buccal drug delivery system

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1 Prepared By : Maulik Kapadiya SEM: II Roll No. 06 Year : 2011-12 RECENT INNOVATIONS IN BUCCAL DRUG DELIVERY SYSTEM Maulik Kapadiya/Buccal DDS


2 Introduction The buccal mucosa lines the inner cheek , and buccal formulations are placed in the mouth between the upper gingivae (gums) and cheek to treat local and systemic conditions. It is richly vascularized and more accessible for the administration and removal of a dosage form. Additionally, buccal drug delivery has high patient acceptability compared to other non-oral routes of drug administration. Extensive first-pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering the drug via buccal route . Maulik Kapadiya/Buccal DDS

Slide 3:

3 Drug absorption through buccal mucosa is mainly by passive diffusion into the lipoidal membrane. After absorption, the drug is transported through facial vein which then drains into the general circulation via jugular vein , bypassing the liver and thereby sparing the drug from first-pass metabolism . Buccal route provides one of the potential routes for typically large, hydrophilic and unstable proteins, oligonucleotides and polysaccharides, as well as conventional small drug molecules Maulik Kapadiya/Buccal DDS


4 Advantages 1. Ease of administration. 2. Termination of therapy is easy. 3. Permits localization of drug to the buccal cavity for a prolonged period of time. 4. Can be administered to unconscious patients. 5. Offers an excellent route, for the systemic delivery of drugs which undergo extensive firstpass metabolism or degradation in harsh gastrointestinal environment. 6. A significant reduction in dose can be achieved thereby reducing dose related side effects. Maulik Kapadiya/Buccal DDS

Slide 5:

5 Drugs, which show poor bioavailability via the oral route, can be dministered conveniently. It offers a passive system of drug absorption and does not require any activation. The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal or transdermal routes. Systemic absorption is rapid as buccal mucosa is thin and highly perfused with blood. Provides an alternative route for the administration of various hormones, narcotic analgesics, steroids, enzymes, cardiovascular agents etc. It allows the local modification of tissue permeability, inhibition of protease activity and reduction in immunogenic response. Thus, delivery of therapeutic agents like peptides, proteins and ionized species can be done easily. Maulik Kapadiya/Buccal DDS


6 Disadvantages Drugs, which irritate the oral mucosa, have a bitter or unpleasant taste or odour ; can not be administered by this route. Drugs, which are unstable at buccal pH, cannot be administered by this route. Only drugs with small dose requirements can be administered. Drugs may get swallowed with saliva and loses the advantages of buccal route. Only those drugs, which are absorbed by passive diffusion, can be administered by this route. Maulik Kapadiya/Buccal DDS

Slide 7:

7 Over hydration may lead to the formation of slippery surface and structural integrity of the formulation may get disrupted by the swelling and hydration of the bioadhesive polymers. Surface area available for absorption is less. The buccal mucosa is relatively less permeable than the small intestine, rectum, etc. Maulik Kapadiya/Buccal DDS


8 Limitations The mucus is constantly removed from the epithelial surfaces. It will eventually wash out the dosage form from the site of application. The mucous turn over rate is different from person to person so fabrication of the dosage form is difficult. The adhesion rate of dosage form in the body may not be as per proposed specification due to disease state, different physiological factors, etc. Maulik Kapadiya/Buccal DDS

Slide 9:

9 The good mucoadhesive polymers that will fulfill all the requirements are less. Mucoadhesive polymers are poly electrolytes. Slight variation in pH, charge of the mucus changes mucoadhesion property of polymer significantly. This type of drug delivery system is not suitable for drugs that causes tissue irritation. Maulik Kapadiya/Buccal DDS

Uses of Buccal Delivery:

10 Uses of Buccal Delivery The oral cavity can be used for local and systemic therapy. Examples of local therapy would be the treatment of oral infections , dental caries, mouth ulcers, stomatitis , gingivitis etc The buccal route is of particular interest with regard to the systemic delivery of small molecules that are subjected to first-pass metabolism. Maulik Kapadiya/Buccal DDS

