BIOADHESIVE DRUG DELIVERY SYSTEMSbyCHIRUMAMILLA SIRI KALYAN1st year M.Pharmacy

Under the guidance of Asst. Prof. Miss Harini

SREE DATTHA INSTITUTE OF PHARMACY

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Contents Intoduction

Bioadhesion and Mucoadhesion

Mechanisms of bioadhesion

Theories of bioadhesion

Evaluation of bioadhesive interactions

Bioadhesive Polymers

Applications of bioadhesive polymers

References

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The term bioadhesion refers to either adhesion between two biological materials or adhesion between some biological material (including cells, cellular secretions, mucus, extracellular matrix, and so on) and an artificial substrate (metals, ceramics, polymers, etc.)

In terms of the pharmaceutical industry, bioadhesion generally refers to adhesion between a polymer-based delivery system and soft tissue in the presence of water

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Bioadhesion

The advantages of using BDDS over traditional dosage forms include

The ability to optimize the therapeutic effects of a drug by controlling its release into the body; Lower and more efficient doses;Less frequent dosing;Better patient compliance;Flexibility in physical state, shape, size, and surface;The ability to stabilize drugs and protect against hydro-Iytic or enzymatic degradation The ability to mask unpleasant taste or odor

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Advantages Of BDDS

Bioadhesion and Mucoadhesion

Targets of orally administered BDDS

• Epithelial cell layer• continuous mucus layer• combination of both

Bioadhesion

Mucoadhesion

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Mechanisms of Bioadhesion

Step 1 : wetting and swelling of polymer to permit intimate contact with biological tissue

Step 2 : interpenetration of bioadhesive polymer(BP) chains and entanglement of polymer and mucin chains

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Step 3 : Formation of chemical bonds between the entangled chains

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Chemical bonds can include strong primary bonds (i.e., covalent bonds) as well as weaker secondary forces such as ionic bonds, Van der Waals' interactions, and hydrogen bonds.

Theories of Bioadhesion

Although the chemical and physical basis of mucoadhesion are not yet well understood, There are six classical theories adapted from studies on the performance of several materials and polymer-polymer adhesion which explain the phenomenon

Electronic theory

Adsorption theory

Wetting theory

Diffusion theory

Fracture theory 8

Electronic theory is based on the premise that both mucoadhesive and biological materials possess opposing electrical charges. Thus, when both materials come into contact, they transfer electrons leading to the building of a double electronic layer at the interface, where the attractive forces within this electronic double layer determines the mucoadhesive strength (Mathiowitz, Lehr, 1999).

Electronic Theory

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According to the adsorption theory, the mucoadhesive device adheres to the mucus by secondary chemical interactions, such as in van der Waals and hydrogen bonds, electrostatic attraction or hydrophobic interactions. For example, hydrogen bonds are the prevalent interfacial forces in polymers containing carboxyl groups.Such forces have been considered the most important in the adhesive interaction phenomenon because, although they are individually weak, a great number of interactions can result in an intense global adhesion

Its most widely accepted theory

Adsorption Theory

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The wetting theory applies to liquid systems which present affinity to the surface in order to spread over it. This affinity can be found by using measuring techniques such as the contact angle. The general rule states that the lower the contact angle then the greater the affinity . The contact angle should be equal or close to zero to provide adequate spread ability

Wetting Theory

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The Diffusion Theory

Diffusion theory describes the interpenetration of both polymer and mucin chains to a sufficient depth to create a semi-permanent adhesive bond It is believed that the adhesion force increases with the degree of penetration of the polymer chains. This penetration rate depends on the diffusion coefficient, flexibility and nature of the mucoadhesive chains, mobility and contact time. According to the literature, the depth of interpenetration required to produce an efficient bioadhesive bond lies in the range 0.2-0.5 μm.

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The Fracture Theory

The most useful theory for studying bioadhesion through tensile experiments has been the fracture theory, which analyzes the forces required to separate two surfaces after adhesion. The maximum tensile stress (aM) produced during detachment can be determined by dividing the maximum force of detachment, Fm, by the total surface area (A0) involved in the adhesive interaction:

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Methods to Evaluate Bioadhesive Interactions

In Vitro Techniques

Tests measuring mucoadhesive strength

Measuring the force required to break the binding between the model membrane and the mucoadhesive. Depending on the direction in which the mucoadhesive is separated from the substrate, is it possible to obtain the detachment, shear, and rupture tensile strengths (Hägerström, 2003)

The force most frequently evaluated in such tests is rupture tensile strength

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Texture Analyzer

Here the force required to remove the formulation from a model membrane is measured, which can be a disc composed of mucin (Bruschi et al., 2007), a piece of animal mucous membrane, generally porcine nasal mucus (Hägerström, 2003) or intestinal mucus from rats.

This method is more frequently used to analyze solid systems like microspheres

It also evaluates the texture of the formulations and assess other mechanical properties of the system.

The Wilhelmy plate technique

Its used for dynamic contact-angle measurement and involves a microbalance or tensiometer. A glass slide is coated with the polymer of interest and then dipped into a beaker of synthetic or natural mucus. The surface tension, contact angle, and adhesive force can be automatically measured using available software

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Microforce Balance

A unique microsphere is attached by a thread to the stationary microbalance. The chamber with the mucous membrane is raised until it comes into contact with the microsphere and, after contact time, is lowered back to the initial position, yielding both contact angle and surface tension.

The shear test measures the force required to separate two polymer-coated glass slides joined by a thin film of natural or synthetic mucus. The results of this technique often correlate well with in vivo test results

Shear test

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In Vivo Techniques

In vivo measurements of GI bioadhesive performance involve administering BPs to laboratory animals and monitoring their transit rate through the gut.

