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       Dr.M.R. BHALEKAR

     Introduction
     Mucosal membrane
     Mucoadhesive polymers
     Mechanism of mucoadhesion
     Theories of mucoadhesion
     Factors affecting mucoadhesion
     Transmucosal routes
     Types of mucoadhesive formulations
     Methods of evaluation of mucoadhesion
     References
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    In biological systems, four types of bioadhesion could be

    1.   Adhesion of a normal cell on another normal cell.
    2.   Adhesion of a cell with a foreign substance.
    3.   Adhesion of a normal cell to a pathological cell.
    4.   Adhesion of an adhesive to a biological substance.

     For drug delivery purpose, the term bioadhesion implies
    attachment of a drug carrier system to a specific biological

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 Adhesion can be defined as the bond produced by contact
    between a pressure sensitive adhesive and a surface.
   Presence of amine and carboxyl groups particularly favours
   Bioadhesion is defined as the state in which two materials, at
    least one of which being of a biological nature, are held together
    for an extended period of time by interfacial forces.
   It is also defined as the ability of a material (synthetic or
    biological) to adhere to biological tissue for an extended period
    of time .
   The biological surface can be epithelial tissue or it can be the
    mucus coat on the surface of a tissue. If adhesive attachment is to
    a mucus coat ,the phenomenon is referred to as mucoadhesion.

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 Mucoadhesive drug delivery system is a system which utilizes the
  property of mucoadhesion of certain polymers which become
  adhesive on hydration and hence can be used for targeting a drug to
  a particular region of the body for extended periods of time.
 Mucoadhesion is an interfacial phenomenon in which two materials
  at least one of which is biological, is held together by means of
  interfacial forces.
 The attachment could be between an artificial material and
  biological substrate such as adhesion between a polymer and a
  biological membrane.

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1)Mucosal DDS has major advantage to bypass first pass hepatic
  metabolism, increasing the bioavailability of drugs.
2) The drug is protected from degradation due to pH and digestive
  enzymes of the middle gastrointestinal tract.
3) As mucosal membranes are relatively permeable, it allows a rapid
  onset of action.
4) Mucosal membrane particularly the nasal mucosa offers potential
  for a rapid absorption of drugs with plasma profile closely
  duplicating that from an intravenous bolus injection. This is
  especially useful in emergency situations.

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5) In controlled release drug delivery
6) These dosage forms are readily localized in the region applied
  to improve and enhance the bioavailability of drugs.
7) Targeted & localized drug delivery
8) Mucoadhesive dosage forms also prolong the residence time of
  the dosage form at the site of application and absorption to
  permit once or twice a day dosing.
9) Avoidance of drug degradation
10) High drug flux through the absorbing tissue
11) Reduction in fluctuation of plasma level.

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    Fig 1: Regions in mucus layer   9/12/2012 3:40:26 PM
 Nature of Mucus Secretion

 Mucus is translucent and viscid secretion which forms a thin ,
  continuous gel blanket adherent to the mucosal epithelial surface.
 Mucus is secreted by the goblet cells lining the epithelia or by
  special exocrine glands with mucus cells .
 Normally the mucus is clear, visco-elastic and adhesive.

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     General composition of mucus :
      Glycoprotiens and lipids….0.5-5%
      Mineral salts……………….1%
      Free proteins………………0.5-1%

     These units contain an average of about             8-10
     monosaccharide residues of five different types.
     They are:
      a) L-fucose
      b) D-galactose
      c) N-acetyl-D-glucosamine
      d) N-acetyl-D-galactosamine
      e) Sialic acid
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  Structure and Composition of Mucus

 Complex-high molecular weight macromolecule consisting of a
  polypeptide (protein) backbone to which carbohydrate side
  chains are attached.

        Fig 2: Generic structure of mucin monomer

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  Mucus forms flexible, threadlike strands that are internally
 cross linked by disulphide bond.

     Fig 3: Disulphide bond present in mucus

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Key macromolecular components are a class of glycoprotein known
 as Mucins.

The mucus layer which covers the epithelial surface has various

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Mucosal membrane
 These are moist membranes that line passage-ways
  and structures in the body that lead to the external
  environment such as the mouth, nose, respiratory
  tract, gastrointestinal tract and vagina.
 They secrete a viscous fluid known as mucus,
  which acts as a protective barrier and also
  lubricates the mucosal membrane.

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 The amount of drug absorbed depends on the drug concentration,
  vehicle of drug delivery, mucosal contact time, venous drainage of
  the mucosal tissue, pH of the absorption site, size of drug molecule
  and relative lipid solubility.
 Parameters such as diffusion coefficient, partition coefficient and
  thickness of the tissue are inherent properties of drug and mucosa.
 Other parameters such as surface area, duration of drug delivery
  and concentration are controlled by the dosage form and
 Free drug concentration is key issue, if drug is bound with other
  components in formulation it is not available for transmucosal
  delivery and bioavailability will be reduced.

