PRESENTED

BIOADHESIVE BIOADHESIVE AND AND MUCOADHESIVEMUCOADHESIVE

DRUG DELIVERY SYSTEMDRUG DELIVERY SYSTEM

Introduction Mechanism of bioadhesionFactors affecting bio/muco

adhesionGastro intesinal mucoadhesive drug

deliveryEvaluation of mucoadhesionTargets for Bioadhesive

formulationsConclusionReferences

• Bioadhesion : it is defined as the attachment of synthetic or biological macromolecules to a biological tissue. /

• Adhesion of a polymer to a biological substrate.

• Mucoadhesion :- it is the special case of bioadhesion where the biological tissue is an epithelium covered by mucus.

Introduction

Adhesion : sticking of materials with one to another by producingBond in between them.

Adv : 1. Prevents first pass metabolism

2. Increases bioavailability with

smaller dosage

3. Prevents enzymatic degradation

Dis adv : 1. Gastric motility2. Mucin turn over rate3. Drugs that irritate mucosa cannot be administered by this route

Advantages and disadvantages

A prolonged residence time at the site

of action or absorption      An increase in the drug concentration gradient.     A direct contact with intestinal cells.• Controlled release• Target and localized drug delivery• Avoidance of first pass effect• High drug flux through the tissue• Reduction of fluctuation of study state plasma level

NEED FOR BDDS ??

STEPS OF BIOADHESION BIOADHESIONTypes:- I, II, III

(1) Initial contact between the 2 surfaces.  (2) Formation of secondary bonds due to

non-covalent interactions. This process of bond formation attributed to     surface of the biological membrane, surface of the adhesive and   interfacial layer between the 2 surfaces.

Mechanisms of bioadhesionMechanisms of bioadhesion

The mechanisms responsible in the formation of bioadhesive bonds are not fully known, however most research has

described bioadhesive bond formation as a three step process.

Step 1 : Wetting and swelling of polymerStep 2 : Interpenetration between the polymer chains and the

mucosal membraneStep 3 : Formation of chemical bonds between the entangled chains

MECHANISM

Step 1Step 1Wetting & swellngThe 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 bioadhesive formulation such as a tablet or paste within the oral cavity or vagina. 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

Step 2 Step 2 InterpenetrationThe surface of mucosal membranes are composed of high molecular weightpolymers known as glycoproteins. In step 2 of the bioadhesive bond formation, thebioadhesive polymer chains and the mucosal polymer chains intermingle andentangle to form semi permeable adhesive bonds. The strength of these bondsdepends on the degree of penetration between the two polymer groups. In order toform strong adhesive bonds, one polymer group must be soluble in the other andboth polymer types must be of similar chemical structure.

Bioadhesive

polymer chains

Mucus

polymer chains

The interpenetration of polymer chainsThe interpenetration of polymer chains

Step 3 Step 3 Interaction of substrate and polymerThis step involves the formation of weak chemical bonds between the entangledThis step involves the formation of weak chemical bonds between the entangledpolymer chains. The types of bonding formed between the chains include primarypolymer chains. The types of bonding formed between the chains include primarybonds such as covalent bonds and weaker secondary interactions such as van derbonds such as covalent bonds and weaker secondary interactions such as van derWaals Interactions and hydrogen bonds. Both primary and secondary bonds areWaals Interactions and hydrogen bonds. Both primary and secondary bonds are

exploited in the manufacture of bioadhesive formulations in which strong adhesions between exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed.polymers are formed.

Step 3Step 3

Mechanisms of bioadhesionMechanisms of bioadhesion

FUNDAMENTALS OF BIOADHESION

Molecular events that take place in the interfacial layer depends on the

       Properties of biological membrane

     Properties of polymer 

Mucous composition :

water - 95% Glycoprotein’s & lipids - 0.5 –

5% Mineral salts - 1%

Free Proteins - 0.5 – 1% 

PROPERTIES OF BIOLOGICALMEMBRANE

PROPERTIES OF BIOADHESIVE POLYMERS

(1)Molecular weight, cross-linking density

(2)Charges and ionization (3)Hydrophilic functional groups and hydration (4)chain segment mobility and expanded nature of network

Molecular weight (100,000) α bioadhesive strengthCritical M W required for sufficient bioadhesion

cross-linking density α Diffusion coefficient, chain segment, flexibility, mobility

1

Ex:-Polycarbophil (Mucoadhesive) cross linked with divinyl glycerol

Charges and ionization

Poly anionic are preferred Adhesive strength & cellular toxicity are consideredPoly anions with COOH is used better than those sulphate

Molecular weight

Chain length & cross-linking density

Nature of the polymer /Hydrophilic functional groups and hydration

Hydrophilic functional groups responsible for formation of hydrogen bonds.

