesive delivery devices . The epithelium that lines the buccal mucosa is a very effective barrier to the absorption of drugs. Substances that facilitate the permeation through buccal mucosa are referred as permeation enhancers 5/27/2011 SNDCOP 21

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Chelators : EDTA, citric acid, sodium salicylate, methoxy salicylates . Surfactants : sodium lauryl sulphate, polyoxyethylene ,, Benzalkonium chloride , cetylpyridinium chloride , cetyltrimethyl ammonium bromide. Bile salts : sodium glycocholate, sodium deoxycholate, sodium taurocholate , sodium glycodeoxycholate , sodium taurodeoxycholate . Fatty acids : oleic acid, capric acid, lauric acid, lauric acid/ propylene glycol, methyloleate , phosphatidylcholine . Non-surfactants : unsaturated cyclic ureas . Inclusion complexes: cyclodextrins . 5/27/2011 SNDCOP 22

Mechanisms of action of P.E.-:

Mechanisms of action of P.E. - Changing mucus rheology Increasing the fluidity of lipid bilayer membrane Acting on the components at tight junctions By overcoming the enzymatic barrier Increasing the thermodynamic activity of drugs 5/27/2011 SNDCOP 23

DRUG of choice (API):

DRUG of choice (API) Choice of drug for buccal formulation is property specific: Physico -chemical properties: Mol.wt . of 1000 dalton or less Should posses lipophilic and hydrophilic properties Should have low melting point Biological properties: Should be potent T half should be shorter Non irritant to oral mucosa Drug degraded in GI tract 5/27/2011 SNDCOP 24


FORMULATIONS: Buccal ahesive dosage forms are broadly classified in following dosage forms: Solid buccal adhesive dosage forms Semi-solid buccal adhesive dosage forms Liquid buccal adhesive dosage forms 5/27/2011 SNDCOP 25

Solid buccal adhesive dosage forms :

Solid buccal adhesive dosage forms Tablets: Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm. Tablets are placed directly onto the mucosal surface tablets adhere to the buccal mucosa in presence of saliva . Tablets are usually prepared by direct compression , but wet granulation techniques can also be used . 5/27/2011 SNDCOP 26

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Designed to release the drug either unidirectionally targeting buccal mucosa or mutidirectionally in to the saliva. However, size is a limitation for tablets due to the requirement for the dosage form to have intimate contact with the mucosal surface . 5/27/2011 SNDCOP 27

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Eg : prochlorperazine maleate buccal tablet glyceryl trinitrate buccal tablet Fentanyl buccal tablet Miconazole buccal tablet. 5/27/2011 SNDCOP 28

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Buccal wafers: Bromberg et al. [160] described a conceptually novel periodontal drug delivery system that is intended for the treatment of microbial infections associated with peridontitis The delivery system is a composite wafer with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents , biodegradable polymers and matrix polymers . O ral wafer medication systems can vary between 2cm² and 8cm² in area, and 20µm and 500µm in thickness . Eg : Nimodepine 5/27/2011 SNDCOP 29

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Lozenges- Used for the delivery of drugs that act topically within the mouth including antimicrobials , corticosteroids, local anaesthetics, antibiotics and antifungals . A slow release bioadhesive lozenge offers the potential for prolonged drug release with improved patient compliance . Eg : fenatyl lozenges. 5/27/2011 SNDCOP 30

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Patches: Buccal-adhesive patches may be up to 10-15 sq.cm in size, but are more usually 1-3 sq.cm so as to be convenient and comfortable for the patient. Two methods used to prepare adhesive Patches: solvent casting direct milling An impermeable backing layer may also be applied to control the direction of drug release, prevent drug loss, and minimize deformation and disintegration of the device during the application period . 5/27/2011 SNDCOP 31

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Flexible films may be used to deliver drugs directly to a mucosal membrane. They provide a measured dose of drug to the site. Films are laminated patches used for controlled drug release. Eg : Nitroglycerine patches, Fenatyl patches 5/27/2011 SNDCOP 32

Semi-solid buccal adhesive dosage forms :

Semi-solid buccal adhesive dosage forms Gels: B ioadhesive polymers include crosslinked polyacrylic acid that has been used to adhere to mucosal surfaces for extended periods of time and provide controlled release of drugs. W idely used in the delivery of drugs to the oral cavity. A bility to form intimate contact with the mucosal membrane and their rapid release of drug at the absorption site . Eg : Itraconazole gel Antibiotics, Antifungals etc . 5/27/2011 SNDCOP 33

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Ointments : F ormulation containing polymethyl methacrylate in a base containing water, sodium hydroxide, glycerol and the active drug. A high-viscosity " gel ointment " containing Carbopol (12.5%), poly(ethylene glycol) or glycerol and an aqueous solution containing sodium salicylate, sustained drug absorption for 5 hours. Eg : Antifungal Antibiotics such as Ofloxacin , T retinoin . 5/27/2011 SNDCOP 34

Liquid dosage forms:

Liquid dosage forms Viscous liquids may be used to coat buccal surface either as protectants or as drug vehicles for delivery to the mucosal surface . Polymers were used to enhance the viscosity of products to aid their retention in the oral cavity. These solutions contain sodium CMC as bioadhesive polymer . Eg : sodium alginate suspension 5/27/2011 SNDCOP 35


Evaluation : Routine evaluations for tablets such as Weight variation, Friability, Hardness, Content uniformity, In vitro dissolution For films and patches Tensile strength, Film endurance, Hygroscopicity 5/27/2011 SNDCOP 36

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For gels and ointements : Spredibility Viscosity pH 5/27/2011 SNDCOP 37

