buccal drug delivery system

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Muco-adhesive drug delivery systems: Buccal Drug Delivery . :

Muco -adhesive drug delivery systems: Buccal Drug Delivery . By: Shibani Raja M.Pharm 1st yr( ceutics ). Vidyabharti college of Pharmacy, Amravati. 1

Contents::

Contents : Concepts. Advantages. Disadvantages. Structure of oral mucosa. Trans mucosal permeability. Permeability enhancers. In vitro and invivo studies. 2

Concepts ::

Concepts : Adhesion : is the bond produced by interaction between an adhesive and a surface. Bioadhesion : is the state of bond formation in which either adhesive or surface is of biological origin. Mucoadhesion : is the interaction of the mucin layer with a polymer. 3

Types of Mucoadhesive systems ::

Types of Mucoadhesive systems : Buccal drug delivery. Sublingual drug delivery. Nasal drug delivery. Occular drug delivery. Gastro intestinal drug delivery. Vaginal drug delivery. Rectal drug delivery. 4

Introduction::

Introduction: Buccal mucosa lines the inner cheek. Drug is placed between upper gingivae and cheek. Treats local and systemic conditions. Usually, large hydrophilic and unstable protiens , oligonucleotides and polysaccharides are delivered. 5

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Advantages::

Advantages: Total dose is low. Reduced GI Reduced dosing frequency. Better patient compliance and acceptance. Increased Safety/Efficacy ratio. Less fluctuation at plasma drug levels. 7

Advantages ::

Advantages : Abundance of blood vessels. Permeability enhancers can be used. Lower inter subject variability. Compared to the skin, Stratum Corneum is absent in the buccal mucosa, therefore moajor barrier is removed. 8

Disadvantages::

Disadvantages: Dose dumping. Reduced potential for accurate dose adjustment. Less surface area (0.01 sq m v/s 100 sq m of git ) Less permeable than small intestine. Need of patient education. Stability problems. 9

Structure of Buccal Mucosa::

Structure of Buccal Mucosa: 10

Structure of Buccal Mucosa::

Structure of Buccal Mucosa: Is marked by presence of Saliva by salivary gland. And also Mucus, secreted by minor and major salivary glands. 11

Structure of Buccal Mucosa: :

Structure of Buccal Mucosa: Role of Saliva : Protective fluid for oral cavity tissues. Continuous mineralization of tooth enamel. Hydrates the oral mucosa. 12

Structure of Buccal Mucosa::

Structure of Buccal Mucosa: Role of Mucus : Bioadhesion . Protective Barrier. Lubrication. 13

Factors affecting buccal absorption::

Factors affecting buccal absorption: Polymer related factors. Environment related factors. Drug related factors. Physiological factors. 14

Factors affecting buccal absorption::

Factors affecting buccal absorption: Polymer related factors: Molecular weight. Conc of active ingredient. Flexibility of polymer chains. Spatial confirmation. 15

Factors affecting buccal absorption::

Factors affecting buccal absorption: Environment related factors : pH Swelling. Applied strength. Initial contact time. Selection of substrate. 16

Factors affecting buccal absorption::

Factors affecting buccal absorption: Drug related factors : Surface area of the drug. Drug load. Adhesivity to buccal mucosa. 17

Factors affecting buccal absorption::

Factors affecting buccal absorption: Physiologic variables : Mucin turnover. Disease states. 18

Buccal drug delivery and mucoadhesivity: :

Buccal drug delivery and mucoadhesivity : Is very important. Drug has to bind to the mucin layer to permeate into the target tissue. These include : tablets, patches, tapes, films, semisolids, powders. 19

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Design of buccal dosage form::

Design of buccal dosage form: Considerations: Protection of drug from the salivary and tissue enzymes. Drug and adhesive materials must not damage teeth. No keratinolysis , irritation, or discoloration of teeth should occur. 24

Considerations: :

Considerations: Hydrophilic macromolecules like peptides, permeation enhancers, etc have to be used. Smaller molecules(75 -100 daltons ) provide greater transport. Non ionized forms show greater transport. More the drug is lipid soluble, more is its permeability. More partition coefficient , more permeability. 25

Theories of bioadhesion ::

Theories of bioadhesion : Electronic theory. Absorption theory. Wetting theory. Diffusion theory. Fracture theory. 26

Electronic theory ::

Electronic theory : Describes adhesion by means of elecrton transfer between mucus and polymer. The electron transfer results in the formation of double layer of electrical charges at interface. The net result of such a process is the formation of attractive forces within this double layer . 27

