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Mucoadesive Drug Delivery System

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CONTENT

• Basics ,concepts & mucosal membrane.• Theories mucoadhesion• Mechanisms of BioadhesionMechanisms of Bioadhesion• Drug AbsorptionDrug Absorption• Bio(muco)adhesive Polymer• Types of Bioadhesive FormulationsTypes of Bioadhesive Formulations• Targets for Bioadhesive FormulationsTargets for Bioadhesive Formulations• Oral Bioadhesive Formulations• Conclusion • Reference

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Muco + adhesiveInner layers called mucosaInner epithelial Cell lining Covered with viscoelastic fluid.Secreted by Goblet cells Composed of water and mucin (an anionic polyelectrolyte )Other components include proteins, lipids and mucopolysaccharides ,electrolytesThickness varies from ≈40–50 μm to ≈300 μm

Tendency substance to remain adhered to surface

If substance adhere to Biological membrane is called as Bioadhesion .

If substance adhere to Biological mucosal layers is called as Mucoahesion.

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Main role is protective and lubricates

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MucinMucin constitute > 95% of water .

Gel like consistency due to glycoproteins

Chemically oligosacharide chain with terminal Sialic acid ( pka=2.6)

Mucins are large molecules with molecular masses ranging from 0.5 to over 20 MDa.

Gastric mucin of Mw ≈10 MDa

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Mucosal membranesMucosal membranes

These are moist membranes that line passageways and structures in thebody that lead to the outside environment such as the mouth, respiratory tract, gastrointestinal tract, nose and vagina

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BioadhesionBioadhesion is used to describe the bonding or adhesion between a synthetic or natural polymer and soft tissues biological substrate such as epithelial cells, which allows the polymer to adhere to the biological surface for an extended period of time .

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Concept

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The drug can be incorporated into a cross linked polymer device that would adhere to mucosal membrane in the body .the drug can diffuse from device directly in the tissue.Adhesion ,anchoring of polymer device result in increase residence time , bioavailability & site specificity.Decrease in frequency of administration with low dose , rate of elimination.

Can bypass Firstpass metabolisum in route is other than oral

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Pharmacological Response

Oral Delivery

Portal Circulation

Pathway to Bypass

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Theories mucoadhesion

The Theories include :-

(a) The electronic theory, (b) The wetting theory, (c) The adsorption theory. (d) The diffusion theory, (e) The mechanical theory (f) The cohesive theory. (g) Fracture theory.

The phenomena of bioadhesion occurs by a complex mechanism

There are seven theories have been proposed till date

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The electronic theory Proposes transfer of electrons amongst the surfaces due to difference in their electrical structure resulting in the formation of an electrical double layer thereby giving rise to attractive forces.

The wetting theory Postulates that if the contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface. If two such substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive amongst the substrate surfaces.

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The diffusion theory Assumes the diffusion of the polymer chains, present on the substrate surfaces, across the adhesive interface thereby forming a networked , semipermeable structure. The extent depth to which the polymer chain penetrate the mucus depend on diffusion coefficient &time of contact .

The adsorption theory After initial contact of the material adhere to surface due to forces acting between the atoms in the two surfaces later result in formation of bonds(primary & secondary )due to the presence of intermolecular forces, viz. hydrogen bonding and Van der Waal’s forces, for the adhesive interaction amongst the substrate surfaces.

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Fracture theory :-This theory attempts to relete the difficulty of separation of two surfaces after adhesion .Adhesion Strength = (E ԑ/L )1/2

E =Young’s modulus of elasticity ԑ = Fracture energy L = Critical crack length when two surfaces are separated

The cohesive theory proposes that the phenomena of bioadhesion are mainly due to the intermolecular interactions amongst like-molecules.

The mechanical theory explains the diffusion of the liquid adhesives into the micro-cracks and irregularities present on the substrate surface thereby forming an interlocked structure which gives rise to adhesion.

Surface roughness =d/h

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Mechanisms of BioadhesionMechanisms of Bioadhesion The mechanisms responsible in the formation of bioadhesive bonds are not fullyknown, however most research has described bioadhesive bond formation as athree step process.

Step 1 : Wetting and swelling of polymer

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

Step 3 : Formation of chemical bonds between the entangled chains

Process of bioadhesion can be classified, 1) Chemical (electronic and adsorption theories) 2) Physical (wetting, Diffusion and cohesive theory)

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StepStep 1 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. Bioadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occur because the components within the polymers have an affinity for water.

The image below shows swelling of a polymerThe image below shows swelling of a polymer

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StepStep 2 2 The surface of mucosal membranes are composed of high

molecular weight polymers known as glycoproteins. In step 2 of the bioadhesive bond formation, the

bioadhesive 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.

