INTRODUCTION:

With the advancement in the drug formulations and different routes of administration; the knowledge of drug transport across tissues have been increased.^[1] Among the various approaches to modifying drug delivery systems (DDS) aiming to increase bioavailability, mucoadhesion (the ability of a object to remain attached to mucous membranes) occupies a special position.

As gates to the entry of nutrients, antigens, and medicinal formulations (MF) into the body, mucosal tissues mediate the assimilation of substances needed by the body and protection against foreign substances^[2]The concept of mucoadhesion was introduced in the field of controlled release drug delivery systems in the early 1980s. Thereafter, several researchers have focused on the investigations of the interfacial phenomena of mucoadhesive hydro gels with the mucus For drug delivery purpose, the term bioadhesion implies attachment of a drug carrier system to a specific biological location.^[3]The use of bioadhesion recently gained considerable attention in the area of soft tissue based mucosal delivery, and several formulations are now commercially available or under development. Such systems dramatically increase dosage form residence time, as well as improve intimacy of contact with the tissue, thereby localizing the drug in a specific region^.[4]In the recent years, mucoadhesion drug delivery system has shown remarkable interest for increasing the residence time at the site where it is applied and to expedite intimate contact of the dosage form with the underlying mucosa, mainly to promote absorption and elevate the percentage bioavailability of drug due to its extensive surface area and high flow rate of blood^.[5]For the desired mucoadhesive strength of the mucoadhesive dosage forms, there are various mucoadhesive polymers that can be used. These polymers are either natural or synthetic macromolecules which are capable of adhering to the mucosal surfaces. From last three decades, the use of various mucoadhesive polymers has achieved a great interest in the field of pharmaceutical technology. The use of mucoadhesive polymers has been accepted as an important strategy to prolong the residence time and to improve the localized effects of drug delivery systems on various mucus membranes of a biological system.^[6]

Structure of Mucous Layer:

Mucous membrane is the main administration site for bioadhesive systems. Membranes of human organism are relatively permeable and allow fast drug absorption. They are characterized by an epithelial layer whose surface is covered by mucus. Mucin is the most important glycoprotein of mucus and is responsible for its structure. The main functions of mucus are protecting and lubricating the epithelium and other additional functions depending on the epithelium covered. Mucus thickness can vary from 50-450 µm in the stomach to less than 1 µm in the oral cavity. The mucous site most used for drug administration and absorption is gastrointestinal but other routes, including nasal, ocular, buccal, vaginal, rectal, oral, and periodontal have also been studied^.[6]

Figure:01 Structure Of mucous layer

Composition of mucus layer:

Mucus is translucent and viscous secretion which forms a thin, continuous gel layer sticking to the mucosal epithelial surface^.[4] Mucus is composed chiefly of mucins and inorganic salts suspended in water. Mucins are a family of large, heavily glycosylated proteins composed of oligosaccharide chains attached to a protein core^[7] Mucus glycoproteins are high molecular weight proteins possessing attached oligosaccharide units containing, L-fructose, D-galactose, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine and Sialic acid.^[4]

Role of Mucous:

· It strongly bonds with the epithelial cell surface as a continuous gel layer i.e. helps in adhesion.

· One of its function is to keep the tissue Moist (eg. Mouth, Nose, Respiratory tract)

· It also play role in Absorbing and transforming nutrients.

· It acts as a protective layer of the intestine which protects it from the intestinal acids like HCl.

· It also prevents many dust particles and Pathogens entering our body by trapping them.

