INTRODUCTION:

Mucoadhesion, or attachment of a natural or synthetic polymer to a biological substrate, is a practical method of drug immobilization or localization and an important new aspect of controlled drug delivery. The motivation for controlled drug release is the necessity to maintain a constant effective drug concentration in the body for an extended time period. A mucoadhesive controlled release device can improve the effectiveness of a drug by helping to maintain the concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids and allowing targeting and localization of a drug at a specific site. A drug can be incorporated into a crosslinked polymeric device that would adhere to a mucous substrate in the body.^1-4

Factors affecting mucoadhesion ^{5, 6}

A. polymer related factors - Molecular weight, concentration of active polymer, flexibility of polymer chains, spacial confirmation and swelling

B. Environment related factors - pH of polymer- substrate interface, applied strength and initial contact time

C. physiological factors - Mucin turnover and disease state

Mechanisms of bioadhesion ^{7, 8}

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

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. Swelling of polymers occurs because the components within the polymers have an affinity for water as shown in Figure 1.

Step 2

The surface of mucosal membranes is 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 as shown in Figure 2.

Step 3

This step involves the formation of weak chemical bonds between the entangled polymer chains (Figure 3). 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.

General theories of bioadhesion ^{9, 10}

(i) The electronic theory is based on the assumption that the adhesive material and the target tissue have different electronic structures. When both surfaces come in contact, electron transfer occurs causing the formation of a double layer of electric charge at the interface.

(ii) The adsorption theory states that the bioadhesive bond is formed due to Van der Waals interactions, hydrogen bonds, and related forces. Although the individual forces are weak, the high number of interaction sites can produce intense adhesive strength.

(iii) The wetting theory was developed predominantly with regard to liquid adhesives. It uses interfacial tension to predict spreading and in turn adhesion.

(iv) The diffusion theory supports the concept that interpenetration and entanglement of bioadhesive polymer chains and mucus polymer chains produce semi permanent adhesive bonds. It is believed that the bond strength increases with the degree of the polymer chain penetration into the mucus layer.

(v) The fracture theory analyzes the forces required to separate two surfaces after adhesion. It is therefore most applicable to studying bioadhesion through mechanical measurements. When determining fracture properties of an adhesive union from separation experiments, failure of the adhesive bond must be assumed to occur at the bioadhesive interface.

Figure 1 - Wetting and swelling of a polymer

Figure 2 - The interpenetration of polymer chains

EVALUATION OF MUCOADHESION^11-14

A. In Vitro Assessment of Mucoadhesion:

1. Methods Based on Measurement of Adhesion Strength:

The adhesion strength method measures the force required to break the adhesive bond between a model membrane and the test bioadhesive. Ponchel et al. used a tensile apparatus to determine the bond strengths of poly (acrylic acid) – hydroxy propyl methyl cellulose tablets. In the bioadhesion test, animal tissue surface and the tablet surface were brought together with an initial force and separated under constant rate of extension. The detachment force or adhesion strength and the work of adhesion were determined when the tablet and tissue were pulled apart.

2. Methods Based on Measurement of Shear Strength:

Shear stress measures the force that causes the bioadhesive to slide with respect to the mucus layer in a direction parallel to their plane of contact. Smart et al. developed this technique for measuring mucoadhesion. Their initial test system was developed wherein a suspension of ion exchange resin particles flowed over the inner mucosal surface of a section of guinea pig intestine, and the adhering weight was determined

Figure 3 – Mechanism of bioadhesion

3. Bioadhesion Test Using Non biological Substances:

Chen and Cyr had performed in vitro bioadhesion testing using non biological substrates. A sample intraoral bandage was attached to wet dialyzing cellophane membrane representing the gingiva. The force for separation was measured as a quantitative expression of wet adhesive strength.

4. Fluorescent Probe Method:

Park and Robinson developed a fluorescent probe method to study polymer interaction with a conjunctival epithelial cell membrane. The experiment consisted of adding a fluorescent liposoluble probe, pyrene, which localizes in the lipid bilayer of the cell membrane, to a suspension of cultured human conjunctival epithelial cells. The cells were then mixed with various bioadhesive polymers.

5. In Situ Method:

Ranga Rao and Buri developed a simple, quantitative, and realistic in situ method to test the bioadhesive potential of polymers. In this technique, glass spheres or drug crystals were first coated with the polymer to be tested. Later, known amounts of these coated particles were placed on rat jejunum or stomach and kept in a humid environment. The tissue was then washed with phosphate buffer or dilutes HCl at a constant rate. The percent of particles retained on the tissue was considered as an index of bioadhesion.

