INTRODUCTION:

Advancements in pharmaceutical industry had significantly donated in improving the quality of life of patients. Among the delivery routes, oral route is most preferred route, because of low cost, ease of administration and high level of patient compliance.^1-3However administration of drugs has short term limitations like first pass metabolism, which leads to a lack significant correlation between Membrane Permeability, Absorption, Bioavailability and Drug degradation within the gastro intestinal (GI) tract that forbid oral administration of certain classes of drugs eg. proteins and peptides. Other absorptive mucosa, are considered as prospective site for drug administration.^4-6

Transmucosal routes (mucosal lining of nasal, rectal, vaginal, ocular and oral cavity) offers some distinct advantages such as possible bypass of the first pass effect, avoidance of pre systemic elimination within the GIT and better enzymatic flora for drug absorption. Within the oral cavity, mucosal drug delivery systems (MDDS) can be categorized into three classes:

· Buccal delivery

· Sublingual delivery

· Local delivery

Approaches for MDDS^7-9:

· The approach of mucoadhesive drug delivery system had been raised in early 1980. Adhesion can be defined as bond formation between a pressure sensitive adhesive and a surface. Mucoadhesion is bond formation between pressure sensitive adhesive with biological substrate (Mucosal layer).

· In design and development of drug delivery systems mucoadhesive drug delivery has been considered as subject of great interest due to various merits. Prolongation of the residence time of the dosage from at the site of application by increasing intimate contact of the dosage form with the underlying absorption surface and leads to improved absorption properties with enhanced bioavailability of therapeutic agents is major quality of these systems. Localization of the active ingredients for therapeutic effect at specific site in the body makes mucoadhesive controlled drug delivery systems more beneficial leads to controlled and predictable drug release from the dosage form and make them potential candidate for treatment of different diseases.

· Different factors play major contributing role in better efficiency of these drug carriers. Various mucosal routes for drug delivery include buccal/oral route, ocular route, vaginal route and gastrointestinal route. This review article provides brief overview of the mucoadhesion, various advantages and factors affecting mucoadhesion.

Advantages of MDDS^{10, 12}:

· Mucoadhesive drug delivery system offer several over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.

· Targeting and localization of the dosage from at a specific site.

· High drug flux at the absorbing tissue.

· It will serve both the purposes of sustain release and presence of dosage form at the site of absorption.

· Excellent accessibility.

· Painless administration.

· Low enzymatic activity and avoid of first pass metabolism.

Disadvantages of MDDS^{13, 14}:

· If mucoadhesive drug delivery systems are adhere too tightly because it is undesirable to exert too much force to remove the formulation after use, otherwise the mucosa could be injured.

· Some patient suffers unpleasant feeling.

· Unfortunately, the lack of standardized techniques often leads to unclear results.

· Costly drug delivery system.

· Medications administered orally do not enter the blood stream immediately after passage through the buccal mucosa.

Structure of mucus membrane:

A mucous membrane or mucosa is a membrane that lines various cavities in the body and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is mostly endodermic origin and is continuous with the skin at various body openings such as the eyes, ears, inside the nose, inside the mouth, lip, vagina, the urethral opening and the anus. Some mucous membranes secrete mucus, a thick protective fluid. The function of the membrane is to stop pathogens and dirt from entering the body and to prevent bodily tissues from becoming dehydrated. The mucosa of organs is composed of one or more layers of epithelial cells that secrete mucus, and an underlying lamina propria of loose connective tissue. The type of cells and type of mucus secreted vary from organ to organ and each can differ along a given tract. Mucous membranes line the digestive, respiratory, and reproductive tracts and are the primary barrier between the external world and the interior of the body; in an adult human the total surface area of the mucosa is about 400 square meters while the surface area of the skin is about 2 m². They are at several places contiguous with skin: at the lips of the mouth, the eyelids, the ears, the genital area, and the anus. Along with providing a physical barrier, they also contain key parts of the immune system and serve as the interface between the body proper and the micro biome. Examples include: Bronchial mucosa and lining of vocal folds, endometrium (mucosa of the uterus), esophageal mucosa, gastric mucosa, intestinal mucosa, nasal mucosa, olfactory mucosa, oral mucosa, penile mucosa, vaginal mucosa, frenulum of tongue, tongue, anal canal and palpebral conjunctiva.^15-17