Amount of water at the interface between adhesive and substrate important

Presence of fixed charges with the macromolecule network establishes theswelling force,/swelling pressure, osmotic pressure

chain segment mobility and expanded nature of network

Applied pressure α intimacy of the contact

Interpenetration α diffusion

chain segment mobility α degree of hydration, expanded nature of the net work, reduced extent of cross linking

FACTORS IMPORTANT TO

BIOADHESION (1) Polymer related factors - • Molecular weight• Concentration of active polymer(liquids-high concentration BS)

solids-high concentration BS)

• Flexibility of polymer chains• Spatial conformation (2) Environment related factors -• pH• Applied strength

• Initial contact time (ICT α mucoadhesive strength )• Selection of model substrate surface, Swelling (optimum

swelling) (3) Physiological variable - Mucin turn over

Disease states

(Dextrans19,500,000 = ==PEG 200,000) BS

THEORIES OF BIOADHESION

Electronic theoryAdsorption theorywetting theoryDiffusion theoryFracture theory (FORCE)

σm = Fm / Ao σm= max. tensile strengthproducedFm= max. force es of detachmentAo = total surface area

? ? ?

1. Gastrointestinal delivery systems.2. Buccal delivery system3. Sublingual delivery system4. Vaginal delivery system5.   Rectal delivery system6.   Nasal delivery system7.   Ocular delivery system  

DIFFERENT MUCOADHESIVE DRUG DELIVERY SYSTEMS

GASTROINTESTINAL BIOADHESIVE

DRUG DELIVERY SYSTEM • The mucous layer is the first surface

encountered by particulate systems and the adhesive interactions are developed with small polymeric particles either through

Non – specific orSpecific interactions

• Non – specific interactions include vander walls and / or hydrophobic interactions and specific interactions include interactions between complementary structures.

SPECIFIC BIOADHESIONDifferent targets can be identified

within the GIT. These targets are   Mucous glycoproteins (mucins)  Epithelial cells M-cells, Peyer’s patches or gut

associated lymphoidal tissue Absorptive windows (GALT)Abnormal glycoproteins secreted

by cancerous cells (local tumors)

STEPS (non-specific adhesion)

• Step-1: Administration of the colloidal particulate system.

 • Step-2: Adsorption of particles

• Step-3: Mucoadhesion and luminal transit particulates.

 • Step-4: Particulate detachment,

luminal transit and fecal elimination. 

Gastrointestinal delivery systems

Syst

emic

Circ

ulat

ion

Polymeric Carrier

Tight Junction

Mucosa

Protein

Proteolitic Enzymes

EVALUATION OF VARIOUS BIOADHESIVE PROPERTIES

• SHEAR STRESS MEASUREMENT OF BIOADHESIVE POLYMERS :

DETACHMENT FORCE MEASUREMENT

Dynamic Contact Angle Measurement

TENSILE STUDIES ON MUCOADHESIVE POLYMER CONJUGATES (Everted sac tech)

CAHN Force Measurement Technique

OTHER INVITRO METHODS

01) Fluorescent Probe Method

02) Flow Channel Method

03) Falling Liquid Film Method

04) Colloidal Gold Staining Method

INVIVO METHODS

• X-RAY STUDIES FOR MONITORING GI TRANSIT

X-Ray studies on Bioadhesive tablets

X-Ray GI transit monitoring of Radio opaque microspheres

Types of Bioadhesive FormulationsTypes of Bioadhesive Formulations1.Solid Bioadhesive Formulations1.Solid Bioadhesive Formulations: Examples of such formulations are givenbelow.

Tablets :Tablets : Dry formulations such as tablets are able to form strong interactions withmucosal surfaces by attracting water from the mucosal surface. An example isBuccastem® which is used in the treatment of nausea, vomiting and vertigo. It is administered to the buccal mucosa (inside of the cheeks).

Inserts: Inserts: These include ocular inserts such as eye drops and eye gels. An example isPilogel® which is used in the treatment of glaucoma (raised pressure in the eye). Pilogel® contains the bioadhesive agent carbomer 940.

Lozenges: Lozenges: Bioadhesive lozenges containing antibiotics and local anaesthetics can be used topically to treat conditions affecting the mouth. Research has shownthat bioadhesive lozenges are able to release drugs in a controlled manner by prolonging the drug release.