6. Organ Culture Technique:

Needleman and Smales utilized an organ culture technique to examine the duration of adhesion on carefully maintained mucosal tissue. In their study, an organ culture was used to maintain hamster cheek pouch mucosa, submerged on stainless steel grids in a growth medium. Small quantities of adhesive gels were syringed onto the mucosal surface. The duration of adhesion was assessed by retention to the gel.

7. Ligand Receptor Binding Method:

For natural bioadhesive polymers, because some possess unique characteristics as bioadhesive histological methods that determine lectin receptors presenting on the oral mucosal surfaces can be utilized to assess lectin mucoadhesive property. Nantwi et al. studied the binding of lectin to mucosal surfaces by using a solution containing a range of lectins exposed to the surface of unprocessed mucosal cells.

8. Flow Channel Methods:

Flow channel methods utilize a thin channel filled with bovine submaxillary mucin. A particle of a bioadhesive polymer was placed on the mucin gel, and its static and dynamic behavior monitored.

9. Falling Liquid Film Method:

Small intestinal segments from the rat were placed at an inclination on a tygon tube flute. The adhesion of particles to this surface was monitored by passing a particle suspension over this surface.

10. Colloidal Gold Staining Method:

This technique utilizes red colloidal gold particles that have been stabilized by an adsorbed mucin molecule (mucin gold conjugate). Bioadhesive hydrogels develop a red color on the surface upon interaction with the mucin gold conjugate. The interaction was measured either by intensity of the red color on the hydrogel surface or by a decrease in the concentration of conjugates from the absorbance changes.

11. Thumb Test:

A simple way that can be used to identify mucoadhesive is the difficulty of pulling the thumb from the adhesive and as a function of pressure and contact time.

12. Viscometric Method:

Viscosity of porcine gastric mucin dispersion was measured in different polymer solutions. The mucin polymer bioadhesive bond strength was quantified and the force of adhesion calculated.

B. In Vivo Assessment of Mucoadhesion:

They mainly focus on the duration time of adhesion of the bioadhesive using humans as subjects. In this case, the criteria of choosing a particular subject, the mucosal sites chosen, the bioadhesive formulation, and a variety of other factors that may affect the in vivo results need to be considered when the experiment is designed.

Bioadhesive polymers:^{15, 16}

A polymer is a substance formed by the linkage of a large number of small molecules known as monomers. A bioadhesive polymer is a synthetic or natural polymer which binds to biological substrates such as mucosal membranes. Such polymers are sometimes referred to as biological ‘glues’ because they are incorporated into drugs to enable the drugs to bind to their target tissues.

Examples of polymers:

Bioadhesive polymers come from both natural and synthetic sources, some common examples are highlighted below:

1. Acacia gum - This natural polymer is a dried gum obtained from the stem and branches of the tree Acacia senegal.

2. Alginic acid – Is a natural polymer found in the cell walls of brown algae. It is widely used in the manufacture of alginate salts such as sodium alginate which is a constituent of Gaviscon liquid®.

3. Carbomers – are polyacrylic acid polymers widely used in the pharmaceutical and cosmetic industries as thickening agents. Carbomers have a huge advantage in formulation science because they adhere strongly to mucosal membranes without causing irritation, they exhibit low toxicity profiles and are compatible with many drugs.

4. Hydroxypropyl methylcellulose (HPMC) – This polymer is included in preparations used to moisten contact lenses and in oral gels.

5. Sodium hyaluronate - A high molecular weight biological polymer made of repeating disaccharide units of glucuronic acid and N-acetyl-D - glucosamine. This polymer is used during intraocular surgery to protect the cornea and also acts as a tear substitute in the treatment of dry eyes.

Other examples of polymers include:

Pectin, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP) and tragacanth

Characteristics of Bioadhesive polymers:¹⁷

In order for polymers to adhere to mucosal surfaces or epithelial cell they must ideally possess certain characteristics:

1. Flexibility - The flexibility of bioadhesive polymers is important because it controls the extent of the interpenetration between the polymers and mucosal/epithelial surfaces.

2. 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 - 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 - Polymers with a high molecular weight are desirable because they provide more available bonding sites.

5. Surface tensions - Surface tensions are needed to spread the bioadhesive polymer into the mucosal layer epithelial surface.

Several mucosal routes have been investigated over the last decades as alternatives to oral and parenteral drug administration, including nasal, buccal, rectal, ocular, pulmonary, and vaginal mucosa as shown in Figure 4. Their advantages are the easy accessibility and circumvention of the hepatic first pass metabolism. ^18,
19

Figure 4 - Various potential mucosal pathways for systemic delivery of therapeutic agents, which bypass the hepatic first pass clearance associated with oral administration.