Oral Mucosa:

11 Oral Mucosa Maulik Kapadiya/Buccal DDS

Slide 12:

12 Three distinctive layers of the oral mucosa are the epithelium , basement membrane and connective tissues . The oral cavity is lined with the epithelium, below which lies the supporting basement membrane. The basement membrane is, in turn, supported by connective tissues. The thickness of buccal epithelium in humans, dogs, and rabbits has been determined to be approximately 500–800 μm. The buccal epithelium is classified as a nonkeratinized tissue. It is penetrated by tall and conical shaped connective tissues. These tissues, which are also referred to as the lamina propria, consist of collagen fibers, a supporting layer of connective tissues, blood vessels, and smooth muscles Maulik Kapadiya/Buccal DDS

Slide 13:

13 The rich arterial blood supply to the oral mucosa is derived from the external carotid artery. The buccal artery , some terminal branches of the facial artery , the posterior alveolar artery , and the infraorbital artery are the major sources of blood supply to the lining of the cheek in the buccal cavity. Maulik Kapadiya/Buccal DDS


14 Mucus Water (95-99.5%) Mucins (0.5-5%)a Other substances like Ig A, Lysozyme , Lactoferin , a1 antitrypsin, Salts, Growth factors, Trefoil peptides. Maulik Kapadiya/Buccal DDS


15 Heavily glycosylated linear proteins Core – single polypeptide chain Side chains – oligosaccharide L- Fucose N- Acetylglucosamine D- Galactose N- Acetylgalactosamine Sialic acid Mucins Maulik Kapadiya/Buccal DDS


16 Mol. Wt. 0.5 to 16 × 10 6 Da Two types: Membrane bound mucins Secretory mucins Characteristics: linear, flexible, and random-coils negatively charged due to sialic acid and sulfate residues. a cross-linked by disulfide bonds heavily hydrated Mucins Maulik Kapadiya/Buccal DDS

Permeability Barrier:

17 Permeability Barrier The permeability barrier property of the oral mucosa is predominantly due to intercellular materials derived from the so-called “ membrane coating granules ” (MCGs) Recent evidence has shown that passive diffusion is the primary mechanism for the transport of drugs across the buccal mucosa, although carrier-mediated transport has been reported to have a small role. Two routes of passive transport are available in the buccal epithelium; one involves the transport of compounds through the intercellular spaces between the cells ( paracellular ), and the other involves passage into and across the cells ( transcellular ) Maulik Kapadiya/Buccal DDS

Slide 18:

18 Another barrier to drug permeability across buccal epithelium is enzymatic degradation. Saliva contains no proteases, but does contain moderate levels of esterases, carbohydrases, and phosphatases. However, several proteolytic enzymes have been found in the buccal epithelium. Walker et al . reported that endopeptidases and carboxypeptidases were not present on the surface of porcine buccal mucosa, whereas aminopeptidases appeared to be the major enzymatic barrier to the buccal delivery of peptide drugs. Maulik Kapadiya/Buccal DDS


19 Mucoadhesion Longer and Robinson defined the term “bioadhesion” as the “attachment of a synthetic or natural macromolecule to mucus and/or an epithelial surface. Maulik Kapadiya/Buccal DDS

Theory of Mucoadhesion:

20 Theory of Mucoadhesion The Electronic theory The Wetting theory The Adsorption theory The Diffusion theory The Fracture theory The Mechanical theory Maulik Kapadiya/Buccal DDS

Electronic theory:

21 Electronic theory Different electronic structures Electron transfer Double layer Maulik Kapadiya/Buccal DDS

Wetting theory:

22 Wetting theory Applied to liquid systems. Based on surface & interfacial energies. Spredability as a prerequisite for adhesion . Spredability co-efficient (S AB ) S AB = γ B - γ A - γ AB Maulik Kapadiya/Buccal DDS

Slide 23:

23 γ A - surface tension of the liquid A, γ B - surface energy of the solid B and γ AB - interfacial energy between the solid and liquid . S AB should be positive for the liquid to spread spontaneously over the solid. Maulik Kapadiya/Buccal DDS

Adsorption theory:

24 Adsorption theory Describes the attachment on the basis of ‘H’ bonding and van der Waals’ forces When mucus is interacting with a solid dosage form, the molecules of the liquid are adsorbed on the solid surface. This is an exothermic process. Maulik Kapadiya/Buccal DDS

Slide 25:

25 The free energy of adsorption is given by Δ G AD = Δ H AD – T Δ S AD Adsorption takes place spontaneously, Δ G AD is negative Maulik Kapadiya/Buccal DDS

Diffusion theory:

26 Diffusion theory States that interpenetration and entanglement of polymer chains are responsible for bioadhesion. Penetration of polymer chains into mucus network depends on concentration gradients & diffusion coefficients. Penetration depth (l) l = (t D b ) 1/2 Penetration depth should be in the range of 0.2–0.5 mm Maulik Kapadiya/Buccal DDS

Mechanical theory:

27 Mechanical theory Assumes that adhesion arises from an interlocking of a liquid adhesive into irregularities on a rough surface Provide an increased surface area Maulik Kapadiya/Buccal DDS

Fracture theory:

28 Fracture theory Most widely applied Accounts for the forces required to separate two surfaces after adhesion σ = F m /A 0 Work of bioadhesion W b = F × l The fracture energy for a zero extension rate Є = W b /A 0 Maulik Kapadiya/Buccal DDS

Slide 29:

29 Thermodynamically Є = W r + W i For low extension rate (1mm/min) Є 0 = W r = W b /A 0 Maulik Kapadiya/Buccal DDS


30 Factors Polymer related factors 1) Molecular weight In general, it has been shown that the bioadhesive strength of a polymer increases with molecular weights above 100,000. 2) Flexibility Bioadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore, it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. In general, mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network. Maulik Kapadiya/Buccal DDS

Slide 31:

31 Hydrogen bonding capacity Hydrogen bonding is another important factor in mucoadhesion of a polymer. For mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds. It was also confirmed that flexibility of the polymer is important to improve its hydrogen bonding potential. Polymers such as poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylicacid), as well as all their copolymers, are polymers with good hydrogen bonding capacity. Maulik Kapadiya/Buccal DDS

Slide 32:

32 Cross-linking density The average pore size , the number average molecular weight of the cross-linked polymers, and the density of cross-linking are three important and interrelated structural parameters of a polymer network. Therefore, it seems reasonable that with increasing density of cross-linking, diffusion of water into the polymer network occurs at a lower rate which, in turn, causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin. It was reported that, this general property of polymers, in which the degree of swelling at equilibrium has an inverse relationship with the degree of cross-linking of a polymer. Maulik Kapadiya/Buccal DDS

Slide 33:

33 Charge Some generalizations about the charge of bioadhesive polymers have been made previously, where nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers. Peppas and Buri have demonstrated that strong anionic charge on the polymer is one of the required characteristics for mucoadhesion. It has been shown that some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium. Additionally, some cationic high-molecular-weight polymers, such as chitosan , have shown to possess good adhesive properties. Maulik Kapadiya/Buccal DDS

Slide 34:

34 Concentration The importance of this factor lies in the development of a strong adhesive bond with the mucus , and can be explained by the polymer chain length available for penetration into the mucus layer. When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable. In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration , above which the polymer produces an “ unperturbed ” state due to a significantly coiled structure. Maulik Kapadiya/Buccal DDS

Slide 35:

35 As a result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in some cases, actually diminish mucoadhesive Properties. One of the studies addressing this factor demonstrated that high concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl alcohol) as filmforming polymers did not further enhance the mucoadhesive properties of the polymer. On the contrary, it decreased the desired strength of mucoadhesion . Maulik Kapadiya/Buccal DDS

Slide 36:

36 7) Hydration (swelling) Hydration is required for a mucoadhesive polymer to expand and create a proper “ macromolecular mesh ” of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin. Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network. However, a critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and bioadhesion occurs. Maulik Kapadiya/Buccal DDS

Slide 37:

37 Environmental factors The mucoadhesion of a polymer not only depends on its molecular properties, but also on the environmental factors adjacent to the polymer. Saliva , as a dissolution medium, affects the behavior of the polymer. Depending on the saliva flow rate and method of determination, the pH of this medium has been estimated to be between 6.5 and 7.5. The pH of the microenvironment surrounding the mucoadhesive polymer can alter the ionization state and, therefore, the adhesion properties of a polymer. Maulik Kapadiya/Buccal DDS

Slide 38:

38 Mucin turnover rate is another environmental factor. The residence time of dosage forms is limited by the mucin turnover time, which has been calculated to range between and 270 min in rats and 12–24 hr in humans. Movement of the buccal tissues while eating, drinking, and talking , is another concern which should be considered when designing a dosage form for the oral cavity. Movements within the oral cavity continue even during sleep , and can potentially lead to the detachment of the dosage form. Therefore, an optimum time span for the administration of the dosage form is necessary in order to avoid many of this interfering factors. Maulik Kapadiya/Buccal DDS


39 CLASSIFICATION SEMI-NATURAL/NATURAL Agarose, chitosan, gelatin, Hyaluron,Various gums (guar, hakea, xanthan, gellan, carragenan, pectin, and sodium alginate) SYNTHETIC Cellulose derivatives [CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, methylhydroxyethylcellulose] Maulik Kapadiya/Buccal DDS

Slide 40:

40 Poly(acrylic acid)-based polymers [CP, PC, PAA, polyacrylates , poly( methylvinylether-comethacrylic acid), poly(2-hydroxyethyl methacrylate ), poly(acrylic acid- coethylhexylacrylate ), poly( methacrylate ), poly( alkylcyanoacrylate ), poly( isohexylcyanoacrylate ), poly( isobutylcyanoacrylate ), copolymer of acrylic acid and PEG] Maulik Kapadiya/Buccal DDS

Slide 41:

41 Others Poly(N-2-hydroxypropyl methacrylamide ) ( PHPMAm ), polyoxyethylene , PVA, PVP, thiolated polymers Water-soluble CP, HEC, HPC, HPMC (cold water), PAA, sodium CMC, sodium alginate Water-insoluble Chitosan (soluble in dilute aqueous acids), EC, PC Maulik Kapadiya/Buccal DDS

Slide 42:

42 Cationic Aminodextran , chitosan , dimethylaminoethyl (DEAE)- dextran , trimethylated chitosan Anionic Chitosan -EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum Non-ionic Hydroxyethyl starch, HPC, poly(ethylene oxide), PVA, PVP, scleroglucan Maulik Kapadiya/Buccal DDS

New Generation Mucoadhesive Polymers:

43 Thiolated polymers Ethyl hexyl acrylate with acrylic acid copolymer PEG/ polyacrylic acid Poloxamers + Polyacrylic acids DOPA + Poloxamers Lectins New G eneration Mucoadhesive Polymers Maulik Kapadiya/Buccal DDS

Formulation Design:

44 Formulation Design Drug substance Bioadhesive polymers Backing membrane Backing membrane plays a major role in the attachment of bioadhesive devices to the mucus membrane. The materials used as backing membrane should be inert, and impermeable to the drug and penetration enhancer. e.g. carbopol, magnesium stearate, HPMC, HPC, CMC, polycarbophil etc. Maulik Kapadiya/Buccal DDS

Slide 45:

45 Penetration enhancers Penetration enhancers are used in buccoadhcsivc formulations to improve the release of the drug. They aid in the systemic delivery of the drug by allowing the drug to penetrate more readily into the viable tissues. The commonly used penetration enhancers are sodium lauryl sulphate, CPC, polysorbate -80, laureth -9, sodium fusidate, polmitoyl carnitine, azone, sodium glycocholate, dimethyl formamide etc. Maulik Kapadiya/Buccal DDS