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 Transmucosal drug absorption
  There are two routes involved in drug permeation across
   epithelial membranes :
 1)Paracellular route
 2)Transcellular route
  Paracellular is the transport of molecules around or
   between cells.Tight junctions exist between cells.
  The intercellular tight junction is the major barrier to
   paracellular transport of macromolecules and polar
  Poly(acrylic acid)derivatives such as carbomer and
   chitosans have been studied for their possible uses as
   absorpion enhancers that cause the loosening of tight
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      A muco(bio)adhesive polymer is a natural or synthetic
       polymer capable of producing adhesive interaction with
       biological membrane which , is thus called as
       mucoadhesive polymer

      There are two broad classes of mucoadhesive polymers:
       1)Hydrophilic polymers , ex: HPMC ,carbomer etc.
       2)Hydrogels ex: Chitosan, carageenan , guar gum, sodium
         alginate , etc.
       3)Thermoplastic polymers :
          a)Non erodible neutral polystyrene
          b)Semi crystalline bioerodible polymers: poly
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           anhydrides and poly lactic acid.
  Polymers adheres to the mucin epithelial surface can be
   divided into three broad categories:
 1)Polymers that become sticky when placed in water and owe
   their mucoadhesion to stickiness,
 2)Polymers that adhere through non specific ,non covalent
   interactions which are primarily electrostatic in
   nature(although hydrogen and hydrophobic bonding may
   be significant)
 3)Polymers that bind to specific receptor sites on the cell

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 The polymer and its degradation products should be non
  toxic and non absorbable from GI tract.
 Non irritant to the mucus membrane.
 Preferably form a strong non covalent bond with the mucin
  epithelial cell surfaces.
 Adhere quickly to moist tissue and should posses some site
 Allow easy incorporation of the drug and offer no
  hindrance to its release.
 Must not decompose on storage or during the shelf life of
  the dosage form .
 The cost should not be high so that the prepared dosge form
  remains competitive.

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     Mucoadhesive interactions
      Ionic bonds
      Covalent bonds
      Van der waals bonds
      Hydrogen bonds
      Hydrophobic bonds

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      Theories of mucoadhesion

     1. 1) Electronic theory
     2. 2 )Adsorption theory
     3. 3 )Wetting theory
     4. 4 )Diffusion theory
       5) Fracture theory

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     Mucoadhesive Drug Delivery Systems

       The term mucoadhesion is used to describe adhesion interactions
       between polymers and mucus or mucosal surfaces.

       Mechanisms of mucoadhesion
       The mechanisms responsible in the formation of mucoadhesive bonds
       are not fully known, however most research has described
       mucoadhesive bond formation as a three step process.

     Step 1 : Wetting and swelling of polymer
     Step 2 : Interpenetration between the polymer chains and the mucosal
     Step 3 : Formation of chemical bonds between the entangled chains

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 Mechanism of Mucoadhesion
 Step 1
   The wetting and swelling step occurs when the polymer
   spreads over the surface of the biological substrate or mucosal
   membrane in order to develop an intimate contact with the
   substrate. This can be readily achieved for example by placing
   a mucoadhesive formulation such as a tablet or paste within
   the oral cavity or vagina.

     Swelling of polymers occur because the components within
     the polymers have an affinity for water.

                                    Fig 4
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     Mechanism of Mucoadhesion

     Step 2
       The surface of mucosal membranes are composed of high
       molecular weight polymers known as glycoproteins. In
       step 2 of the mucoadhesive bond formation, the
       mucoadhesive polymer chains and the mucosal polymer
       chains intermingle and entangle to form semi permeable
       adhesive bonds.

      The strength of these bonds depends on the degree of
      penetration between the two polymer groups. In order to
      form strong adhesive bonds, one polymer group must be
      soluble in the other and both polymer types must be of
      similar chemical structure.

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  The interpenetration of polymer

      polymer chains
     polymer chains
                       Fig 5

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Mechanism of Mucoadhesion
 Step 3
   This step involves the formation of weak chemical bonds
 between the entangled polymer chains. The types of
 bonding formed between the chains include primary bonds
 such as covalent bonds and weaker secondary interactions
 such as van der Waals Interactions and hydrogen bonds.
 Both primary and secondary bonds are exploited in the
 manufacture of mucoadhesive formulations in which
 strong adhesions between polymers are formed.

                                                   Step 3

                                           Fig 6
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 Factors affecting Mucoadhesion (13)
 1. Polymer related factors:
    i) Molecular weight
   ii) Concentration of active polymer
  iii) Flexibility of polymer chains
  iv) Spacial confirmation
   v) Cross linking density
  vi) Charge
 vii) Hydration

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 2. Environment related factors:
    i) pH of polymer - substrate interface
   ii) Applied strength
  iii) Initial contact time
  iv) Swelling
 3. Physiological factors:
    i) Mucin turn over
   ii) Disease states

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 Enhancement of transmucosal agent transport

 Non enhanced drug delivery is based solely on diffusion.
 Hydrophilic ionic drugs diffuse through intercellular space, while
  hydrophobic are able to pass through cellular membranes
 Permeation of drugs throghout epithelial barriars could be
  promoted by penetration enhancers such as physical or chemical
 Enhancer efficacy depends upon the physicochemical properties
  of drug, the administration site and nature of the vehicle.