Absorption theory ::

Absorption theory : Adhesion is defined in terms of surface interactions between surface and polymer. Interaction gives rise to two types of forces. Primary forces : which are covalent, have high strength and undesirable for bioadhesion . Secondary forces : which are Vaan der Waals forces, hydrophobic bonds and hydrogen bonds. They are favored because they break easily. 28

Wetting theory ::

Wetting theory : Mainly applicable to the liquid bioadhesive system. Determines the ability of polymer paste to spreadd on the surface. It is expressed as (Y ) which is the energy per square cm. Thus work of adhesion is given by 29 Wa = Ya + Yb - Yab

Wetting theory ::

Wetting theory : Where ‘ a’ and ‘b’ are biological membrane and bioadhesive system resp. For a bioadhesive material ‘b’ spreading on a biological surface ‘a’ Spreading Coefficient is given by : Sb /a = Ya – ( Yb + Yab ) 30

Diffusion theory ::

Diffusion theory : Polymer chains and mucus mix to a certain extent to form a semi permanent adhesive bond. The depth to which polymer penetrates depends on diffusion coefficient and time of contact. This in turn depends on molecular eight of polymer. 31

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32 The diffusion theory of adhesion. (a) Top (polymer) layer and bottom (mucus) layer before con-tact; (b) top layer and bottom layer immediately after contact; (c) top layer and bottom layer after contact for a period of time

Fracture theory ::

Fracture theory : The adhesive bond between systems is related to the force required to separate both surfaces from one another. ‘‘Fracture theory” relates the force for polymer detachment from the mucus to the strength of their adhesive bond. It is given by : 33

Fracture theory ::

Fracture theory : 34 Fracture strength (σ) following the separation of two surfaces via its relationship to Young’s modulus of elas-ticity (E), the fracture energy (epsilon) and the critical crack length (L).

Permeation enhancers: :

Permeation enhancers: Are substances that enhance the drug permeation through the buccal mucosa and should be: Safe. Nontoxic. Non irritating. Non allergic. Pharmacologically and chemically inert. 35

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Category Per meation enhancers Chelators Edta , Sod.salicyltae , Citric acid, Methoxy salicylates . Surfactants Sls , Polyoxyethylene , Polyoxyethylene-9-laurylether, Benzalkonium chloride. Bile salts Sodium glycholate , Sod.dioxyglycholate , Sod. Taurodeoxycholate . Fatty acids Oleic acid, Capric acid, Lauric acid, Propylene glycol,. Non surfactants Unsaturated cyclic ureas . Inclusion complexes Cyclodextrins . Others Dextran sulfate, Menthol, Polysorbate80, Azone . 36

MOA of permeation enhancers::

MOA of permeation enhancers: By changing mucus and saliva viscosity. Increasing the fluidity of lipid bilayer membrane. By acting on desmosomes at tight junctions. By overcoming the enzymatic barrier. Enhancing the partition coefficient of the drug and thus increasing the solubility. 37

Buccal mucoadhesive polymers ::

Buccal mucoadhesive polymers : Ideal characteristics: Non toxic, non irritable, free from leachable impurities. Polymer pH should be biocompatible. Quick adherence, and suffice mechanical strength. Bioadhesive in both dry and liquid state. Acceptable shelf life. Optimum molecular weight. 38

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Classification criteria Examples Natural polymers Examples Synthetic polymers Source Agarose , Chitosan , Gelatin, Pectin, CMC, Thiolated CMC,HPMC, Methylcellulose. Carbapol , Polyacrylic acid, Polycarbophil , PEG, Methacrylic acid, PVA, PVP, Thiolated polymers. Solubility in Water Water soluble : Thiolated CMC, Na CMC, CMC, HPC, HPMC, PVA, PVP, Ethyl cellulose. Water insoluble : Carbapol , Polyacrylates , PEG, Polyacrylic acid, Methacrylic acid, Polycarbophil . Charge Cationic or Anionic : Aminodextran , Chitosan , Chitosan EDTA, Pectin, Sod alginate, CMC, Na CMC. Uncharged : Hydroxyethylated starch, HPC, PEG, PVA, PVP Possible mechanism of formation of Bioadhesive bonds Covalent Hydrogen bonds Electrostatic interactions Cyanoacrylate Acrylates , carbopol , polycarbophil , PVA Chitosan 39

Buccal mucoadhesive polymers ::

Buccal mucoadhesive polymers : 1 st generation polymers : PAA, NaCMC , HPMC, Carbapol , Chitosan , Xanthan gum, PVA etc. 2 nd generation polymers : Lectins , Multifunctional polymers, Thiolated polymers etc. 40

