Presented by:

Swapnil singh

M.S. (Pharm.) Semester II

Dept. of Pharmaceutics

NIPER Mohali

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Adhesion can be defined as the bond produced by contact between a pressure sensitive adhesive and a surface

Ability to stick adhere or hold

Bioadhesion is defined as the state in which two materials, at least one of which is biological in nature, are held together, if it is mucus then called as mucoadhesion

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These dosage forms are readily localized in the region applied to improve and enhance bioavailability of drugs

Facilitate intimate contact of the formulation with the underlying absorption surface

Allows modification of tissue permeability for absorption of macromolecules, such as peptides and proteins

Prolongs residence time at the site of application thus decreases dosing frequency

Local delivery to the intestine and proximal small intestine

Effective for delivery of drugs with narrow absorption window

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Buccal delivery system

Sub-lingual delivery system

Nasal delivery system

Occular delivery system

Gastro intestinal delivery system

Rectal delivery system

Vaginal delivery system

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Rapid adherence to the mucosal layer without any

change in the physical property of the delivery matrix

Minimum interference to th release of the active

agent

Biodegradable without producing any byproducts

Enhance the penetration of the active agent

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Mucoadhesive inner layers called mucosa inner epithelial cell lining is covered with viscoelastic fluid

Secreted by Goblet cells lining the epithelia or by special exocrine glands

Composed of water and mucin (an anionic polyelectrolyte)

Thickness varies from 40 µm to 300 µm

General composition of mucus

Water…………………………………..95%

Glycoproteins and lipids……….0.5-5%

Mineral salts………………………..1%

Free proteins…………………………0.5-1%

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Complex high molecular weight macromoleculeconsisting of a polypeptide backbone to whichcarbohydrate chains are attached

The mucus which covers the epithelial surface hasvarious roles:

Protective

Barrier

Adhesion

Lubrication

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Mucus secreting cells

Structure of mucin

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The mechanism responsible in the formation of mucoadhesive bonds are not fully known, however most researcher has described it as a three step process

Step 1 : Wetting and swelling of the polymer(contact stage)

Step 2 : Interpenetration between the polymer chains and the mucosal membrane

Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)

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Wetting and swelling step occurs when polymer spreads over the surface of mucosal membrane to develop intimate contact

Swelling of polymer occur because the components of polymer have an affinity for water

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In this step the mucoadhesive polymer chain and the mucosal polymer chains intermingle and entangles to form adhesive bonds

Strength of bonds depends upon the degree of penetration of the two polymer groups

Interpenetration of mucoadhesive and mucous polymer chains

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This step involves formation of weak chemical bonds between the entangled polymer chains

Bonds includes primary bonds such as covalent bonds and secondary interactions such as vanderWaals and hydrogen bonds

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Electronic theory

Wetting theory

Adsorption theory

Diffusion theory

Fracture theory

Mechanical theory

Cohesive theory

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Electronic theory

This theory considers that both mucoadhesiveand biological materials possess opposing electrical charges; when both materials come in contact with each other they form double electronic layer at interface leading to mucoadhesion

Wetting theory

Best applied to liquid or low viscosity bioadhesives

Postulates that if the contact angle of liquids on the substrate surface is lower, then there is a great affinity for the liquid to the substrate surface. This affinity can be measured by contact angle

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Wetting theory calculates the contact angle and work of adhesion (Wa), given by Dupre’s eq.

Ƴb & Ƴt are surface tension of polymer and substrate respectively and Ƴbt is interfacial tension

The adhesive work done is a sum of the surface tensions of the two adherent phases, less the interfacial tensions apparent between both phases

t

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Horizontal resolution of the forces gives the Young eq.

Where, Ƴbt, Ƴba, and Ƴta are surface tension between tissue and polymer, polymer and air, and tissue and air respectively

If the vector Ƴta greatly exceeds Ƴbt + Ƴba, that is:

then θ will approach zero and wetting will be complete

A liquid bioadhesive spreading over a typical soft tissue surface

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Adsorption theoryThe mucoadhesive device adheres to mucus by

secondary chemical interactions such as vanderWaals,hydrogen bonding or hydrophobic interaction

Such forces are considered most important in adhesiveinteraction because, although they are individuallyweak, a great number of interactions can result instrong adhesionDiffusion theory

Diffusion theory describes that polymeric chainsfrom the bioadhesive interpenetrate into glycoproteinmucin chains and reach a sufficient depth within theopposite matrix to allow formation of asemipermanent bond

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The depth of 0.2-0.5 µm is required to produce an efficient mucoadhesive bond

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Fracture theory:

This theory describes the force required for the separation of two surfaces after adhesion

Where σ is the fracture strength, ε fracture energy, E young modulus of elasticity, and L the critical crack length

It is used for rigid or semi-rigid bioadhesive materials, in which the polymer chains do not penetrate into the mucus layer

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Mechanical theory

Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area available to interactions

Cohesive theory

It proposes that the phenomena of bioadhesionare mainly due to the intermolecular interactions amongst like-molecules

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Polymer related factors:

Molecular weight

Conc. of polymer

Flexibility of polymer chains

Presence of functional group

Spatial conformation

Cross linking density

Environment related factors:

pH of polymer substrate interface

Applied strength

Physiological factors:

Mucin turn over

Disease state

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They are water soluble and water insoluble polymers which are swellable networks joined by cross linking agent

Characteristic of ideal polymer

Degradation products should be non toxic and non absorbable from GIT

Good spreadibility, wetting, swelling and biodegradable properties

Optimum molecular weight

Non irritant to mucous membrane

Form a strong non-covalent bond with mucinepithelial cell surface

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Adhere quickly to moist tissue

Allow easy incorporation of the drug

Stable, cost effective and approved by regulatory authorities

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According to source

Natural and semisynthetic Synthetic

Agarose Carbopol

Chitosan Polycarbophil

Gelatin Polyacrylic acid

Hyaluronic acid Methacrylic acid

Carrageenan Polyacrylates

Pectin PVA

CMC PVP

Thiolated CMC Ethylhexa acrylate

Sodium CMC Thiolated polymer

Hydroxyethylcellulose

Hydroxypropylcellulose

HPMC

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According to water solubility

According to charge

Soluble Insoluble

CMC, Sodium CMC, HEC, HPMC,

MC, PVA, PVP, etc.

Carbopol, Polycarbophil,

Polyacrylic acid, PEG, etc.

Charged Uncharged

Aminodextran, Chitosan,

Carbopol, SodiumAlginate,

Pectin, SodiumCMC, etc.

Starch, HPC, PEG, PVA, PVP, etc.

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Route Formulation

Oral(Buccal and Sublingual) Tablet, patch, gel, ointment

Nasal Gel, microspheres, dry powder

Ocular Insert, gel

Gastrointestinal Gel, tablet, microsphere,

capsule

Skin/Transdermal Patch, liposome

Vaginal Gel, microsphere, tablet

Rectal Gel

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In vitro studies

1) Tensile stress measurement

a) Wilhelmy’s plate technique: Traditionally used to measure dynamic contact angle, measures bioadhesive force between mucosal tissue and dosage form

By using CAHN software fracture strength and work of adhesion can be analysed

Apparatus to determine

mucoadhesion in vitro, using

Wilhemy’s technique

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2) Everted gut sac procedure(ex vivo)

Can be applied to liposomes, microspheres and nanoparticles

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3) Colloidal gold staining method: Employs red colloidal gold particles stabilised by adsorbed mucin forming mucin-gold conjugates

Upon interaction with conjugates bioadhesivehydrogel develop red colour on surface

Interaction can be quantified by :

Measuring red colour intensity on Hydrogel

Measuring decrease in concentration of conjugates at 525nm

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Tests measuring mucoadhesive strength

Depending on the direction in which themucoadhesive is separated from the substrate,iti spossible to obtain the detachment, shear, andrupture tensile strengths

The force most frequently evaluated in such tests isrupture tensile strength

Generally, the equipment used is a texture analyzerIn this test,

The force required to remove the formulation from amodel membrane is measured

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Bioadhesion test using the texture analyzer

Microbalance methodWilhemy’s plate technique, or the microforce balance technique, can also be modified in order to measure the specific adhesion force of microparticles

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The general problem of adhesion force and from the rheological methods is that the mucoadhesive response is seen macroscopically while the interactions occur at a microscopic level

Following methods are used to study molecular interactions

a) Dielectric Spectroscopy: Study of material response to the application of an electrical field

the impedance or permittivity of the sample is obtained and the property of charges changing in the system can be determined

b) Zeta potential: Mucin particles are suspended in an appropriate buffer and mixed with a solution of the polymer, If the zeta potential value of the mucin particles changes, this can suggest greater affinity between polymer and mucinparticles

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c) Optical biosensor: One molecule is immobilized other remains in solution, The molecules in solution, when binding to the immobilized molecules, alter the refraction index of the medium and this change is detected by the screening of a laser beam

d) Falling Liquid Film Method :

In the case of particulate systems, the amount remaining on the mucous membrane can be counted with the aid of a coulter counter, For semi-solid systems, the non adhered mucoadhesive can be quantified by high performance liquid chromatography

This methodology allows the visualization of formation of liquid-crystalline mesophase on the mucous membrane

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In vivo Techniques

1) GI transit using radio-opaque technique: It involves use of radio opaque markers, e.g., barium sulphate, encapsulated in BDDS

Mucoadhesive labelled with Cr51, Tc99, In113 Have been also used

2)Gamma scintigraphy: Information are obtained noninvasively

Provides various information like:

Dosage form across different regions of GI tract

Time and site of disintegration

Site of absorption

Effect of food and disease

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Flavia Chiva Carvalho, Marcos Luciano Bruschi, Raul Cesar Evangelista, Maria Palmira Daflon Gremiao ; Mucoadhesivedrug delivery systems; Brazilian Journal of Pharmaceutical Sciences vol. 46, 2010;1-18.

Formulation and in vitro evaluation of mucoadhesive buccaltablets of Timolol maleate;Int J Pharm Biomed Res 2010, 1(4), 129-134

Smart, J. D., Kellaway, I. W., Worthington, H. E. C., An in-vitro investigation of mucosa-adhesive materials for use in controlled drug delivery, J. Pharm. Pharmacol., 1984,295-299

Pranshu tangri: mucoadhesive drug delivery: mechanism and methods of evaluation, Int J. of Pharma and biosciences: vol. 2, 2011, 458-461

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