The interpenetration of polymer chainsThe interpenetration of polymer chains

Bioadhesive polymer chains

Mucus polymer chains

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StepStep 3 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 bioadhesive formulations in which strong adhesions between polymers are formed. Mechanisms of bioadhesionMechanisms of bioadhesion

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Types of intecraction Involved

1)Physical And Mechanical.

2)Secondary chemical bond.

3)Ionic,primary or covalent chemical bonds

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Drug AbsorptionDrug Absorption Drug absorption is the process by which a drug leaves its site of administration and enters the general circulation

Pinocytosis.

Passive diffusion Facilitated passive diffusion

Active transport

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In Bioadhesive Drug Delivery System the drug molecules Is either dispersed in matrix of polymer or matrix type is coated with bio(muco)adhesive polymer.

Bio(muco)adhesive Polymer

A bioadhesive polymer is a synthetic or natural polymer which binds to biological substrates such as mucosal membranes.

Sometimes referred to as biological ‘glues’

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2) The nonspecific bioadhesive polymers Are the ability to bind with both the cell surfaces and the mucosal layer. e.g.polyacrylic acid, cyanoacrylates

Classification of Bio(Muco)adhesive polymers

A )Based on Specificity :-

1) The specific bioadhesive polymers Are the ability to adhere to specific chemical structures

within the biological molecules e.g. lectins, fimbrin

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(I) Synthetic polymers:(a) Cellulose derivatives:-methylcellulose, ethylcellulose, hydroxy-ethylcellulose, Hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose.(b) Poly (acrylic acid) polymers (carbomers, Polycarbophil, poly(methylacrylate).(c) Poly (hydroxyethyl methylacrylate).(d) Poly (ethylene oxide).(e) Poly (vinyl pyrrolidone).(f ) Poly (vinyl alcohol).

B ) Based on Origen

(II) Natural polymers:Tragacanth ,Sodium alginate, Karaya gum, Guar gum ,Xanthan gum ,Lectin ,Soluble starch, Gelatin, Pectin, Chitosan , Hyaluronic acid .

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Relative mucoadhesive performance of some polymers :-Polymer Relative

mucoadhesive forceQuality of bioadhesion

CMC 193 Excellent

Carbopol 185 Excellent

Tragacanth 154 Excellent

Sod. alginate 126 Excellent

HPMC 125 Excellent

Gelatin 116 fair

Pectin 100 Poor

Acacia 98 Poor

Providone 98 Poor

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Molecular properties of mucoadhesive :-

1. Strong hydrogen bonding groups (-OH, -COOH).

2. Strong anionic charges.(cellulose derivatives) but some cationic (e.g., Chitosan)

3. Sufficient flexibility to penetrate the mucus network ortissue crevices.

4. Surface tension characteristics suitable for wetting mucus/ mucosal tissue surface.

5. High molecular weight.

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Characteristics of Bioadhesive polymers

1)Flexibility1)Flexibility- - important because it controls the extent of the interpenetration between the polymers and mucosal/epithelial surfaces.2)Hydrophilicity2)Hydrophilicity – Polymers that are hydrophilic in nature are able to form strong adhesive bonds with mucosal membranes because the mucus layer contains large amounts of water.3)Hydrogen bonding 3)Hydrogen bonding – – Hydrogen bonding between the entangled polymer chains forms strong adhesive bonds, therefore the presence of hydrogen bond – forming groups such as OH and COOH groups are vital in large quantities.4)High molecular weight 4)High molecular weight – – Polymers with a high molecular weight are desirable because they provide more bonding sites.5)Surface tensions 5)Surface tensions – – Surface tensions are needed to spread the bioadhesive polymer into the mucosal layer epithelial surface.

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Characteristics of an ideal mucoadhesive polymer

1. The polymer and its degradation products should benontoxic and should be nonabsorable from thegastrointestinal tract.

2. It should be nonirritant & non abrasive to the mucous membrane.

3. It should preferably form a strong noncovalent bond with the mucin-epithelial cell surfaces.

4. It should adhere quickly to most tissue and should possess some site-specificity.

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5. It should allow easy incorporation to the drug and offer no hindrance to its release.

6. The polymer must not decompose on storage or during the shelf life of the dosage form.

7. The cost of polymer should not be high so that the prepared dosage form remains competitive.

8.It should get Wash out at desired period.

Continued…

9.The mucoadhesive should be with high drug-loading capability.

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Factor affecting Mucoadhesion A)Polymer related :- 1)molecular weight –up to 10 00 000 and beyond this there is not much effective . 2)Concentration of active polymer –optimum not too high that significantly drops strength. 3)Flexibility of polymer chain – 4)spatial conformation –B)Environmental related :- 1)PH 2)Applied strength – increase up to optimum level 3)Initial contact time 4)swelling –too greater decrease the adhesion 5)mucus compossionC)Physiological factors :- 1)Mucin turn over 5)Diseased state

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Delivery Systems

1 )Monolithic (or matrix) systems:- where the drug is dissolved or dispersed in the polymer system diffusion of drug from the drug/polymer matrix controls the overall rate of its release from the device.