Types of Buccal Dosage forms : :

Types of Buccal Dosage forms : Matrix type. Reservoir type. 41

Matrix type ::

Matrix type : Drug, Adhesive, Additives are mixed together. Bidirectional patches. i.e. release drug both in Mucosa, and Mouth. 42

Components : :

Components : Liner - Protects the patch during storage. The liner is removed prior to use. Drug - Drug solution in direct contact with release liner Adhesive - Serves to adhere the components of the patch together along with adhering the patch to the skin Membrane - Controls the release of the drug from the reservoir and multi-layer patches Backing - Protects the patch from the outer environment 43

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Reservoir type ::

Reservoir type : Contains a cavity for drug, and additives separate from drug adhesive. Has an impermeable backing. For regulating direction of drug flow. Also prevents patch deformation, disintegration in mouth. Prevents drug loss. 45

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Types of reservoir patches::

Types of reservoir patches : Type 1 : single layer device with multidirectional release. significant drug loss due to swallowing. Type 11 : impermeable backing layer is superimposed. prevents drug loss into the oral cavity. Type 111 : unidirectional release device, drug loss is minimal. achieved by coating every face except contact face. 47

Others ::

Others : Buccal tablets : Most commonly investigated dosage form for Buccal drug. Tablets are small, flat, and oval, with a diameter of approximately 5–8 mm. Tablets can be applied to different sites in the oral cavity. Drawback : lack of physical flexibility, poor patient compliance 48

Others ::

Others : Buccal Patches: Laminates consist of an impermeable backing layer, a drug-containing reservoir layer, a bioadhesive surface for mucosal attachment. Similar to those used in transdermal drug delivery. Backing layer control the direction of drug release, prevent drug loss, minimize deformation and disintegration 49

Others ::

Others : Buccal films : Most recently developed dosage form for Buccal administration. Preferred over adhesive tablets in terms of flexibility and comfort. Flexible, elastic, and soft, yet adequately strong. Effective in oral disease. 50

Others::

Others: Buccal gels : Semisolid dosage forms, have the advantage of easy dispersion throughout the oral mucosa May not be as accurate as from tablets, patches, or films. Poor retention of the gels at the site of application has been overcome by using bioadhesive formulations. 51

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Denti Patch This is a band-aid-like patch inserted on your gum to numb it before an injection 54

Evaluation parameters::

Evaluation parameters: In vitro Methods In vivo Methods 55

In vitro drug release studies::

In vitro drug release studies: 56

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In vitro drug release studies::

In vitro drug release studies: Now a days, modified diffusion cells are used. These include Franz type diffusion cells, Modified , Flow through diffusion cell, Modified Ussing chamber. Animal mucosa like that of rabbit, hammock are used. 58

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59 Carbogen Area available for diffusion Tissue-mounting pins Figure : The modified Ussing chamber consisting of a donor and a receptor chamber which when clamped together are separated by tissue.

Swelling properties for film::

Swelling properties for film: 60

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Swelling index = W1- W2/W1 61

FTIR Study::

FTIR Study: 62

In vivo stdies::

In vivo stdies : Includes the Buccal Absorption Test. It is performed on the mucosa of the human volunteers. If animal models, are to be correlated sturctural similarity to human mucosa must be considered. Model like rabbit buccal mucosa (non keratinised ), hammock mucosa etc are used. 63

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In vivo studies ::

In vivo studies : Also, sometimes marker compounds are added (like Phenol red, PEG). But herein, absorption kinetics cannot be determined. Modified test implied collection of swirl liquid every few min to determine kinetics. 66

In vivo studies ::

In vivo studies : Disadvatages : Only absorption of drug can be estimated, and not its blood concentration. Amount of drug that diappears during swirling, cannot be equalised with that of drug entering the blood. 67

Reference ::

Reference : Punitha . S, Polymers in mucoadhesive drug delivery system – A Review, Vol-1, Issue-2, 170-186, 2010. James Swarbrick , Encylopedia of Pharmaceutical Technology, Third edition, 1071-1080. Wang, Saihaan , Soltero ; Drug Delivery- Basic principles and Applications, John Wiley and sons Publications, 15-28. Tapash Ghosh , Wlliam Pfister , Drug delivery to Oral Cavity – Molecules to market, Taylor and Francis Group, 111-124. 68

Reference ::

Reference : Yei . W. Chein , Novel Drug Delivery System, Marcel Dekker Inc., 139-196. www.pharmainfo.net 69