Types of Bioadhesive FormulationsTypes of Bioadhesive Formulations2. Semi-solid bioadhesive Formulations2. Semi-solid bioadhesive Formulations

Gels :Gels :Bioadhesive polymers that are able to form gels include polyacrylic acidpolyacrylic 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. An

advantage of gels is that they are able to form a very close contact with mucosalvery close contact with mucosal

membranesmembranes and rapidly release drugs at their site of absorption.

Films:Films: Bioadhesive films that are flexible in natureflexible in nature can be used to directly deliver

drugs to specific mucosal membranes. They form a very close contact withvery close contact with

the membranethe membrane and are able to deliver an accurate dose of drug to the site of

absorption. An example of a bioadhesive film is Zilactin® which is used in the

treatment of cold sores and mouth ulcers.

Types of Bioadhesive Formulations3.Liquid Bioadhesive Formulations3.Liquid Bioadhesive Formulations

Viscous liquids: Viscous liquids: Viscous liquids containing bioadhesive polymers such as

carboxymethyl cellulosecarboxymethyl cellulose may be used to protect mucosal membranesprotect mucosal membranes from damage

and irritation. They can also be used to deliver drugs to specific sites. An example is

artificial tears, a carbomer solution used to treat dry eyes.

Gel-forming liquids: 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.

Targets for Bioadhesive Formulations

Bioadhesive or mucoadhesive

formulations have been targeted to

various anatomical locations to aid drug

delivery and absorption. TheseThese

structures possess mucous membranesstructures possess mucous membranes

which protect the cell from damage.which protect the cell from damage.

Drug delivery to each anatomical region

is discussed below.

Sites to which bioadhesive formulations Sites to which bioadhesive formulations are targetedare targeted

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

The oral cavity or the mouth comprises of the cheeks, hard and soft palates and the tongue. Some of these functions are impaired by diseases such as ulcers, microbial infections and inflammation.

The oral cavityThe oral cavity

Mouth ulcers, Mouth ulcers,

Oral thrush, Oral thrush,

GingivitisGingivitis

EXAMPLES OF PRODUCTSEXAMPLES OF PRODUCTS

Corlan pellets are used in the treatment of mouth ulcers to mouth ulcers to reduce the painreduce the pain, swelling and inflammationswelling and inflammation associated with mouth ulcers. The active ingredient of the pellet is Hydrocortisone Hydrocortisone succinate.succinate. It also contains the bioadhesive polymer Acacia which helps prolong the effect of the drug in the oral cavity.

•BonjelaBonjela®® This gel is used in the treatment of the soreness associated with mouth mouth ulcers.ulcers.• The gel is applied over the ulcer every three to four hoursevery three to four hours or when needed. •Bonjela® contains hypromellose 4500hypromellose 4500 which lubricates the ulcers .

• Daktarin®Daktarin® oral gel contains the antifungal agent Miconazole Miconazole and is used to treat oral thrushoral thrush. It also contains an adhesive agent known as pregelatinised potato starch which increases the viscosity of the gel and also enables it to stick to the oral mucosa.

• Corsodyl®Corsodyl® oral gel contains the active ingredient chlorhexidine chlorhexidine gluconategluconate and is brushed on the teeth to inhibit the formation of plaque and therefore improve oral hygiene. The gel also contains the bioadhesive polymer Hydroxypropyl cellulose(HPC) which helps retain the gel inside the oral cavity.

The buccal mucosa refers to the inner lining of the lips and cheeksinner lining of the lips and cheeks. The epithelium of the buccal mucosa is about 40-50 cells thick40-50 cells thick and the epithelial cells become flatter as they move from the basal layers to the superficial layers.

The buccal mucosa is less permeableless permeable compared to other oral drug delivery systems and is unable to retain dosage forms at the site of absorption. Theuse of bioadhesive polymers in buccal drug delivery systems allows a bettera betterretention of a dosage formretention of a dosage form by spreading it over the absorption site. Examples of ProductsExamples of Products

• BuccastemBuccastem®® Is a drug used in the treatment of nausea, vomiting and vertigo. It contains the bioadhesive agents Polyvinylpyrrolidone and Xanthan gum. Polyvinylpyrrolidone and Xanthan gum.

• SuscardSuscard®® Is a buccal tablet used in the treatment of angina. It contains the bioadhesive agent (HPMC).(HPMC).

Examples of sublingual products include Glyceryl Trinitrate (GTNGlyceryl Trinitrate (GTN) aerosol spray and tablet which is administered under the tongue for the prophylacticprophylactic treatment of angina.

The Buccal MucosaThe Buccal Mucosa

The sublingual mucosaThe sublingual mucosa

Nasal drug delivery systemcomplex structure

inflamed during conditions such as the common cold, nasal allergies and flu.

