INTRODUCTION:

Mucoadhesive drug delivery system is oldest and effective dosage form for various categories of drugs. For delivering drug to biological system Mucoadhesion means adhesion between polymer and biological membrane¹ The biological membrane can be epithelial tissue. If adhesive attachment is to a mucus layer, concept is referred to as Mucoadhesion. Mucoadhesion is relatively new and emerging concept in drug delivery²

Mucoadhesion always connect formulation to the mucus membrane. There are various mucosal routes for drug delivery such as³

· Buccal /oral route

· Nasal route

· Ocular route

· Vaginal route

· Gastrointestinal route

Buccal route involves the administration of the number of drug through the buccal mucosal membrane lining of the oral cavity. It provides good environment for drugs, mostly high molecular weight substances like proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a little milder environment for drug absorption same like other oral routes of absorption⁴. Various effective Mucoadhesive dosage forms have been developed for a variety of drugs. Number of peptides, including thyrotropin releasing hormone octreotide, leuprolide, insulin, and oxytocin, have been delivered via the mucosal route⁵

Bioadhesion and Mucoadhesion:

Bioadhesion’ means adhesive interactions with any biological or biologically derived substance. For the drug delivery, bioadhesion is utilized to construe the adhesion between synthetic or natural polymers and mucosal soft tissues. ‘Mucoadhesion’ can be used when the bond with a mucosal surface is formed⁶. Mucoadhesion means two components, one from the biological source, are joined together for prolonged periods of time by the aid of interfacial forces. Bioadhesion can be classified into

Three types:

· Adhesion between two different biological phases.

· Adhesion of a biological membrane to an artificial substrate.

· Adhesion of an artificial material to a biological substrate⁷

Mechanism of Mucoadhesion:

It consists of Contact stage, Consolidation Stage and Interpenetration Stage. In Contact stage the wetting and then swelling step ensues when the polymer spreads over the mucosal membrane in order to establish an intimate contact with the substrate. Polymer swells because the polymer components have an affinity for water⁸. In interpenetration stage the mucous membrane surface has high molecular weight polymers called glycoprotein. In second step of the bioadhesive bond formation, the mucosal polymer chains and the bioadhesive polymer chains intermingle and embrangle to form adhesive bonds⁹. In Consolidation stage the activation of mucoadhesive materials occur in presence of moisture where the mucoadhesive molecules break free and link up again by weak Van der Waals and hydrogen bonds. Basically, two theories explain the consolidation step: the theory of

diffusion and the theory of dehydration¹⁰.

Figure 1: Two Step Mucoadhesion Process Figure 2: Dehydration theory of Mucoadhesion

Advantages:

1. It has prolonged residence time at the site of absorption which increases bioavailability.

2. It has good accessibility, rapid onset of action and low dosing frequency.

3. Drugs are protected from degradation in acidic media in Gastrointestinal Track.

4. It has Quick absorption because of high blood supply and good perfusion rate.

5. It shows better patient compliance than other oral formulation.

6. Maximum utilization of drug enables reduced total quantity of drug administration.

7. Increases safety margin for highly potent drug due to improved control of plasma level concentration.

8. Mucoadhesive Drug Delivery system can be used in Unconscious and less co-operative patients¹¹

Disadvantages:

1. Drug having unplseant taste, odors, or nauseating drugs cannot be given by these routes.

2. Only drugs having low dose can be given by this route.

3. Drugs whose absorption is by passive diffusion can only be administered by this route.

4. Over hydration may structurally disrupt the formulation or forms slippery surface due to swelling and hydration of the bioadhesive polymers.

5. Patients feel discomfort in eating, drinking and speaking¹²

Overview of the Oral Mucosa:

Structure

The oral mucosa is made up of squamous stratified epithelium cells, basement membrane, the lamina propria and submucosa. It also contains various sensory receptors which includes the taste receptors of the tongue. The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains fewer amounts of cells¹³. The permeability of the buccal mucosa is 4-4000 times greater than cutaneous tissues. So the order of permeabilities of the oral mucosa decreases like sublingual greater than buccal and buccal greater than palatal. This order is based on the relative thickness and degree of keratinization of these tissues. The sublingual mucosa is relatively thin and non-keratinized, the buccal mucosa is thicker and non-keratinized, and the palatal intermediate in thickness but keratinized¹⁴. The cells of the oral epithelia are surrounded by an intercellular ground substance, mucus, the major components of which are complexes made up of carbohydrates and proteins. These complexes may be free and few are attached to certain regions on the cell surfaces. These layers may actually play a role in cell-cell adhesion, as well as acting as a lubricant, allowing cells to move relative to one another¹⁵.

Figure 3: Structure of Oral Mucosa

Composition of Mucus Layer:

Mucus consist of translucent and viscus secretion which forms a thin, contentious gel, mean thickness of this layer varies from about 50-450 μm in humans secreted by the globet cells lining the epithelia. It has the following general composition¹⁶.

- Water -95%

- Glycoprotein and lipids – 0.5-3.00%

- Mineral salts – 1%

- Free proteins – 0.5-1.0%

Functions of Mucus Layer:

It acts as protective, protect from hydrophobicity.