· It influences the bioavailability of drugs as it hinders the tissue absorption of drugs and other substrates.^[5]

MUCOADHESION\ BIOADHESION:

As stated mucoadhesion is the attachment of drug along with suitable carrier to the mucous membrane. Mucoadhesion is a complex phenomenon which involve wetting, absorption and interpetration of polymer chains.^[8]

“Bioadhesive” is defined as a substance that is capable of interacting with biological material and being retained on them or holding them together for extended period of time.^[9]In case of mucoadhesion, the biological tissue is the mucous membrane.The first stage involves an intimate contact between a mucoadhesive polymer and a membrane, either from good wetting of the mucoadhesive surface or from the swelling of the mucoadhesive. In the second stage, after contact is established, penetration of the mucoadhesive into the crevice of the tissue surface or interpenetration of the chains of the mucoadhesive with those of the mucus takes place^[10]

In biological systems, bioadhesion can be classified into 3 types:

· Type 1, adhesion between two biological phases, for example, platelet aggregation and wound healing.

· Type 2, adhesion of a biological phase to an artificial substrate, for example, cell adhesion to culture dishes and bio-film formation on prosthetic devices and inserts.

· Type 3, adhesion of an artificial material to a biological substrate, for example, adhesion of synthetic hydro gels to soft tissues and adhesion of sealants to dental enamel.^[2]

NEED OF MUCOADHESION:

· For Control release.

· Target and localized drug delivery.

· By pass first pass metabolism.

· Avoidance of drug degradation.

· Prolonged effect.

· High drug flux through absorbing tissues.

· Reduction in fluctuation in steady state plasma level^[9].

Advantages of Mucoadhesive Drug Delivery System:

· Rapid absorption because of enormous blood supply and good blood flow rates.

· Drug is protected from degradation in the acidic environment in the GIT.

· Improved patient compliance and ease of drug administration.

· Due to an increased residence time it enhances absorption and hence the therapeutic efficacy of the drug.^[2]

· The mucosal membranes are highly vascularized so that the administration as well as removal of a dosage form is easy.

· The sustained drug delivery can be achieved by using the mucoadhesive polymers of ‘SR’ grades.

· Due to the high extent of perfusion the rate of drug absorption is faster.

· The side effect that can arise due to oral administration, such as, nausea and vomiting, they can be avoided completely

· The mucoadhesive drug delivery can be easily used in case of unconscious and less Co-operative patients.^[12]

Disadvantages of Mucoadhesive Drug Delivery System:

· Some paitent suffer unpleasant feeling.

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

· Occurrence of local ulcerous effects due to prolonged contact of the drug possessing ulcerogenic property.

· Patient acceptability in terms to taste, irritancy and mouth feel is to be checked.^[2]

· The release rate may vary from a variety of factors like food and the rate of transit though gut, mucin turnover rate etc.

· Differences in the release rate can be found from one dose to another.

· Any loss of integrity in release pattern of the dosage form may lead to potential toxicity.

· These kinds of dosage forms cannot be crushed or chewed.^[13]

THEORY OF MUCOADHESION:

The phenomena of bioadhesion occur by a complex mechanism^[14].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^[15]

There are mainly 6 theories of mucoadhesion which are the following:

1) Electronic theory

2) Absorption theory

3) Wetting theory

4) Diffusion theory

5) Fracture theory

6) Mechanical theory

1. Electronic Theory:

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^[14]. Interaction between positively charged polymers chitosan and negatively charged mucosal surface which becomes adhesive on hydration and provides an intimate contact between a dosage form and absorbing tissue^[13]. Electrostatic forces are an important cause of bond adhesion rather than merely a result of high joint strength^[15]

2. Adsorption theory:

According to this theory the bioadhesive bond formed between an adhesive substrate and the tissue is due to the weak vanderwaals forces and hydrogen bond formation. For example, hydrogen bonds are the prevalent interfacial forces in polymers containing carboxyl groups^[2]Two types of chemical bonds resulting from these forces can be distinguished as primary chemical bonds of covalent nature and Secondary chemical bonds having many different forces of attraction likes electrostatic forces, Vander Walls forces, hydrogen and hydrophobic bonds^[13].

3. Wetting Theory:

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^[14]. The contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface^[13]. The contact angle should be equal or close to zero to provide adequate spreadibility.