2)Reservoir (or membrane) systems :- where diffusion resistance across a polymeric membrane controls the overall drug release rate.

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Types of Bioadhesive FormulationsTypes of Bioadhesive Formulations

1.Solid Bioadhesive Formulations :-1.Solid Bioadhesive Formulations :-Tablets , Tablets , Inserts ,Inserts ,Powders, tapes

2. Semi-solid bioadhesive Formulations:- 2. Semi-solid bioadhesive Formulations:- GelsGels , FilmsFilms, , solutions,

aerosol sprays

3.Liquid Bioadhesive Formulations:- 3.Liquid Bioadhesive Formulations:- Viscous liquids , Viscous liquids ,

Gel-forming liquidsGel-forming liquids

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Targets for Bioadhesive FormulationsTargets for Bioadhesive Formulations

Body siteBody site SystemsSystems

Eye Mucoadhesive eye drops / inserts

Nasal cavity Nasal drug delivery systems

Oral cavity Dental gels / buccal systems

Skin Patches, tapes, dressings

Vagina Local vaginal delivery systems

Rectum Local/systemic rectal delivery systems

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Oral Bioadhesive Formulations

Oral bioadhesive formulations are topical products designed to deliver drugs to the oral cavity which act by adhering to the oral mucosa and therefore produce localised effects within the mouth

The oral cavityThe oral cavityImportant functions which include chewing, speaking and tasting. Some of these functions are impaired by diseases such as ulcers, microbial infections and inflammation.

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In contact with saliva Dosage form become adhesive and render system attached to mucosa

Drug solution rapidly absorbed throug the the reticulated vein which is underneath the oral mucosa & transported through facial vein ,internal jugular vein ,Brachiocephalic vein .

Rapid absorption –peak 1to 2 min

Some of the common conditions - Mouth ulcersMouth ulcers , Oral thrush, Oral thrush, Gingivitis.Gingivitis.

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The buccal mucosa refers to the inner lining of the lips and cheeks.

The epithelium of the buccal mucosa is about 40-50 cells thick and the epithelial cells become flatter as they move from the basal layersbasal layers to the superficial layers.

The buccal mucosa is less preferable compared to other oral drug delivery systems because of vary short transit time. The bioadhesive polymers can retention of a dosage form by spreading it over the absorption site.

A ) The Buccal MucosaA ) The Buccal Mucosa

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B ). The sublingual mucosaB ). The sublingual mucosa

The sublingual mucosa surrounds the sublingual gland which is a mucin-producing salivary glandsalivary gland located underneath the tongue.

Examples :- Glyceryl Trinitrate (GTNGlyceryl Trinitrate (GTN) (aerosol spray and tablet in prophylacticprophylactic treatment of angina.) Brand name:-Susadrin ,Nitrogard.

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3 ) The Gingival Mucosa

Hardest muscle of bodyCan retain dosage form for long duration

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Conclusion Mucoadhesive dosage forms have a high potential of being useful means of delivering drugs to the body.Current use of mucoadhesive polymers to increase contact time for a wide variety of drugs and routes of administration has shown dramatic improvement in both specific therapies and more general patient compliance. The general properties of these polymers for purpose of sustained release of chemicals are marginal in being able to accommodate a wide range of physicochemical drug properties. Hence mucoadhesive polymers can be used as means of improving drug delivery through different routes like gastrointestinal, nasal, ocular, buccal, vaginal and rectal .

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Reference

1 )Donald L. Wise ,Handbook of pharmaceutical Controlled Release Technology,Marcel Dekker’s Pg .No-168-172255-268.2)Yie W. Chaine ,NDDS ,Informa Healthcare USA-2009 ,2nd edition ,pg no- 197-229.3) S. B. Patil*, R. S. R. Murthy, H. S. Mahajan, R. D. Wagh, S. G. Gattani**,” Mucoadhesive polymers: Means of improving drug delivery” Pharma Times - Vol 38 - No. 4 - April 2006,pg no -25-28.4) D r s B h a s k a r a J a s t i , X i a o l i n g L i and G a r y C l e a r y,” Recent Advances in Mucoadhesive Drug Delivery Systems” B U S I N E S S B R I E F I N G : P H A R M A T E C H 2 0 0 3,pg no-194-198.5) S.E. Harding ,” Mucoadhesive interactions” Biochemical Society Transactions (2003) Volume 31, part 5,pg no-1036-1041.6) S. Roy1, K. Pal, A. Anis, K.Pramanik and B.Prabhakar“ Polymers in Mucoadhesive Drug Delivery System: A Brief Note “esigned Monomers and polymers 12(2009),pg no 483-485.7)Pharmainfonet.com Prof. G.S. Asane “Mucoahhesive anGI DDS ,Vol 5,issu 06,2007.

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