Drugs such as antihistamines and steroidsantihistamines and steroids are administered as nasal drops or nasal sprays to treat conditions affecting the nose. However nasal mucociliary clearance mucociliary clearance affects the retention and therefore the effects of the drugs in the nose.

Mucociliary clearance transports mucus from the cells lining the nose and protects the respiratory tract from damage caused by inhaled substances including dirt particles and medicines.

Site of drug

spray &

absorption

a – nasal vestibule d – middle turbinate

b – palate e – superior turbinate (olfactory mucosa)

c – inferior turbinate f – nasopharynx

EXAMPLES OF PRODUCTS EXAMPLES OF PRODUCTS

•RhinocortRhinocort®® Nasal spray is a powdered mixture of the steroid Beclomethasone powdered mixture of the steroid Beclomethasone dipropionate(50dipropionate(50μμg) and 30mg of Hydroxypropyl cellulose(HPC).g) and 30mg of Hydroxypropyl cellulose(HPC). The powder sticks to and swells on The powder sticks to and swells on the cells lining the nosethe cells lining the nose and remains there until approximately six hours after administration.

•BeconaseBeconase®® Nasal spray is used to treat nasal inflammation and nasal allergies associated with hayfever. It contains the active ingredient Beclometasone dipropionateBeclometasone dipropionate and the bioadhesive polymers carboxymethyl carboxymethyl cellulose and microcrystalline cellulose.

Nasacort®Nasacort® Nasal spray is used to treat allergies that result in inflammation of the nose. The active ingredient in this product is Triamcinolone acetonideTriamcinolone acetonide as well as the bioadhesive polymer microcrystalline cellulose.

The polymer swells in the presence of water and is able to spread across the nasal mucosa thus helping the distribution of the drug over the mucosal surface.

Once administered, rapid removal of the

therapeutic agent from the site of

absorption is difficult

Pathologic conditions such as cold or

allergies may alter significantly the nasal

bioavailability

Limitations

Drugs containing polymers attach to the mucinmucin on the conjunctival surfaceconjunctival surface by means of non-covalent bonding. The polymer is able to remain in contact with the surface of the eye until mucin replaces itself or until the pressure of blinking removes the drug from the eye.

A brief anatomy of the eyeA brief anatomy of the eye

Conjunctivitis, Dry eye, GlaucomaConjunctivitis, Dry eye, Glaucoma

Ocular drug delivery system

•Many proteins and peptides that have been investigated for ocular delivery

Ocular Bioadhesive Formulations EXAMPLES OF PRODUCTSEXAMPLES OF PRODUCTS

• HypotearsHypotears® ® and Sno Tears® Sno Tears® Eye drops are used for dry eye and tear deficiency and they generally lubricate the eyes. They both contain the polymer polyvinyl alcohol (PVA) which increases tear productionpolyvinyl alcohol (PVA) which increases tear production and protects the eye from further irritation.

The monomer from which PVA is made Vinyl alcohol

•GelTearsGelTears® and Viscotears®® and Viscotears® Liquid gel eye drops are used for dry eye conditions and contain carbomer 980 (polyacrylic carbomer 980 (polyacrylic acid).acid). Carbomers lubricate the eye by clinging to the surface of the eye.

•PilogelPilogel®® Is an eye gel used in the treatment of glaucoma. It contains the polymer polyacrylic acid. The polymer increases the viscosity of the gel which provides a Prolonged retention of the gel in the eye.

POLYACRYLIC ACIDPOLYACRYLIC ACID

The vagina is the lower part of the female reproductive tract. It is a muscular tube lined with mucous membrane which is covered with a layer of stratified squamous epithelium with an underlying layer of connective tissue (lamina proprialamina propria) .

Vaginal delivery system

Histology of the vaginal mucosaHistology of the vaginal mucosa The female reproductive SystemThe female reproductive System

Vaginitis , Bacterial vaginosis, Candidiasis (Thrush),Vaginitis , Bacterial vaginosis, Candidiasis (Thrush),

ProductProduct Function of Function of ProductProduct

Bioadhesive Bioadhesive AgentAgent

DosageDosage

FormForm

Aci-Jel® Maintains vaginal acidity

Acacia, Tragacanth

Vaginal Gel

Crinone®

Used for Progesterone deficiency

Carbomer Vaginal Gel

Estring®

Restores Oestrogen

deficiency

Silicone Polymers

Vaginal

Ring

Gynol-II®

Spermicidal

Contraceptive

Carboxymethyl

cellulose

Vaginal

Gel

Zidoval®

Treatment of

bacterial

vaginosis

Carbomer Vaginal

Gel

Examples of vaginal productsExamples of vaginal products

VAGINAL BIOADHESIVE SYSTEMS:

1.Bioavailability can be increased

2.Local action of the drugs can be increased

3.For extended periods of time

4.Lower dosing frequency

Polymers included: HPMC,Poly acrylic acid

Rectal delivery system

Bioadhesive polymers are incorporated into rectal suppositories to prolong the retention of the active drug in the rectum.