S_AB=Ƴ _B-Ƴ_A-Ƴ_AB(1)

The spreadability coefficient, SAB, can be calculated from the difference between the surface energies γB and γA and the interfacial energy γAB,The greater the individual surface energy of mucus and device in relation to the interfacial energy, the greater the adhesion work, WA, i.e. the greater the energy needed to separate the two phases^[14].

W_A
=Ƴ_A+Ƴ_B-_ƳAB(2)

4. Diffusion theory:

The theory explains interpenetration of both polymer and mucin chains to a sufficient depth to create a semi-permanent adhesive bond. The adhesion force increases with the degree of penetration of the polymer chains. [15] The depth of interpenetration required to produce an efficient bioadhesive bond lies in the range 0.2–0.5 μm. The depth of penetration 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.

5. Fracture theory:

According to this theory, the adhesive bond between systems is related to the force required to separate both surfaces from one another. ‘‘Fracture theory” relates the force for polymer detachment from the mucus to the strength of their adhesive bond^[15]. This 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 interaction-

Sm = F_m\A_o

6. 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.^[14] Adhesive bonds are formed when non-uniformities on a rugged surface are filled by a mucoadhesive liquid. Irregularity increases the interfacial area which enhances the potency for interactions^[1]

Polymers used in Mucosal Drug Delivery:

Polymers have played an important role in designing such systems so as to increase the residence time of the active agent at the desired location. Polymers used in mucosal delivery system may be of natural or synthetic origin. In this section we will briefly discuss some of the common classes of mucoadhesive polymers^[19]

Nature of polymer^[19]

Polymers Based on Charge:

Numerous polymers possessing charge have proved to be crucial in the development of mucoadhesive formulations with sustained release. Derivatives of polyacrylic acid (PAA) showed enhanced mucoadhesive properties as compared to cellulose derivatives. Ionic complex with the counter-ionic drug molecules may be formed with the ionic polymers to develop mucoadhesive property exhibiting drug delivery matrix. Cationic polysaccharide chitosan has been used in some mucoadhesive formulations for its unique properties such as mucoadhesion, biocompatibility, and non-toxiciy.

Anionic polymers:

Polymers like carboxymethyl cellulose are popularly deployed for developing mucoadhesive drug delivery. Anionic polymers are highly used and are a very popular choice in the pharmaceutical sector. As these types of polymers possess functional groups such as carboxyl and sulfate which, in turn, result in general negative charge at pH which is higher than its pKa value. Since strong hydrogen bonds are formed between mucosal mucin layer and these polymers that’s responsible for outstanding mucoadhesive properties.

Cationic polymers:

Of all the mucoadhesive polymers of cationic nature, chitosan is the most popular and widely studied and are involved in developing several formulations in pure or in derivatized forms. Through deacetylation of chitin, the cationic polysaccharide chitosan is formed.

Non-ionic polymers:

Mucoadhesives are created utilizing polymers of non-ionic nature such as methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), and poly(vinyl pyrrolidone) (PVP). Out of a few classifications of polymers, non-ionic have demonstrated the best mucoadhesive quality.

Polymers Based on Generation:

First generation mucoadhesives:

These hydrophilic molecules are natural or synthetic in nature which contains various organic functional groups that can generate bonds of hydrogen such as hydroxyl, amino, and carboxyl groups, which never specifically cohere to different surfaces. Polymers of this class can further be classified into three subcategories: Anionic, cationic, and nonionic. Since cationic molecules are negatively charged at physiological pH, so these molecules can interact the mucous surface. Mucoadhesion occurs in cationic polymers (e.g. chitosan) as the electrostatic interactions that take place between the polymers amino groups and the mucins sialic groups in the mucus layer.