Fig. 1: Structure of mucus membrane

Mechanism of mucoadhesion:

The mechanism of adhesion of certain macromolecules to the surface of a mucous tissue is not well understood yet. The mucoadhesive must spread over the substrate to initial close contact and increase surface contact, promoting the diffusion of its chains within the mucus. Attraction and repulsion forces arise and, for a mucoadhesive to be successful, the attraction forces must dominate. Each step can be facilitated by the nature of the dosage form and how it is administered. For example, a partially hydrated polymer can be absorbed by the substrate because of the attraction by the surface water. Thus, the mechanism of mucoadhesion is generally divided in two steps, the contact stage and the consolidation stage. The first stage is characterized by Mucoadhesive drug delivery systems. The contact between the polymer and the mucous membrane, with spreading and swelling of the formulation, initiating its deep contact with the mucus layer. In some cases, such as for ocular or vaginal formulations, the delivery system is mechanically attached over the membrane. In other cases, the deposition is promoted by the aerodynamics of the organ to which the system is administered, such as for the nasal route. On the other hand, in the gastrointestinal tract direct formulation attachment over the mucus membrane is not feasible. Peristaltic motions can contribute to this contact, but there is little evidence in the literature showing appropriate adhesion. Additionally, an undesirable adhesion in the esophagus can occur. In these cases, mucoadhesion can be explained by peristalsis, the motion of organic fluids in the organ cavity, or by Brownian motion. If the particle approaches the mucous surface, it will come into contact with repulsive forces (osmotic pressure, electrostatic repulsion, etc.) and attractive forces (Vander Waals forces and electrostatic attraction). Therefore, the particle must overcome this repulsive barrier.^18-20

Fig. 2. Two methods of mucoadhesion process

In the consolidation step, the mucoadhesive materials are activated by the presence of moisture. Moisture plasticizes the system, allowing the mucoadhesive molecules to break free and to link up by weak Vander Waals and hydrogen bonds. Essentially, there are two theories explaining the consolidation step: the diffusion theory and the dehydration theory. According to diffusion theory, the mucoadhesive molecules and the glycoprotein of the mucus mutually interact by means of interpenetration of their chains and the building of secondary bonds. For this to take place the mucoadhesive device has features favoring both chemical and mechanical interactions. For example, molecules with hydrogen bonds building groups (-OH, -COOH), with an anionic surface charge, high molecular weight, flexible chains and surface-active properties, which induct its spread throughout the mucus layer, can present mucoadhesive properties. According to dehydration theory, materials that are able to readily jellify in an aqueous environment, when placed in contact with the mucus can cause dehydration due to the difference of osmotic pressure. The difference in concentration gradient draws the water into the formulation until the osmotic balance is reached. The process leads to the mixture of formulation and mucus and can thus increase contact time with the mucous membrane. Therefore, it is the water motion that leads to the consolidation of the adhesive bond, and not the interpenetration of macromolecular chains.

Fig. 3. Dehydration theory of mucoadhesion

Mucoadhesion theories:

Mucoadhesion is a complex process and numerous theories have been presented to explain the mechanism involved. The theories include electronic theory, adsorption theory, wetting theory, diffusion theory, and fracture theory. There are five classical theories adapted from studies on the performance of several materials and polymer, polymer adhesion. These theories include mechanical-interlocking, electrostatic, diffusion-interpenetration, adsorption and fracture processes. These numerous theories should be considered as supplementary processes involved in the different stages of mucus substrate interaction. These theories were originally developed to explain the performance of such diverse materials such as glues, adhesives: paints have been adopted to study the mucoadhesion.^21-23

Electronic theory:

According to electronic theory, attractive electrostatic forces between glycoprotein mucin network and the bioadhesive material. Because of different electronic properties of the mucoadhesive polymer and the mucus glycoptotein, electron transfer between these two surfaces occurs. Electron transfer occurs between the two forming double layer of electric charge at the interface. This theory describes adhesion occurring by means of electron transfer between the mucus and the mucoadhesive system arising through differences in their electronic structure. Thus it results in the formation of double layer of electric charges at the mucus and the mucoadhesive interface with subsequent adhesion due to attractive forces.