Prolonged retentionProlonged retention in the rectum increases the chances of reaching a therapeutic outcome.

The drugs absorbed from the rectum can escape breakdown by hepatic enzymes. For this

reason mucoadhesive suppositories have been developed for the local treatment of

diseases such as haemorrhoids and rectal cancer.

EXAMPLES OF PRODUCTSEXAMPLES OF PRODUCTS

• AnacalAnacal®® Is a rectal ointment used to relieve the symptoms associated with haemorrhoids. It contains the bioadhesive agent polyethylene high polymer 1500.

• Germoloids®Germoloids® Is a rectal ointment used to relief the pain, swelling, itchiness and irritation associated with haemorrhoids. It contains the polymer propylene glycol.

• Preparation H®Preparation H® Suppositories help shrink the haemorrhoidal tissue which is swollen by irritation. It contains the polymer polyethylene glycolpolyethylene glycol.

The drug delivery systems used in this case are required to adhere to the skin for the purpose of:

Collecting body fluids Protecting the skin Providing local or systemic drug delivery

Examples of ProductsExamples of Products• VoltarolVoltarol® Emulgel:® Emulgel: This is a gel which provides a local relief from pain and

inflammation in the tendons, muscles and joints. It contains the bioadhesive polymer carbomer carbomer which aids the absorption of the active drug by spreading it into the affected area.

TOPICAL DRUG DELIVERY (TOPICAL DRUG DELIVERY (SKINSKIN))

•Feldene®:Feldene®: This gel is used in the treatment of conditions which are characterised by pain, pain, inflammation and stiffness.inflammation and stiffness. The active ingredient in this formulation is piroxicampiroxicam but the gel also contains two bioadhesive agents to increase its retention at the absorption site. These agents are Carbopol 980 and hydroxyethyl cellulose.Carbopol 980 and hydroxyethyl cellulose.

•Evorel®:Evorel®: Is a patch used in hormone replacement therapyhormone replacement therapy (HRT) for oestrogen deficiency. It consists of an adhesive matrix through which the active drug (estradiol)estradiol) is evenly distributed. The adhesive polymers used are guar gum and polyacrylicguar gum and polyacrylic acid which holds the patch firmly on the skin surface.

• Several properties of chitosan make it potentially valuable as a pharmaceutical excipient.

• Ability to become hydrated and form gels in acidic aqueous environments.

• Chitosan (obtained by deacetylation of chitin) is a cationic polymer that has been proposed for use in microsphere systems by a number of authors. Chitosan was selected as a polymer in the preparation of mucoadhesive microspheres because of its good mucoadhesive and biodegradable properties.

• Mechanism? • Due to swelling of polymers in stomach environment. it will

available to adhere to the mucin in inestine & alg-ca linking will release drug in intestine only.

Mucoadhesive Microspheres

Ex:- Metronidazole mucoadhesive Microspheres

giardiasis, trichomoniasis

Limitations:-

• Practically Uniform & complete coating cannot be ensured in case of microsphere but in case of metro u can get good & near abt uniform coating• Non-reproducibility of release of the content but it can be avoided because it is multiple unit system.• Bulkiness of formulation

Protection against environment (moisture, light, heat&/oxidation)Protection against environment (moisture, light, heat&/oxidation)• Economy• Economy• Stable at gastrointestinal pH.• Stable at gastrointestinal pH.

Able to incorporate drug along with dispersed additive polymer.Able to incorporate drug along with dispersed additive polymer.

Improve the efficiency of the treatment Cure or control condition more promptly Reduce the Improve the efficiency of the treatment Cure or control condition more promptly Reduce the fluctuation in drug level. Improves bioavailabilityfluctuation in drug level. Improves bioavailability

Employ less total drugEmploy less total drug Taste & odour masking Taste & odour masking Minimizing or eliminate local side effects. Minimizing or eliminate local side effects. Reducing the dosing frequency. Reducing the dosing frequency. Minimize drug accumulation. Minimize drug accumulation.

Advantages

• Controlled drug delivery by S.P.Vyas and Roop K. Khar.

• Text book of Novel drug delivery by N.K. Jain

• Pharma info.net• www.online book bank.com• GOOGLE SEARCH