BIOADHESIVE AND MUCOADHESIVE DRUG DELIVERY SYSTEM

PRESENTED

 Introduction  Mechanism of bioadhesion  Factors affecting bio/muco adhesion  Gastro intesinal mucoadhesive drug delivery

Evaluation of mucoadhesion
 Targets for Bioadhesive formulations

Conclusion References

Introduction
Adhesion : sticking of materials with one to another by producing Bond in between them.

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.

Advantages and disadvantages

Adv : 1. Prevents first pass metabolism
2. Increases bioavailability with smaller dosage 3. Prevents enzymatic degradation

Dis adv : 1. Gastric motility

2. Mucin turn over rate 3. Drugs that irritate mucosa cannot be administered by this route

NEED FOR BDDS ??

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

STEPS OF BIOADHESION
BIOADHESION Types:- I, II, III

(1)

Initial contact between the 2 surfaces.

(2) Formation of secondary bonds due to noncovalent interactions.

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

MECHANISM
Mechanisms 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 polymer Step 2 : Interpenetration between the polymer chains and the mucosal membrane Step 3 : Formation of chemical bonds between the entangled chains

Step 1Wetting & swellng

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 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 polymer

Step 2 Interpenetration
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 chains

Bioadhesive polymer chains

Mucus polymer chains

Step 3 Interaction of substrate and polymer

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 bioadhesion

Step 3

FUNDAMENTALS OF BIOADHESION
Molecular events that take place in the interfacial layer depends on the  Properties of biological membrane

Properties of polymer

PROPERTIES OF BIOLOGICALMEMBRANE Mucous composition : water Glycoproteins & lipids Mineral salts Free Proteins 95% 0.5 5% 1% 0.5 1%

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
Molecular weight (100,000) bioadhesive strength Critical M W required for sufficient bioadhesion

Chain length & cross-linking density 1

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

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

Charges and ionization

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

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 the swelling force,/swelling pressure, osmotic pressure

chain segment mobility and expanded nature of network

Applied pressure Interpenetration

chain segment mobility

intimacy of the contact diffusion

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 (Dextrans19,500,000 = ==PEG 200,000) BS (2) Environment related factors pH Applied strength Initial contact time (ICT mucoadhesive strength ) Selection of model substrate surface, Swelling (optimum swelling) (3) Physiological variable Mucin turn over Disease states

THEORIES OF BIOADHESION
???
 Electronic theory  Adsorption theory  wetting theory  Diffusion theory  Fracture theory (FORCE)
m = Fm / Ao m= max. tensile strengthproduced Fm= max. force es of detachment Ao = total surface area

DIFFERENT MUCOADHESIVE DRUG DELIVERY SYSTEMS

1. Gastrointestinal delivery systems. 2. Buccal delivery system 3. Sublingual delivery system 4. Vaginal delivery system 5. Rectal delivery system 6. Nasal delivery system 7. Ocular delivery system

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

SPECIFIC BIOADHESION
Different targets can be identified within the GIT. These targets are  Mucous glycoproteins (mucins)  Epithelial cells  M-cells, Peyers patches or gut associated lymphoidal tissue  Absorptive windows (GALT)  Abnormal glycoproteins secreted by cancerous cells (local tumors)

STEPS (non-specific adhesion) Step-1: Administration particulate system. of the colloidal

Step-2: Adsorption of particles Step-3: Mucoadhesion and luminal transit particulates. Step-4: Particulate detachment, transit and fecal elimination. luminal

Gastrointestinal delivery systems

Tight Junction

Polymeric Carrier

Protein Proteolitic Enzymes

Mucosa

Systemic Circulation

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 Formulations

1.Solid Bioadhesive Formulations: Examples of such formulations are given Formulations below. Tablets : Dry formulations such as tablets are able to form strong interactions with mucosal surfaces by attracting water from the mucosal surface. An example is Buccastem which is used in the treatment of nausea, vomiting and vertigo. It is vertigo administered to the buccal mucosa (inside of the cheeks). Inserts: These include ocular inserts such as eye drops and eye gels. An example is Pilogel which is used in the treatment of glaucoma (raised pressure in the eye). Pilogel contains the bioadhesive agent carbomer 940. Lozenges: Bioadhesive lozenges containing antibiotics and local anaesthetics can be used topically to treat conditions affecting the mouth. Research has shown that bioadhesive lozenges are able to release drugs in a controlled manner by prolonging the drug release.

Types of Bioadhesive Formulations

2. Semi-solid bioadhesive Formulations SemiGels : :Bioadhesive 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. An advantage of gels is that they are able to form a very close contact with mucosal membranes and rapidly release drugs at their site of absorption. Films: Bioadhesive films that are flexible in nature can be used to directly deliver drugs to specific mucosal membranes. They form a very close contact with the 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 Formulations

3.Liquid Bioadhesive Formulations
Viscous liquids: Viscous liquids containing bioadhesive polymers such as carboxymethyl cellulose may be used to protect 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. GelGel-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

Body site
Bioadhesive or mucoadhesive formulations have been targeted to various anatomical locations to aid drug delivery and absorption. These structures possess mucous membranes which protect the cell from damage. Drug delivery to each anatomical region is discussed below. Sites to which bioadhesive formulations are targeted

Systems
Mucoadhesive eye drops / inserts Nasal drug delivery systems Dental gels / buccal systems Patches, tapes, dressings Local vaginal delivery systems Local/systemic rectal delivery systems

Eye Nasal cavity Oral cavity Skin Vagina Rectum

The oral cavity

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.