Slide 46:

46 BIOADHESIVES Bioadhesives are the substances that are capable of interacting with the biological material and being retained on them or holding them together for extended period of time. Bioadhesive can be used to apply to any mucous or nonmucous membranes and it also increases intimacy and duration of contact of the drug with the absorbing membrane. The commonly used bioadhesives are sodium alginate, carbomers, polycarbophil, HPMC, HPC, gelatin etc. Maulik Kapadiya/Buccal DDS

Slide 47:

47 Enzyme Inhibitors Enzyme inhibitors may be incorporated in the dosage forms to increase drug bioavailability. some bioadhesive polymers , such as poly(acrylic acid), polycarbophil , and carbopo l , can also inhibit certain proteolytic enzymes ( trypsin , a- chymotrypsin , carboxypeptidases A and B , and leucine aminopeptidase . Solubility Modifiers Cyclodextrin has been used to solubilize and increase the absorption of poorly water- soluble drugs delivered via the buccal mucosa. Maulik Kapadiya/Buccal DDS

Buccal Mucoadhesive Dosage Forms:

48 Buccal Mucoadhesive Dosage Forms Type I: It is a single layer device with multidirectional drug release . This type of dosage form suffers from significant drug loss due to swallowing . Type II: It is a device in which an impermeable backing layer is superimposed on top of the drug loaded bioadhesive layer , creating a double-layered device and preventing drug loss from the top surface into the oral cavity. Maulik Kapadiya/Buccal DDS

Slide 49:

49 Type III It is a unidirectional drug release device, from which drug loss is minimal, since the drug is released only from the side adjacent to the buccal mucosa. This can be achieved by coating every face of the dosage form, except the one that is in contact with the buccal mucosa. Maulik Kapadiya/Buccal DDS

Slide 50:

50 Design of buccal mucoadhesive dosage forms Maulik Kapadiya/Buccal DDS

Buccal Tablets:

51 Buccal Tablets Buccal tablets are small, flat, and oval shaped dosage form. Unlike conventional tablets, buccal mucoadhesive tablets allow for drinking and speaking without major discomfort . They soften, adhere to the mucosa , and are retained in position until dissolution and/or release is complete . These tablets can be applied to different sites in the oral cavity, including the palate, the mucosa lining the cheek, as well as between the lip and the gum . Maulik Kapadiya/Buccal DDS

Slide 52:

52 These tablets are usually prepared by direct compression , but wet granulation techniques can also be used. Multilayered tablet may be prepared by sequentially adding and compressing the ingredients layer by layer. Some newer approaches use tablets that melt at body temperature. Maulik Kapadiya/Buccal DDS

Slide 53:

53 Maulik Kapadiya/Buccal DDS

Slide 54:

54 The two buccal bioadhesive tablets Commercially available buccoadhesive tablets in UK are " Bucastem “ (Nitroglycerine) and " Suscard buccaP '(Prochloroperazine). Examples: a) Nitroglycerin bioadhesive tablets for the treatment of anginapectories. b )Sumatriptan succenate buccal adhesive tablet which is effective in the acute treatment of mygrain and cluster headache. c) Verapamin buccal tablet with compressed verapamin (15ml) mucoadhesive polymer like sodium alginate and HPC - EXF with standard tablet excepitints. Maulik Kapadiya/Buccal DDS

Buccal Patch/Film:

55 Buccal Patch/Film Patches are laminates consisting of an impermeable backing layer, a drug-containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment . Two methods used to prepare adhesive patches include solvent casting and direct milling . In the solvent casting method , the intermediate sheet from which patches are punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer sheet and subsequently allowing the solvent(s ) to evaporate . Maulik Kapadiya/Buccal DDS

Slide 56:

56 In the direct milling method , formulation constituents are homogenously mixed and compressed to the desired thickness, and patches of predetermined size and shape are then cut or punched out. 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 . Maulik Kapadiya/Buccal DDS