1) Nasal drug delivery:

The nasal cavity offers a number of unique advantages such as easy accessibility, good permeability especially for lipophilic, low molecular weight drugs, avoidance of harsh environmental conditions and hepatic first pass metabolism, potential direct delivery to the brain, and direct contact for vaccines with lymphatic tissue and action as inducer as well as effector of the mucosal immune system. The nasal epithelium is well suited for the transmucosal drug delivery although it is less permeable for hydrophilic and high molecular weight drugs.

Several nasal dosage forms are under investigation including solutions (drops or sprays), gels, suspensions and emulsions, liposomal preparations, powders and microspheres, as well as inserts.

Examples of products are

Rhinocort® Nasal spray is a powdered mixture of the steroid Beclomethasone dipropionate(50μg) and 30mg of Hydroxypropyl cellulose(HPC).

Beconase® Nasal spray is used to treat 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.

2) Oral drug delivery: ²⁰

The oral cavity is lined by a stratified squamous epithelium. The epithelium has a cornified surface in regions subject to mechanical forces during mastication, which resembles that of the upper epidermis in the skin. Non-keratinized epithelium occupies approximately 60% of the total oral cavity including the buccal, lingual, and sublingual mucosa and is of interest for systemic drug delivery. Although non keratinized, the buccal mucosa contains intercellular lipids which are responsible for its physical barrier properties resulting in poor permeability for larger drugs, especially for peptides and proteins. Dosage forms for buccal drug delivery include tablets, patches, films, lozenges, sprays, hydrogels, lollypops, chewing gums, powders, solutions, a freeze-dried sublingual dosage form wafers and liposomal formulations.

Common conditions affecting the oral cavity are Mouth ulcers, Oral thrush and Gingivitis.

Examples of products are

Corlan® Corlan pellets are used in the treatment of mouth ulcers to reduce the 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® 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 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.

2a.The Buccal Mucosa:^{21, 22}

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 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 are

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

Suscard® Is a buccal tablet used in the treatment of angina. It contains the bioadhesive agent hydroxy propyl methyl cellulose.

2b.The sublingual mucosa:

The sublingual mucosa surrounds the sublingual gland which is a mucin-producing salivary gland located underneath the tongue. This mucosa is relatively permeable and gives a rapid absorption of many drugs due to its excellent blood supply. The sublingual route of drug delivery is convenient, accessible and generally well accepted by patients.

Drugs administered via the sublingual route are formulated as tablets, powders, solutions or aerosol sprays. This route is appropriate for many drugs as long as the drug is able to go into solution with saliva in the mouth.

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

3) Ocular drug delivery:-

Ocular delivery of drugs is typically for the treatment of ocular inflammation, corneal wounds, and glaucoma. In addition, this route has been investigated for the systemic delivery of peptides and proteins.

The local drug delivery is restricted by the dynamics of the lachrymal drainage system, which is the natural defense mechanism of the eye. This system introduces tear fluid to the eye and rapidly drains the fluid together with any instilled formulation from the precorneal area to the nasal cavity and throat. The high elimination rate results in short duration of contact of the drug with its absorption sites and consequently in a low local bioavailability. Increased ocular bioavailability can be achieved by the use of viscosity enhanced aqueous eye drops, suspensions, oily drops and unguents, mucoadhesive ocular delivery systems such as solutions and microparticle suspensions, in-situ gelling systems triggered by pH, temperature, or ions, colloidal delivery systems such as liposomes and nanoparticles, and ocular inserts.

Some conditions of the eye are Conjunctivitis, Dry eye and Glaucoma and examples of products are

Hypotears® and 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 production and protect the eye from further irritation.

GelTears® and Viscotears® Liquid gel eye drops are used for dry eye conditions and contain carbomer 980 (polyacrylic acid). Carbomers lubricate the eye by clinging to the surface of the eye. This can help reduce the frequency of their application into the eye.

Pilogel® Is an eye gel used in the treatment of glaucoma. It contains the high molecular weight polymer polyacrylic acid. The polymer increases the viscosity of the gel which provides a prolonged retention of the gel in the eye.

4) Pulmonary drug delivery:-

Direct delivery of drugs to the lung by inhalation for the local treatment of respiratory diseases grew rapidly in the second half of the 20^th century as a result of the availability of effective asthma drugs in convenient, portable devices. The lung offers a number of advantages which render it also a suitable organ for systemic drug delivery: a large surface area of about 150 mm² and an extremely well vascularized, thin epithelium. Thus, various drugs including peptides and proteins (e.g. insulin, human growth hormone, luteinizing hormone releasing hormone analogue, glucagon, calcitonin) have efficiently been delivered via the lung.

A number of technologies for the delivery of drug formulations have been developed

(i) Pressurized metered dose inhalers using propellants to deliver micronized drug suspensions (Autohaler, Spacehaler)

(ii) Dry powder inhalers which dispense micronized drug particles with / without carrier (lactose) by inhalation activation (Spinhaler, Rotohaler, Diskhaler), and

(iii) Nebulizers and aqueous mist inhalers which aerosolize drug solutions using compressed air or ultrasound (AERx, Respimat).