They are orally force-fed by gavage surgically implanted in the stomachinfused with a perfusion pump through an in situ loop of the small intestine

monitored transit using radiopaque markersradioactive elements fluorescent labeling techniques

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Bioadhesive Polymers

First generation mucoadhesive materials

These materials are natural or synthetic hydrophilic molecules containing numerous organic functions that generate hydrogen bonds such as carboxyl, hydroxyl and amino groups, which do not adhere specifically onto several surfaces.These polymers can be subdivided into three classes:

•Cationic

•Anionic

•Nonionic

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Cationic polymers These can interact with the mucus surface, since it is

negatively charged at physiological pH. E.g.. chitosan

Anionic polymers mucoadhesion results from physical-chemical processes,

such as hydrophobic interactions, hydrogen and van der Waals bonds.

Eg: polyacrylic acid (carbomers) carboxymethylcellulose alginates.

Nonionic polymers. Eg. Hydroxypropylmethylcellulose Hydroxyethylcellulose methylcellulose

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Hydrogels

Hydrogels are three-dimensional and hydrophilic polymer networks capable of swelling in water or biological fluids and retaining a large amount of fluids in the swollen state.They have ability to gelify in situ after exposure to an external stimulusThey can be classified as

*Thermosensitive, e.g. Poloxamers and carbomers*Ph sensitive, e.g. Polyacrylic acid, presenting increased viscosity at higher ph values*Glucose sensitive, e.g. Polymers linked to concavalin A, *Electric signal sensitive e.g. Polymethacrylic acid * Light sensitive, like hyaluronic acid (qiu, park, 2001)*Ionic concentration sensitive, such as gellan gum (hagerstrom et al., 2000)

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Second generation mucoadhesive materials

An ideal polymer should exhibit the ability to incorporate both hydrophilic and lipophilic drugs, show mucoadhesive properties in its solid and liquid forms, inhibit local enzymes or promote absorption, be specific for a particular cellular area or site, stimulate endocytosis and finally to have a broad safety range

•Lectins,

•Invasins,

• Fimbrial proteins (woodley, 2001),

•Antibodies (chowdary, rao, 2004)

• Those obtained by the addition of thiol groups

to known molecules

Possible means of administration for BDDSs include

occularrespiratorybuccalnasalGIrectalurethralVaginal

GI bioadhesive devices that can be administered orally are of considerable interest owing to the ease of administration and targeted contact with the absorbing intestinal epithelium

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Applications of Bioadhesive Polymers

Common BDDS shapes and forms used in current research efforts have includes

Bioadhesive patches (buccal and transdermal)

Bioadhesive tablets (buccal, gingival, vaginal)

Bioadhesive powers (mouth)

Bioadhesive gels (eye, mouth, rectum, vagina, open wounds)

Bioadhesive microsperes (GI track)

Bioadhesive liposomes25

Mucoadhesive Tablets

Mucoadhesive tablets have been developed to increase the retention of drug in GIT and/or to keep a sustained release of drug towards the medium from where it is constantly removed.

Thus, treatment of many diseases is done.

These mucoadhesive formulations offer many advantages in comparison to traditional treatments against dental and buccal diseases and disturbances.

The microbeads are made from a hydrogel polymer specifically developed for use as a temporary pre-meal gastric bulking agent.

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The development of efficient orally delivered BDDSs could enable the following four important effects:

1. enhanced bioavailability and effectiveness of drug due to targeted delivery to a specific region of the GI tract

2. maximized absorption rate due to intimate contact with the absorbing membrane and decreased diffusion barriers

3. improved drug protection by polymer encapsulation and direct contact with absorbing cell layers

4. longer gut transit time resulting in extended periods for absorption

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are most commonly prepared by the solvent casting technique in which various substrates including mercury, Teflon, glass and aluminium are used for film formation.

Among these substrates, mercury was found to give best results.

Mucoadhesive Buccal Films

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Mucoadhesive microspheres

Microsphere are small spherical particles, with diameters in the micrometer range (typically 1 μm to 1000 μm (1 mm)).

have advantages of efficient absorption and enhanced bioavailability of drugs, a much more intimate contact with the mucus layer, and specific targeting of drugs to the absorption site.

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Mucoadhesive Microparticles

Microparticles are particles between 0.1 and 100 μm in size.

Mucoadhesive microparticles is an improved drug delivery system which are believed to bind to the mucus layer coating the stomach and other regions of the GIT.

These mucoadhesive microparticles bind to the mucus layer leading either to slow release into the GIT or direct delivery to the gastrointestinal mucosa.

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Mucoadhesive Microcapsules

Micro-encapsulation is a process in which tiny particles or droplets are surrounded by a coating to give small capsules many useful properties. In a relatively simplistic form, a microcapsule is a small sphere with a uniform wall around it.

Mucoadhesive microcapsules are a type of controlled-release dosage form.

They offer numerous benefits including reducing stress resulting from restraint, handling, and dosing .

Avoiding expensive or difficult drug administration procedures.

They can be used for vaginal administration to treat vaginal infections and to increase patient convenience. 31

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References

Encyclopedia Of Controlled Drug Delivery by Edith Mathiowitz

Encyclopedia Of Pharmaceutical Technology Third Edition

edited by James Swarbrickpg. no . 2021 - 2039Novel Drug Delivery Systems, Second Edition

By Yie W. Chienpg. no. 197 - 228

Braz. J. Pharm. Sci. vol.46 no.1 São Paulo Jan./Mar. 2010