Work as a barrier in tissue absorption of the drugs and affect the bioavailability.

It shows adhesive properties.

It kept the mucus from the goblet cell which is necessary to compensate for the removal of the mucus layer due to digestion, bacterial degradation and solubilisation of mucin molecules and act as lubricant¹⁷.

Role of Saliva:

Saliva usually consists of 99% water and other complex fluid consisting of organic and inorganic material. Saliva is secreted more and more during working period.

1. It acts as Protective fluid for all tissues of the oral cavity.

2. Continuous mineralization / demineralization of the tooth enamel.

3. It Moisten the oral cavity¹⁸.

Mucoadhesion Theories

Mucoadhesion is a mixed process and various theories have been proposed to explain its mechanisms involved. These theories like mechanical interlocking, electrostatic, diffusion interpenetration, adsorption and fracture processes. The contact angle and time plays important role in mucoadhesion¹⁹.

1) Physical

a) Wetting

b) Diffusion

c) Fracture

d) Mechanical

2) Chemical

a) Electronic

b) Adsorption

Wetting theory:

The wetting theory is applicable to liquid, a system which shows affinity to the surface in order to spread over it. This affinity is found by using measuring techniques known as the contact angle. In general rule states that the lower the contact angle, the greater is the affinity the contact angle should be equal or close to zero to provide adequate spreadability. The spreadability coefficient, SAB, can be calculated from the difference between the surface energies γB and γA and the interfacial energy γAB, as indicated in the equation given below. This theory explains the importance of contact angle and reduction of surface and interfacial energies to achieve good amount of mucoadhesion²⁰.

SAB = γB – γA – γAB

Diffusion theory:

This theory explains the interpenetration of 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. The above penetration rate depends on the diffusion coefficient, flexibility and nature of the muco-adhesive chains, mobility and contact time. According to the history, the depth of interpenetration required to produce an efficient bioadhesive bond lies in the range 0.2–0.5 μm. This interpenetration depth of polymer and mucin chains can be estimated by the following equation

l = (tDb)½

Where, t is the contact time and Db is the diffusion coefficient of the mucoadhesive material in the mucus. The adhesion strength for a polymer is reached when the depth of penetration is approximately equivalent to the polymer chain size. In the way of diffusion to occur, it is important that the components present must have good mutual solubility, that is, both the bioadhesive and the mucus have similar chemical structures. So we can say that greater the structural similarity, the better is the mucoadhesive bond²¹.

Figure 4: Secondary Interaction resulting from inter diffusion of polymer chain of bioadhesive device and of mucus.

Fracture theory

This theory is the mostly used in various studies on the mechanical measurement of mucoadhesion. This theory analyzes the force required to separate two surfaces after adhesion is produced. This theory examines the force needed to dissociate two surfaces after adhesion is takes place^[22]. The work of fracture has been found to rise when the polymer network fibres are longer or if the degree of cross-linking within such a system is decreased. This concept aids in the measurement of fracture strength (σ) after the separation of two surfaces via its relationship to the Young’s modulus of elasticity (E), the fracture energy (ε) and the critical crack length (L) through the following equation:

σ=(E*ε/L)1/2

The force, Sm, is frequently calculated in tests of resistance to rupture by the ratio of the maximal detachment force, Fm, and the total surface area, A0, involved in the adhesive interaction²³.

Sm= Fm/Ao

Mechanical theory:

Mechanical theory guided that the adhesion process is only because of the filling of the imperfections of a rough surface by a mucoadhesive liquid. The systems which show mucoadhesion are also determined by the intrinsic properties of the formulation and by the environment in which it is applied. Intrinsic factors of the polymer are related to its molecular weight, concentration and chain flexibility. For various linear polymers, mucoadhesion is directly proportional to molecular weight, but it is not same for non-linear polymers²⁴.

Electronic theory:

The electronic theory based on hypothesis that the bioadhesive polymer material and the targeted mucous membrane have diverse features of electronic surface. According to this, when the surfaces come in contact with each other, there is an electron transfer to balance the Fermi levels, arising due to the formation of electrical double layer at the interface of the bioadhesive and the mucous membrane. The bioadhesive force is assumed to be present due to the attractive forces over this double layer²⁵.

Adsorption theory:

Adsorption theory gives an idea that the bioadhesive bond is formed between an adhesive substance and polymer and the tissue is only because of the weak Van der Waals forces and hydrogen bond formation. Various mucoadhesive interactions are: Ionic bonding, Covalent bonding, Hydrogen bonding, Van der Waals bonding, Hydrophobic bonding. For example, hydrogen bonds are the dominant interfacial forces in polymers having carboxyl groups²⁶.

Factors Affecting Mucoadhesion:

The mucoadhesion of a drug formulation to the mucous membrane depends on the below mentioned factors.