5) Rectal drug delivery:²³-

The lower digestive tract is less harmful to administered drugs than the stomach and the small intestine due to the lower enzymatic activity and neutral pH. Also the rectal route of drug administration is safe and convenient, although the acceptance can be low in other states, particularly among adults. This may be overcome by the use of colon-specific drug targeting via the peroral route, which is under intensive investigation.

Traditional rectal dosage forms are suppositories, unguents and creams, as well as enemas. More recent studies have evaluated thermogelling dosage forms, gels, osmotic mini pumps and hard gelatin capsules as rectal drug delivery system.

Examples of products are

Anacal® Is a rectal ointment used to relieve the symptoms associated with 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

6) Vaginal drug delivery:-

The large surface area, rich blood supply and permeability to a wide range of compounds including peptides and proteins make the vagina also attractive for systemic drug administration. The vaginal route has also the potential for uterine targeting of active agents such as progesterone and danazol commonly used dosage forms are creams, gels, tablets, capsules, pessaries, foams, films, tampons, vaginal rings, and douches. Limitations of systemic vaginal drug delivery next to the physiological barriers are also the gender specificity and the relatively low convenience.

Common vaginal infections are Vaginitis,Candidiasis (Thrush)and Trichomoniasis

Vaginal bioadhesive formulations are

Zidoval® Crinone® Estring® Gynol-II® and Aci-Jel®

7. Topical drug delivery:^{24, 25}

The skin is the outer covering of the body and consists of different layers. It performs several functions which include:

Protecting the body from injury and invasion by pathogens

Preventing the body from becoming dehydrated

Regulating body temperature

Production of Vitamin D

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 and providing local or systemic drug delivery. Adhesion can be described as the formation of a new mechanical bond between the skin and the adhesive agent. Bioadhesive products targeted to the skin are formulated into different dosage forms which include liquids, powders and semi-solids such as ointments and transdermal patches.

Transdermal patches are sustained-release devices that release a specific amount of drug whilst firmly attached to the skin. They must provide a firm, soft contact with the skin but also allow the patch to be easily removed with minor effort.

Examples of Products are

Voltarol® 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 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 adhesive polymers used are guar gum and polyacrylic acid which holds the patch firmly on the skin surface.

Types of Bioadhesive Formulations:^{26, 27}

1. Solid Bioadhesive Formulations:

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 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, which minimises irritation and prevents the loss of product by keeping the gel in place.

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.

2. Semi-solid bioadhesive Formulations:

Gels: 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.

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.

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.

Recent developments ^{28, 29}

Recent work in the area of bioadhesion shows promising evidence to support the diffusion theory of adhesion for both crosslinked and uncrosslinked polymers. Grafting mucophilic copolymers onto the backbone of a crosslinked polymer has been found to increase the mucoadhesive capacity of some polymers. The grafted polymer chains are able to diffuse from the network and into the mucus layer to aid in the bioadhesion process.

When the hydrogel system comes into contact with mucus, over time the concentration gradient across the interface is expected to cause the free mucophilic chains of the mucoadhesive device to diffuse from the network into the mucous layer, while the glycoprotein chains of the mucus diffuse into the polymer. This phenomenon acts to reinforce the attachment of the device to the mucus.Several different methods of preparing the polymers have been investigated in order to limit the amount of unreacted and crosslinked monomer the remained in the networks following polymerization.

When the microparticles are used in a drug delivery device, it is necessary to enclose the dry particles in the capsule of a substance that dissolves only at the pH of the intestinal fluid. Assuming that the dissolution of the coating is rapid, the particles would not be swollen to a large extent when they come into contact with the mucus that lines the G I tract.

CONCLUSION:

The concept of bioadhesion involves the binding of a natural or synthetic bioadhesive polymer to biological substrates such as mucous membranes. Bioadhesive drug delivery systems have been available since the late 1940s and have become an important route of delivering drugs. The earlier applications of bioadhesive formulations mainly involved the oral cavity and the gastrointestinal tract. These days’ bioadhesive drug delivery systems have been developed to target a wider variety of mucosal and epithelial surfaces; these include the vagina, the skin and the nasal cavity. In most instances bioadhesive formulations are preferred over the conventional methods of drug delivery. This is because bioadhesion allows the retention of the active drug over the mucosal surface and prolongs the contact time between the polymer and mucosal surface. Bioadhesive drug delivery also offers a controlled release of drugs. From a patient’s point of view this is ideal because the frequency of drug administration is reduced which in turn improves patient compliance.

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Received on 24.06.2009 Modified on 20.08.2009

Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 25-31