Slide 57:

57 Example: a) Isosorbid dinitrate in the form of unidirectional errodible buccal film are developed and characterised for improving bioavailability. b) Buccal film of salbutamol sulphate and terbutalin sulphate for the treatment of asthma. c) Buccoadhesive film of clindamycin used for pyorrhoea treatment. Maulik Kapadiya/Buccal DDS

Buccal Gel/Ointment:

58 Buccal Gel/Ointment Such semisolid dosage forms have the advantage of easy dispersion throughout the oral mucosa . Poor retention of the gels at the site of application has been overcome by using bioadhesive formulations . Certain bioadhesive polymers undergo a phase change from a liquid to a semisolid; this change enhances the viscosity , which results in sustained and controlled release of drugs. Maulik Kapadiya/Buccal DDS

Table 2 : List of Active Ingredients delivered via a BUCCAL ROUTE:

59 Table 2 : List of Active Ingredients delivered via a BUCCAL ROUTE Sr. no Active Ingredients Sr. no Active Ingredients 1 Acitretin 11 Danazol 2 Acyclovir 12 Denbufylline 3 Arecoline 13 Diclofenac sodium 4 Buprenorpine 14 Diltiazem Hydrochloride 5 Carbamazepine 15 Ergotamine tartrate 6 Cetyl Pyridinium chloride 16 Fluride 7 Chlorhexidine diacetate 17 Flurbiprofen 8 Chitosan 18 Glucagon-like peptide (GLP)-1 9 Chlorpheniramine maleate 19 Insulin 10 Cyanocobalamin 20 Hydrocortisone acetate Maulik Kapadiya/Buccal DDS



Slide 61:

61 Parameters of Evaluation Determination of residence time. Permeation studies Swelling studies Release rate studies Toxicity and irritation study Bioadhesion measurement. Maulik Kapadiya/Buccal DDS

Slide 62:

62 Folding Enduance Content uniformity Surface pH: 1% agar solution for 2 hrs and equill. for 1 min. Maulik Kapadiya/Buccal DDS

Slide 63:

63 Determination of Residence time 1.In vitro residence time 2. In vivo residence time Maulik Kapadiya/Buccal DDS

Slide 64:

64 1]In vitro residence time. -For this test we use the USP dissolution test apparatus shown in fig. Maulik Kapadiya/Buccal DDS

Slide 65:

65 Composition of dissolution medium=800ml ISOTONIC PHOSPHATE BUFFER SOLUTION. A segment of rabbit buccal mucosa, 3 cm long, is glued to the surface of a glass slab. Which is vertically attached to the apparatus. The mucoadhesive tablet is hydrated from one surface using 15ml IPB and then the hydrated surface is brought into contact with the mucosal membrane. Maulik Kapadiya/Buccal DDS

Slide 66:

66 The glass slab is vertically fixed to the apparatus and allowed to move up and down so that the tablet is completely immersed in the buffer solution at the lowest point and is out at the highest point. The time necessary for complete erosion or detachment of the tablet from the mucosal surface is recorded. Maulik Kapadiya/Buccal DDS

Slide 67:

67 [B]In vivo residence time. Plain bioadhesive tablets with optimized properties are selected for the evaluation. Procedure The bioadhesive tablet is 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 30s. Maulik Kapadiya/Buccal DDS

Slide 68:

68 The tablet and the inner upper lip are carefully moistened with saliva to prevent the sticking of the tablet to the lip. The time necessary for complete erosion of the tablet is simultaneously monitored by carefully observing for residual polymer on the mucosa. Maulik Kapadiya/Buccal DDS

Slide 69:

69 In addition,any complaints such as discomfort, bad taste, dry mouth or increase of salivary flux, difficulty in speaking, irritation or mucosal lesions are carefully recorded. Repeated application of the bioadhesive tablets is allowed after a two days period for the same volunteer . Maulik Kapadiya/Buccal DDS

Slide 70:

70 II. Permeation studies. Principle: “to determine the feasibility of this route of administration for the candidate drug and to determine the type of enhancer and its concentration required to control the rate of permeation of drugs.” Maulik Kapadiya/Buccal DDS

Slide 71:

71 Types of Permeation studies methods In vitro method Ex vivo method In vivo method Maulik Kapadiya/Buccal DDS

Slide 72:

72 1]In vitro method. For this we use an apparatus consisting of a water jacket and an internal compartment Which containing 50 ml of simulated saliva as dissolution medium to study the release of drug. The tablet is placed in the metal die sealed at the lower end by paraffin wax to ensure the drug release from one end alone. The medium is stirred with a rotating stirrer at 250 rpm. Maulik Kapadiya/Buccal DDS

Slide 73:

73 2]Ex vivo method ex vivo studies examins drug transport,across buccal mucosa using buccal tissues from animal models. Immediately after sacrificing the animals the buccal mucosal tissue is surgically removed from the oral cavity. The membranes are stored in Krebs buffer at 4 °C until mounted in the diffusion cells for the exvivo permeation experiment. Maulik Kapadiya/Buccal DDS

Slide 74:

74 For example Fig of FRANZ DIFFUSION CELL is given below, Maulik Kapadiya/Buccal DDS

Slide 75:

75 3]In vivo method. Animal model: In this method we have to use only the animal which has nonkeratinised oral lining. rabbit is mostly used. dog,monkey and pig also have nonkeratinised oral lining but they are not used much because they are expensive. Maulik Kapadiya/Buccal DDS

Slide 76:

76 Different methods used for in vivo methods are, (a)Buccal absorption test (b)Modified buccal absorption test (c)Perfusion system (d)Buccal perfusion cell apparatus Maulik Kapadiya/Buccal DDS

Slide 77:

77 (a)Buccal absorption test a method to measure the kinetics of drug absorption. Procedure It is carried out by swirling of a 25 ml sample of the test solution for 15 min by human volunteers followed by the expulsion of the solution. The amount of drug remaining in the expelled volume is then determined to assess the amount of drug absorbed. Maulik Kapadiya/Buccal DDS

Slide 78:

78 Limitation Inability to localize the drug solution within a specific site of the oral cavity. Accidental swallowing of a portion of the sample solution The salivary dilution of drug. Maulik Kapadiya/Buccal DDS

Slide 79:

79 (b)Modified buccal absorption test. In this method modifications are done with salivary dilution and accidental swallowing, but these modifications also suffer from the inability of site localization Maulik Kapadiya/Buccal DDS

Slide 80:

80 (c)Perfusion system. A circulating perfusion chamber attached to the upper lip of anesthetized dogs by cyanoacrylate cement. The drug solution is circulated through the device for a predetermined period of time. Sample fractions are collected from the perfusion chamber and blood samples are drawn at regular intervals. Maulik Kapadiya/Buccal DDS

Slide 81:

81 (d) Buccal perfusion cell apparatus This apparatus provides continuous monitoring of drug loss as a function of time offers larger area for drug transfer and has no leakage problem. These methods have provided information on the mechanism by which drugs are transported across oral cavity membranes and suggest that passive diffusion or carrier mediated transport systems may be involved. Maulik Kapadiya/Buccal DDS

Figure 1. A flow cell reactor system :

82 Figure 1. A flow cell reactor system Maulik Kapadiya/Buccal DDS

Slide 83:

83 III.Swelling studies Buccal tablets are weighed individually (W1) and placed separately in 2% agar gel plates with the core facing the gel surface and incubated at 37 ± 0.1 0 C. The tablet was removed from the petridish and excess surface water is removed carefully using filter paper. Maulik Kapadiya/Buccal DDS

Slide 84:

84 The swollen tablet is then reweighed(W2), and the swelling index (SI) or percent hydration is calculated using the following formula, % of hydration = (W2-W1) X 100 / W2 W1=initial weight of tablet, W2=weight of disk at time t. Maulik Kapadiya/Buccal DDS