Methods for evaluation of BIOADHESIVE interaction:

Methods for evaluation of BIOADHESIVE interaction IN-VITRO techniques Tests measuring mucoadhesive strength: Measuring the force required to break the binding between the model membrane and the mucoadhesive . Depending on the direction in which the mucoadhesive is separated from the substrate, is it possible to obtain the detachment, shear, and rupture tensile strengths. 5/27/2011 SNDCOP 38


TEXTURE ANALYZER Here the force required to remove the formulation from a model membrane is measured, which can be a disc composed of mucin , a piece of animal mucous membranes. This method is more frequently used to analyze solid systems like microspheres. It also evaluates the texture of the formulations and assess other mechanical properties of the system. 5/27/2011 SNDCOP 39

Microforce Balance:

Microforce Balance A unique microsphere is attached by a thread to the stationary microbalance. The chamber with the mucous membrane is raised until it comes into contact with the microsphere and, after contact time, is lowered back to the initial position, yielding both contact angle and surface tension . 5/27/2011 SNDCOP 40

Shear test :

The shear test measures the force required to separate two polymer-coated glass slides joined by a thin film of natural or synthetic mucus. The results of this technique often correlate well with in vivo test results. 5/27/2011 SNDCOP 41 Shear test

Determination of residence time:

Determination of residence time IN-VITRO residence time: Modified USP dissolution appratus Dissolution medium: 800 ml isotonic phosphate buffer pH 6.75 maintained at 37 °C . A segment of rabbit intestinal mucosa, 3 cm long, was glued to the surface of a glass slab, vertically attached to the apparatus. Hydrated surface from buccal tablet brought into the contact with the membrane The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded. 5/27/2011 SNDCOP 42

IN VIVO residence time:

IN VIVO residence time Experiments should conducted on 4 or more than 4 human volunteers of 25 to 50 years old. The bioadhesive tablet was placed on the buccal mucosa between the cheek and gingiva in the region of the upper canine and gently pressed onto the mucosa for about 30 s . The volunteers were asked to note any tendency for detachment . The time necessary for complete erosion of the tablet was simultaneously monitored by carefully observing for residual polymer on the mucosa. 5/27/2011 SNDCOP 43

Permeation studies:

Permeation studies IN-VITRO METHOD Buccal mucosa of experimental animal species with underlying connective tissue is surgically removed from the oral cavity and the buccal mucosal membrane is isolated . Then mounted between side-by-side diffusion cells for the in-vitro permeation experiments. 5/27/2011 SNDCOP 44

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IN-VIVO METHODS Using this method, the kinetics of drug absorption was measured. The methodology involves the swirling of a 25 ml sample of the test solution for up to 15 minutes by human volunteers followed by the expulsion of the solution . The amount of drug remaining in the expelled volume is then determined in order to assess the amount of drug absorbed . 5/27/2011 SNDCOP 45

Slug mucosal irritation assay :

Slug mucosal irritation assay developed at the University of Ghent (Belgium) in the Laboratory of Pharmaceutical Technology. formulations remain in contact with the mucosal surface for a longer time period, therefore it is important to assess their mucosal irritation potency . Principle: T he body wall of slug ( Arion lustanicus ) has a highly mucosal surface as a test organism. Slugs that are placed on an irritant substance will produce mucus and tissue damage results in the release of proteins and enzymes. Based on estimation of the levels of protein & enzymes irritation potency can be predicted . 5/27/2011 SNDCOP 46


RECENT INNOVATIONS: 1. Biobadhesive Spray: Buccoadhesive sprays are gaining popularity over other dosage forms because of flexibility, comfort, high surface area a vailability of drug in solution form. Drugs genrally given by these routes are fentanyl, buprenorphine. Naloxone etc . 5/27/2011 SNDCOP 47

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2. Gel Forming Liquids: This type of a formulation is liquid upon instillation and undergoes a phase transition to form a viscoelastic gel in response to stimulus such as temperature, ionic stength or pH . Carbomers become more viscous upon increased pH . Gellan gum and alginate both form gel in response to increased ionic strength (particularly with Ca +2 ions ). Poloxamers and smart hydrogel ® ( Adnaced medical solution) gel at approximately body temperature . 5/27/2011 SNDCOP 48


References: Mathiowitz , Edith. 1999. Encyclopedia Of Controlled Drug Delivery . Vol.1, New York, John Wiley & Sons, Inc. McElnay , J. C. and Hughes, C. M. 2007 .”Drug Delivery: Buccal Route” Pp. 1071-81 In Encyclopedia of Pharmaceutical Technology, 3rd Edition, Vol. 2, edited by James Swarbrick, New York, USA: Informa Healthcare, Inc. Hoogstraate , J., Benes, L., Burgaud , S., Horriere,F.,and Seyler I. 2005. “ Oral Trans-mucosal Drug Delivery” Pp. 168-88 In Drug Delivery and Targeting , edited by A. M. Hillery , A. W. Lloyd and J. Swarbrick, London, Taylor & Francis Inc. 5/27/2011 SNDCOP 49


References: Bandyopadhyay , A. K ., 2006. “Buccal bioadhesive drug delivery — A promising option for orally less efficient drugs.” Journal of Controlled Release 114 ( 2006)15–40. Smart J. D ., 1993. “ Drug delivery using buccal-adhesive systems.” Advanced Drug Delivery Reviews, ll (1993) 253-270. Senel Sevda , Hincal A . A., 2001. “ Drug permeation enhancement via buccal route: possibilities and limitations.” Journal of Controlled Release 72 (2001) 133–144. 5/27/2011 SNDCOP 50

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5/27/2011 SNDCOP 51

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