1. Molecular weight of the polymer

2. Concentration of polymer used of polymer chain.

3. Swelling factor stereochemistry of polymer.

4. PH at Polymer Substrate

5. Applied Strength

6. Contact time

7. Mucin Turnovers^27-30

Figure 5: Schematic Diagram Showing Factors Affecting Mucoadhesion

Figure 6: Schematic Diagram Showing Environmental Factors Affecting Mucoadhesion

Mucoadhesive Dosage Form:

Tablets

Generally tablets are flat, small and oval, with a diameter range from 5–8 mm. Unlike other conventional tablets, mucoadhesive tablets allow for drinking and speaking without major discomfort. Tablets are easily softened, adhere to the mucosa, and are retained in position until dissolution and release is complete³¹. Mucoadhesive tablets are able to deliver controlled release drug delivery, but coupling of mucoadhesive properties to tablet has additional advantages, for example, it offers more absorption and improved bioavailability of the drugs due to a high surface to volume ratio and facilitates a much more intimate contact with the mucus layer. This mucoadhesive tablet allowed patients to eat and speak without discomfort and caused no irritation, bad taste or pain³².

Figure 7: Factors related to influencing the mucoadhesion tablets behavior and their release profile.

Patches:

Various different patches can be prepared which adhere to the oral mucosa and are designed to deliver drugs have been developed. There are basically three different types of Oro-adhesive patches: patches with a dissolvable matrix for drug delivery to the oral cavity. Generally patches act for long time than solid forms such as tablets and lozenges and can produce sustained drug release for treating oral infections and injuries³³.

Films:

Mucoadhesive films can be preferred over adhesive tablets in terms of flexibility and comfort. They can avoid the relatively short residence time of oral gels on the mucosa, which can be easily washed away and removed by saliva. Thin strips of polymeric films, capable of loading up to 20 mg of drugs, dissolve on the tongue in less than 30 s and deliver drugs directly to the blood supply for rapid treatment of conditions such as impotence, migraines, motion sickness, pain relief and nausea^34-35.

Evaluation of mucoadhesive formulations:

Swelling Index:

The swelling rate of the buccal tablet is evaluated by using of pH 6.8 phosphate buffer.

The swelling index is calculated by the formula⁴¹

Swelling index = (wt-w0) / w0.

wt= weight of tablet at time t

w0= weight before placing in beaker

Mucoadhesion strength:

It is measured by using a modified 2-arm balance with rabbit buccal mucosa. The rabbit buccal mucosa was taken as the membrane and phosphate buffer (PB) pH 6.8 as moisturizing liquid. The rabbit buccal mucosa was obtained and stored in krebs buffer at 4 °C upon collection. The experiment was conducted within 3 h of the procurement of rabbit mucosa. The mucous layer was separated by using a surgical blade and washed with PB pH 6.8. It was then tied on a glass vial using a thread. This set was kept in a glass beaker, which was filled with PB pH 6.8 up to the surface of the buccal mucosa to maintain buccal mucosa viability. Various procedures are followed by number of researchers to measure Mucoadhesive strength; force of adhesion and then the averages of three determinations were calculated⁴²

Force of adhesion (F) = [W x g] / 1000

Where g is acceleration due to gravity (9.80665 m/sec2)

Water absorption ratio:

A piece of tissue paper folded twice was placed in a Petridish containing 5ml of water. A pre weighed tablet was placed on the paper and the time for complete wetting was measured which is characterized by coloring of tablet

Moisture absorption study:

Agar (5% w/v) was dissolved in hot water, transferred into Petri plates and allowed to solidify. Then tablets were placed on the surface of the agar and incubated at 37 0C for 1 hour. At the end of test, tablets were reweighed and the percentage moisture absorption was calculated using the following formula⁴⁴

% Moisture Absorption = Final weight – Initial weight X 100 Initial weight

Uniformity of drug content

Determination of surface pH

Residence Time

In vitro drug release study

Ex vivo permeation studies

EVALUATION OF MUCOADHESIVE POLYMERS

Mucoadhesive polymers can be evaluated by testing their adhesion strength by both in vitro and in vivo tests.

In vitro tests / Ex-vivo

The importance is layer on the elucidation of the exact mechanisms of bioadhesion. These methods are,

1. To determine tensile strength

2. To determine shear stress

3. Adhesion weight method

4. Fluorescent probe method

5. Flow channel method

6. Adhesion number

7. Falling liquid film method

Swelling properties:

In- vitro drug release studies and mucoretentability studies

CONCLUSION:

The mucoadhesion system is used to improve patient compliance and easy for formulation also. This can be used as a model for the controlled drug delivery approaches for a number of drug candidates. Oral route is the most favoured and probably most complex route of drug delivery. The buccal mucosa gives several advantages for controlled drug delivery for extended periods of time. The mucosa is connected with vascular as well lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract is avoided. Nowadays mucoadhesion moving towards new area with these new specific targeting compounds (lectins, thiomers, etc.) with researchers and drug companies looking further into potential involvement of more smaller complex molecules, new polymer entity, nano formulations, potent substances and supply various local and systemic drug molecules to patients by suing Mucoadhesion techniques.

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Received on 21.11.2020 Modified on 11.12.2020

Research Journal of Science and Technology. 2021; 13(2):133-141.

DOI: 10.52711/2349-2988.2021.00020