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 Various chemical enhancers used across epithelial tissues; among
  them chelators (eg: sodium EDTA or salicylates), surfactants
  (eg: sodium Dodecylsulfate), bile salts (eg: sodium deoxycholate,
  sodium Glycocholate), fatty acids (eg: oleic acid, lauric acid)
  and non surfactants(eg: cyclodextrins)
 Different mechanical penetration enhancements such as electro
  osmosis , electrophoresis, electroporation.
 Electrophoretic enhancement is mostly used, most effective for
  water soluble ionized compounts. Rate of migration is limited by
  maximum electric current which can be applied across
  mucosa(below 0.5 mA/ cm2 )

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Pharmaceutical consideration and formulation
  An ideal transmucosal drug delivery system must meet several
   prerequisites to be successful
 1) It should rapidly attach to the mucosal surface and maintain a
    strong interaction to prevent displacement.
    Contact time should also be sufficiently long at the target site
    normally longer than that needed for complete drug release.
 2) Bioadhesion performance should not be impacted by
    surrounding environmental pH.
    Drug release from a polymeric material takes place either by
    diffusion or by polymer degradation or by their combination.

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  Drug absorption through a mucosal surface is generally efficient
   because the stratum corneum epidermidis, the major barrier to
   absorption across the skin, is absent.
  Mucosal surfaces are usually rich in blood supply, providing
   the means for rapid drug transport to the systemic circulation
   and avoiding, in most cases, degradation by first-pass hepatic

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     Transmucosal Routes includes:

       1. Nasal Transmucosal Administration
       2. Oral Transmucosal Administration
        Buccal
        Sublingual
       3. Rectal Transmucosal Administration
       4. Vaginal Transmucosal Administration
       5. Ocular Transmucosal Administration
       6. Gastrointestinal Transmucosal Administration

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 Types of Mucoadhesive Formulations
1. Solid Bioadhesive Formulations:

Tablets : Dry formulation such as tablets are able to form strong interactions
         with mucosal surfaces by attracting water from the mucosal surface.

Inserts: These include ocular inserts such as eye drops and eye gels

Lozenges: Mucoadhesive lozenges containing antibiotics and local
          anaesthetics can be used topically to treat conditions affecting the

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 Types of Mucoadhesive Formulations (5)
 2. Semi-solid mucoadhesive Formulations

 Gels : Mucoadhesive polymers that are able to form gels include polyacrylic
   acid which adheres to mucosal surfaces in a cross-linked form.
   Gel formulations are used to target several parts of the body including the eye,
   vagina and oral cavity.

 Films: Mucoadhesive films that are flexible in nature can be used to directly
   deliver drugs to specific mucosal membranes.

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Types of Mucoadhesive Formulations

 3. Liquid Bioadhesive Formulations

 Viscous liquids: Viscous liquids containing mucoadhesive polymers such as
   carboxymethyl cellulose may be used to protect mucosal membranes from
   damage and irritation.

 Gel-forming liquids: These formulations are administered as liquids but undergo
   a change in their form in response to conditions such as temperature and pH.
   Such formulations are used for the controlled-release of drugs into the eye.

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Targets for Mucoadhesive Formulations
Table 1: Sites to which mucoadhesive formulations are targeted

Body site         Systems                          Formulation

Eye               Occular drug delivery system      Hypotears , Gel Tears and

Nasal cavity      Nasal drug delivery systems      Rhinocort , Beconase ,

Oral cavity       Dental gels / buccal systems     Corlan, Daktarin ,
Vagina            Local vaginal delivery systems    Aci-Jel, Crinone

Rectum            Local/systemic rectal delivery    Anacal, Germoloid
       Methods for evaluation of mucoadhesion
     1)In vitro methods
      Shear stress method
      Detachment force measurement (Modified balance method)
      Fluorescent probe method
      Flow channel method
      Falling liquid film method
      Adhesion number

     2)In vivo methods

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 Fig.7. Measurement of mucoadhesive tensile strength with
 an automatic surface tensiometer.

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     Fig 8. Mucoadhesion by modified balance method

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     Fig 9.Apparatus for falling liquid film method.

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     1)James Swarbik ,James C. Boylan,″ Encyclopedia of
       Pharmaceutical Technology″,vol 10,page no: 133
     2) N.K.Jain , ″Controlled and novel drug delivery ″, C.B.S.
       publisher and distributers,1st edition, page no:353-380
     3) Yie W.Chien, ″Novel drug delivery system ″, second
       edition, vol.50,Marcel Dekker and Inc. New york, hang
       kong, page no:-197-228

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 4) http://
   polymers-review , accessed on 14/4/2010
 5) http:/ , accessed on 15/4/2010
 6) http:/ Shojaei/ buccal review
 7)http:/ , accessed on
 8) Gavin P. Andrews , Thomas P. Laverty and David S. Jones
    European Journal of Pharmaceutics and Biopharmaceutics
   Volume 71, Issue 3, March 2009, Pages 505-518

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