Mouth ulcers, Oral thrush, Gingivitis

EXAMPLES OF PRODUCTS

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

Bonjela Bonjela

This gel is used in the treatment of the soreness associated with mouth

ulcers. The gel is applied over the ulcer every three to four hours or when needed. Bonjela contains hypromellose 4500 which lubricates the ulcers .

 Daktarin oral gel contains the antifungal agent Miconazole and is

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

Corsodyl

oral gel contains the active ingredient chlorhexidine gluconate 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

The buccal mucosa refers to the inner lining of the lips and cheeks The epithelium cheeks. of the buccal mucosa is about 40-50 cells thick and the epithelial cells become 40flatter as they move from the basal layers to the superficial layers. The buccal mucosa is less permeable compared to other oral drug delivery systems and is unable to retain dosage forms at the site of absorption. The use of bioadhesive polymers in buccal drug delivery systems allows a better retention of a dosage form by spreading it over the absorption site. Examples of Products Buccastem Buccastem Is a drug used in the treatment of nausea, vomiting and vertigo. It contains the bioadhesive agents Polyvinylpyrrolidone and Xanthan gum. Suscard Suscard Is a buccal tablet used in the treatment of angina. It contains the bioadhesive agent (HPMC).

The sublingual mucosa

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

Nasal drug delivery system

complex structure inflamed during conditions such as the common cold, nasal allergies and flu. Drugs such as antihistamines and steroids are administered as nasal drops or nasal sprays to treat conditions affecting the nose. However nasal 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.

a nasal vestibule turbinate b palate turbinate (olfactory mucosa) c inferior turbinate

d middle e superior f nasopharynx

Site of drug spray & absorption

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

Beconase Nasal spray is used to treat Beconase

nasal inflammation and nasal allergies associated with hayfever. It contains the active ingredient Beclometasone dipropionate and the bioadhesive polymers carboxymethyl cellulose and microcrystalline cellulose.

Nasacort Nasal spray is used to treat

allergies that result in inflammation of the nose. The active ingredient in this product is Triamcinolone 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.

Limitations
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

Ocular drug delivery system

Drugs containing polymers attach to the mucin on the conjunctival 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.

Conjunctivitis, Dry eye, Glaucoma Many proteins and peptides that have been investigated for ocular delivery

A brief anatomy of the eye

Ocular Bioadhesive Formulations

EXAMPLES OF PRODUCTS

Hypotears and Sno Tears Eye drops are used for dry Hypotears

eye and tear deficiency and they generally lubricate the eyes. They both contain the polymer polyvinyl alcohol (PVA) which increases tear production and protects the eye from further irritation. The monomer from which PVA is made Vinyl alcohol

GelTears and Viscotears Liquid gel eye drops are GelTears

used for dry eye conditions and contain carbomer 980 (polyacrylic acid). Carbomers lubricate the eye by clinging to the surface of the eye.

Pilogel 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 ACID

Vaginal delivery system

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 propria . lamina propria)

Vaginitis , Bacterial vaginosis, Candidiasis (Thrush),

Histology of the vaginal mucosa The female reproductive System

Examples of vaginal products

Product Function of Product Maintains vaginal acidity Used for Progesterone deficiency Restores Oestrogen deficiency Bioadhesive Agent Acacia, Tragacanth Carbomer Dosage Form Vaginal Gel Vaginal Gel Vaginal Ring

Aci-Jel

Crinone Estring 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 Zidoval GynolII

Silicone Polymers

Spermicidal Carboxymeth Contraceptiv yl e cellulose Treatment of bacterial vaginosis Carbomer

Vaginal Gel

Vaginal Gel

Rectal delivery system

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.

Bioadhesive polymers are incorporated into rectal suppositories to prolong the retention of the active drug in the rectum. Prolonged retention in the rectum increases the chances of reaching a therapeutic outcome.

EXAMPLES OF PRODUCTS

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

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

Suppositories help shrink the haemorrhoidal tissue which is swollen by irritation. It contains the polymer polyethylene glycol glycol.

TOPICAL DRUG DELIVERY (SKIN) (SKIN)

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 Products
Voltarol Emulgel: This is a gel which provides a local relief from pain and Voltarol
inflammation in the tendons, muscles and joints. It contains the bioadhesive polymer carbomer which aids the absorption of the active drug by spreading it into the affected area.

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

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

Mucoadhesive Microspheres Ex:- Metronidazole mucoadhesive Microspheres giardiasis, trichomoniasis

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.

Advantages
Protection against environment (moisture, light, heat&/oxidation) Economy Stable at gastrointestinal pH. Able to incorporate drug along with dispersed additive polymer. Improve the efficiency of the treatment Cure or control condition more promptly Reduce the fluctuation in drug level. Improves bioavailability Employ less total drug Taste & odour masking Minimizing or eliminate local side effects. Reducing the dosing frequency. Minimize drug accumulation.

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

 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