85 RELEASE RATE STUDY For patch A modified dissolution apparatus, consisting of jacketed vertical glass beaker The patch is stuck on the depression on a teflon block and placed in the medium. For tablet USP XXIII method (apparatus II-paddle) For film Dissolution apparatus type I Maulik Kapadiya/Buccal DDS

Slide 86:

86 For microspheres Modified USP XXII rotating basket, the rotating cups. Maulik Kapadiya/Buccal DDS


87 BIOADHESION A). Tensile strength I nstruments - Tensile testers - Modified pan balance - Texture profile analyzer (TPA) Sources of tissue model - Rabbit buccal mucosa - Rabbit intestinal mucosa - Porcine buccal mucosa - Hamster cheek pouch Maulik Kapadiya/Buccal DDS

Slide 88:

88 B). Shear strength C). Fluorescent probe method D). Atomic force microscopy (AFM) E). Falling liquid film method F). Adhesion number Na = (N/N 0 ) 100 Where, Na = adhesion no. N 0 = total no of applied particles N = no of particles attached to the substrate Maulik Kapadiya/Buccal DDS

Slide 89:

89 Bioadhesion measurement. i). Duration of bioadhesion a) In vivo: Gamma Scintigraphy, Electron Paramagnetic resonance Transit study with flouroscent b) In vitro: Modified disintegration test ii). Tensile test. Maulik Kapadiya/Buccal DDS

Slide 90:

90 Modified apparatus for in vitro bioadhesion test. Maulik Kapadiya/Buccal DDS

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91 Continuous-flow adhesion cell for the assessment of Hydrogel adhesion Maulik Kapadiya/Buccal DDS


92 REFRENCES 1. International journal of pharmaceutics, Mucoadhesive Drug Delivery System; Sep 2003,Pg no-175. 2. International journal of pharmaceutics, Mucoadhesive Drug Delivery System; March 2009,Pg no-208. 3. Advances in controlled and novel drug delivery, N. K. JAIN,1 st edition, Pg no-78 & 79. Maulik Kapadiya/Buccal DDS

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93 4. Junginger, H. S.; Verhoef, J. C.; Thanou, M.; Drug Delivery: Mucoadhesive Hydrogels; Encyclopedia of pharmaceutical technology; Third edition; Vol. 2; 1169-1182. 5. Smart, J. D.; The basics and underlaying mechanisms of mucoadhesion; Advanced drug delivery reviews; vol. 57/11 (2005); 1556-1568. 6. Chowdary K P R and Srinivas L, “Mucoadhesive drug delivery systems:a review of current status”, Indian Drugs, 2000, Sept., 37-9, 400-406. Maulik Kapadiya/Buccal DDS

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94 7. Salamat-Miller, N.; Chittchang, M.; Johnston, T.; The use of mucoadhesive polymers in buccal drug delivery; Advanced drug delivery reviews; vol. 57/11 (2005); 1666-1691. 8. Valenta, C.; The use of mucoadhesive polymers in vaginal delivery; Advanced drug delivery reviews; vol. 57/11 (2005); 1692-1712. Maulik Kapadiya/Buccal DDS

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95 9. Ludwig, A.; The use of mucoadhesive drug delivery in ocular drug delivery; Advanced drug delivery reviews; vol. 57/11 (2005); 1595-1639. 10. Ugwoke, M.; Agu, R.; Verbeke, N.; Kinget, R.; Nasal mucoadhesive drug delivery: Background, applications, trends and future perspective; Advanced drug delivery reviews; vol. 57/11 (2005); 1640-1665. Maulik Kapadiya/Buccal DDS


96 STUDY QUESTIONS Explain the structure of buccal mucosa.Give a brief account of mucoadhesive polymers for buccal delivery. Discuss the merits and demerits of mucoadhesive buccal drug delivery. How one can evaluate muccoadhesive buccal formulation? Maulik Kapadiya/Buccal DDS

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97 Thank you Maulik Kapadiya/Buccal DDS