Adsorption theory:

According to the adsorption theory, bioadhesive bond is due to Vander Waals interactions, hydrogen bonds, electrostatic attractions or hydrophobic interactions. It has been proposed that these forces are main contributors to the adhesive interaction. Adhesion is defined as being the result of various surface interactions (primary and secondary bonding) between the adhesive polymer and mucus substrate. Strong Polymer Forces: Covalent bonds; weak secondary Forces: Ionic bond, hydrogen bond, Vander Waals forces. Primary bonds are due to chemisorptions result in adhesion due to ionic, covalent and metallic bonding. Secondary bond arise mainly due to Vander Waals forces, hydrophobic interactions and hydrogen bonding.

Wetting theory:

The wetting theory postulates that the adhesive component penetrates the surface irregularities, hardness and anchors itself to the surface. The wettability theory is mainly applicable to liquid or low viscosity mucoadhesive system and is essentially a measure of the spreadability of active pharmaceutical ingredient delivery system across the biological substrate. Wetting theory is the ability of bioadhesive to spread and develop intimate contact with the mucus membrane. Spreading coefficient of polymers must be positive in order to adhere to a biological membrane, and contact angle between the polymer and cells must be near to zero. The wetting theory emphasizes the intimate contact between the mucoadhesive polymer and the mucous, primarily in liquid systems. It uses interfacial tension to predict spreading and subsequent adhesion. 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 use of measuring techniques such as the contact angle. It is predominantly applicable to liquid bioadhesive systems. It analyses and contact behavior in terms of the ability of a liquid or paste to spread over a biological systems. The adhesive performance of viscous liquids may be defined, using wettability and spread ability; critical parameters are determined from solid surface contact angle measurements.

Diffusion theory:

The diffusion theory states that interpenetration and entanglement of both polymer and mucin chains are responsible for mucoadhesion. The more structurally similar a mucoadhesive to the mucosa, the greater is the mucoadhesion. It is believed that an interpenetration layer of 0.2-0.5 µm is required to produce and effective bond. This process is driven by concentration gradient and is affected by the molecular chain lengths and their motilities. This theory describes the physical entanglement and interpenetration of mucosa strand into the porous structure of the polymer substrate. The interpenetration is governed by diffusion coefficients and contact time which in turn is dependent on the molecular weight and flexibility of the chains probable penetration depth (L) can be estimated by formula:

L = (t*D_b)^1/2 Eq. No. (1)

Where: t = time of contact, D_b=diffusion coefficient of the bioadhesive material in mucus.

This is a two-way diffusion process with penetration rate being dependent upon the effective coefficient of both interacting polymers. Sufficient polymer chain flexibility, adequate exposure for the surface contact of polymers, similar chemical structures and the diffusion coefficients of the bioadhesive polymer are among the factors which influence the inter-diffusion of the macromolecule network.

Fracture theory:

The fracture theory analyses the force that is required for the separation of two surfaces after adhesion. The maximum tensile strength produced during detachment can be determined by dividing the maximum force of detachment (F_m) by the total surface area (A_o), involved in the adhesion interactions.

S_m=F_m/A_oEq. No. (2)

The fracture theory analyzes the force required to separate two surfaces after adhesion. This assumes that the failure of the adhesive bond occurs at the interface. However, failure normally occurs at the weakest component, which is typically a cohesive failure within one of the adhering surfaces. Since the fracture theory is concerned only with the force required to separate the parts, it does not take into account the interpenetration or diffusion of polymer chains. Mechanical theory considers adhesion to be due to the filling of the irregularities on a rough surface by a mucoadhesive liquid. Moreover, such roughness increases the interfacial area available to interactions thereby aiding dissipating energy and can be considered the most important phenomenon of the process. It is unlikely that the mucoadhesion process is the same for all cases and therefore it cannot be described by a single theory. In fact, all theories are relevant to identify the import ant process variables.

Mucoadhesive polymers²⁴:

Mucoadhesive polymers are water soluble and water insoluble polymers which are swellable networks jointed by cross linking agents. The polymers should possess optional polarity to make sure it is sufficiently wetted by the mucus and optimal fluidity that permits the mutual adsorption and interpenetration of polymer and mucus to take place.

Characteristics of ideal mucoadhesive polymer:

· The polymer and its degradation products should be nontoxic and non- absorbable from the GIT.

· It should be nonirritant to the mucous membrane.

· It should preferable form a strong non-covalent bond with the mucin-epithelial cell surfaces.

· It should adhere quickly to soft tissue and should posses some site specificity.

· It should allow some easy incorporation of the drug and offer no hindrance to its release.

· The polymer must not decompose on storage or during shelf life of the dosage form.

Some of the mucoadhesive polymers along with their mucoadhesive property are summarized below:

Table1. Mucoadhesive polymers with their mucoadhesive property

Polymer	Mucoadhesive property*
Carbopol 934	+++
Carboxymethylcellulose	+++
Polycarbophil	+++
Tragacanth	+++
Sodium alginate	+++
Hydroxyethyl cellulose	+++
Hydroxypropyl methylcellulose	+++
Gum karaya	++
Guar gum	++
Polyvinylpyrrolidone	+
Polyethylene glycol	+
Hydroxypropyl cellulose	+

* +++ Excellent, ++ Fair, + Poor

Evaluation parameters for MDDS (In vitro / ex vivo):

1. Methods for mucoadhesive strength measurement:

a) Methods determining tensile strength:

There is uniform distribution of stress over the adhesive joint in tensile and shear experiments, while the stress is focused at the edge of the joint in the peel strength. Thus the mechanical properties are measures through tensile and shear measure, while the peel strength measures the peeling force. Texture profile analyzer is one method used for measuring the force required to peel out bioadhesive films from cut out tissue in vitro. For this, a piece of animal mucous membrane was used and it was tasted for the force required to pull the formulation from a model membrane which is made from disc of mucin. The texture analyzer operates in tensile test mode and is paired with a low sliding platform which is also used to determine peel strength. On a movable platform the animal skin was placed and on top of it the bioadhesive film was placed, which was later on pulled vertically to determine the peel strength. The different forces like detachment strength, shear strength and rupture tensile strength is shown.^25-30

Fig. 4. Various forces evaluated in mucoadhesion.

Another method uses modified physical balance to measure mucoadhesive strength of the dosage form. The apparatus is made from a modified double beam physical balance wherein the right pan is replaced by a glass slide with copper wire and additional weight, to equalize the weight on both sides of pan.^31-34

Fig. 5. Measurement of mucoadhesive strength by physical balance.

Fig. 6. Measurement of mucoadhesive strength by falling liquid film method.

A Teflon block of specific dimensions is kept in a beaker filled with buffer of 0.1N HCL and pH 1.2, which is then placed at the bottom of the balance. Goat or rat stomach mucosa can be used as a model membrane and buffer is used as moistening fluid. One side of the formulation is fixed to the glass slide of the right arm of the balance and then the beaker is slowly lifted until contact between goat mucosa and mucoadhesive dosage form is established. A preload of 10g is placed on the slide for 5 min (preload time) to establish adhesive bonding between mucoadhesive dosage form and the stomach mucosa. The preload and preload time are kept constant. At the end of preload time, preload is removed from the glass slide and water is then added in the plastic bottle in left side arm by peristaltic pump at a constant rate of 100 drops per min. The addition of water is stopped when mucoadhesive dosage form is detached from the goat or rat stomach mucosa. The weight of water required to detach mucoadhesive dosage form from stomach mucosa is noted as mucoadhesive strength in grams.^35-42

Force of Adhesion (N) = (Mucoadhesive strength*9.81)/1000 Eq. No. (3)

Bond strength (N/m²) = Force of adhesion (N)/surface area of tablet (m²) Eq. No. (4)

b) Falling liquid film method:

In this method, the mucous membrane is placed in a longitudinally cut stainless steel cylindrical tube. This support is placed inclined in a cylindrical cell with a temperature controlled at 37°C in thermostatic bath. An isotonic solution is pumped through the mucous membrane by peristaltic pump and collected in a collection container. Subsequently, in the case of particulate systems, the amount remaining on the mucous membrane can be counted with the aid of a coulter counter. For semi-solid systems, the non-adhered mucoadhesive can be quantified by high performance liquid chromatography. This methodology allows the visualization of formation of liquid-crystalline mesophase on the mucous membrane after the flowing of the fluids and through analysis by means of polarized light microscopy.^43-46

c) Fluorescent probe method:

In this method, pyrene and fluorescein isothiocyanate are used to label the membrane lipid bilayer and membrane proteins respectively. The mucoadhesive agents are mixed with cells and changes in fluorescence spectra are observed. This gives an indication of polymer binding and its role in polymer adhesion.⁴⁷

d) Colloidal gold mucin conjugate method:

Colloidal gold staining technique is proposed for studying bioadhesion. The method user red colloidal gold particles, which are adsorbed on molecules of mucin to form mucin-gold conjugates. These conjugates on interaction with boiadhesive hydrogels develops a reddish tint. This can be evaluated by measuring either the intensity of red color on the hydrogel surface or by measuring decline in the concentration of the conjugates through absorbance change at 525 nm.⁴⁸

2. Swelling index:

The amount of swelling is quantified in terms of % weight gained by the formulation. It is calculated using following formula:

SI = (W_t-W_o) / W_oEq. No. (5)

Where, SI = Swelling index: W_t = Weight of tablet at time t; W_o = Weight of tablet before placing in the beaker.⁴⁹

3. Thumb method:

This is used for the qualitative determination of peel adhesive strength of the polymer and is useful in the development of buccal adhesive delivery systems. The adhesiveness is measured by the strain required for pulling the thumb from the adhesive as a function of the pressure and the contact time.⁵⁰

4. Electrical conductance:

The rotational viscometer was modified to determine electrical conductance of various semisolid mucoadhesive ointments and found that the electrical conductance was low in the presence of adhesive material.⁵¹

5. Stability studies:

The success of an effective formulation can be evaluated only through stability studies. The purpose of stability testing is to obtain a stable product which assures its safety and efficacy up to the end of shelf life at defined storage conditions and peak profile. ICH guidelines can be followed in this regard.⁵²

6. Measurement of the Residence Time/ In vivo techniques:

Measurements of the residence time of mucoadhesive at the application site provide quantitative information on their mucoadhesive properties. The GI transit times of many mucoadhesive preparations have been examined using radioisotopes and the fluorescent labeling techniques.^{53, 54}

a) GI Transit using Radio-opaque Tablets:

It is a simple procedure involving the use of raido-opaque markers, e.g. barium sulfate, encapsulated in mucoadhesive tablets to determine the effects of mucoadhesive polymers on GI transit them.

b) Gamma Scintigraphy Technique:

A study has reported the intensity and distribution of radioactivity in the genital tract after administration of technetium-labeled hyaluronam based biomaterial (HYAFF) tablets. The retention of mucoadhesive-radio labeled based on HYAFF polymer was found to be more for the dry power formulation than for the pessary formulation after 12 h of administration to stomach epithelium.

CONCLUSION:

Mucoadhesion have great pharmaceutical applications and this phenomenon can serve as a good approach in the area of controlled drug delivery systems for a number of active drug molecules. These drug delivery systems with significant advantages including prolonged retention time of the drugs which directly affects the absorption rates are key factors in the oral bioavailability of various drugs. Many potential mucoadhesive systems with different rate controlling agents are being explored which may results into better treatment approach in the market in near future and provide effective healthcare benefits to the community.

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Received on 17.11.2019 Modified on 08.12.2019

Res. J. Pharma. Dosage Forms and Tech.2019; 11(4):280-287.

DOI: 10.5958/0975-4377.2019.00047.8