Second-generation mucoadhesive materials:

These are multifunctional novel mucoadhesive systems which can be named as second-generation polymers. They act as an alternate option to non-specific bioadhesives as they can cohere to cell or mucous surface having specific chemical structures on them. Molecules similar to invasins, lectins, antibodies, and those acquired by means of adding thiols to know molecules are considered in this group

Table No. 1:

Mucoadhesive polymers with their mucoadhesive property^[20]

S. No	Polymers	Mucoadhesive Property
1.	Carbopol 934	+++
2.	Carboxymethylcellulose	+++
3.	Polycarbophil	+++
4.	Tragacanth	+++
5.	Sodium alginate	+++
6.	Hydroxymethylcellulose	+++
7.	Gum karya	+++
8.	Guar gum	++
9.	Polyvinylpyrrolidone	++
10.	Polyethylene glycol	+
11.	Hydroxypropyl cellulose	+

+++Excellent, ++Good, +Poor

MECHANISM OF MUCOADHESION:

The mechanism of mucoadhesion is generally divided into two steps:

1. Contact stage:

This stage is characterized by the contact between the mucoadhesive and the mucous membrane, with spreading and swelling of the formulation, initiating its deep contact with the mucus layer in some cases these two surfaces can be mechanically brought together, e.g. placing and holding a delivery system within the oral cavity, eye or vagina. For example within the nasal cavity or bronchi of the respiratory tract deposition onto the ‘sticky’mucus coat is encouraged by processes such as inertial impaction, in order to ‘filter out’ particles from the air stream^[4]

2. Consolidation stage:

It has been Stated that if strong or prolonged adhesion is required, for example with larger formulations exposed to stresses such as blinking or mouth movements, then a second consolidation stage is required. Mucoadhesive materials adhere most strongly to solid dry surfaces as long as they are activated by the presence of moisture. Moisture will effectively plasticize the system allowing mucoadhesive molecules to become free, conform to the shape of the surface, and bond predominantly by weaker van der Waal and hydrogen bonding there are Mainly two theories explaining the consolidation step:

1. The diffusion theory

2. The dehydration theorys^[4]

FACTOR AFFECTING MUCOADHESION:

Polymer related factors:

Molecular weight:

The mucoadhesion strength of a mucoadhesive polymer mainly depends upon its molecular weight and polymeric linearity. Mucoadhesive property of the polymer increases with increase in molecular weight of polymeric chain^[17] Generally, for the linear polymers (e.g., Polyethylene glycol),the bioadhesive property is directly proportional to the molecular weight i.e., PEG-200000 having greater mucoadhesive strength than that of PEG-20000 ^[12]

Concentration of polymer:

The concentration of a mucoadhesive polymer is a significant factor of determining its mucoadhesive strength.Thereis an optimum concentration for a mucoadhesive where it produces the maximum mucoadhesion^[12] Polymer concentration is dependent on physical state of the delivery system, with differences between semisolid and solid-state dosage form. In the semisolid state, polymer concentration is low which reduces adhesion. Hence lower number of polymer chains are available for interpenetration with mucus ^[18].

Flexibility:

Flexible nature of polymer is another important parameter for mucoadhesive property because chain length of polymer facilitates good penetration and attachment of the polymer chains with mucosal lining of the biological membrane and helps in improvement of bioadhesive property^[17]. Greater the flexibility of the mucoadhesive chain causes the greater diffusion into the mucus The flexibility of polymer chain depends on the viscosity and diffusion coefficient of that chain^[12].

Swelling or hydration:

The proper hydration of mucoadhesive polymer is essential for the desired mucoadhesive strength. With increase in hydration the pore size of polymer increases which results induced mobility and enhanced interpenetration^[12]

Hydrogen bonding:

Adhesion of polymers is greatly depend upon the hydrogen bonding that higher the hydrogen bonding stronger is the adhesive strength of the polymers. Main functional groups responsible for such type of interactions are hydroxyl, carboxyl and amino groups^.[17]

Charge:

The bioadhesive property of ionic polymer is always higher than that of non-ionic polymer. In neutral or slightly alkaline medium, the cationic polymer shows superior mucoadhesive property. It has been proven that, cationic high molecular weight polymer such aschitosan possess good bioadhesive property^[11]

Environmental factors:

In addition to various physicochemical factors of the polymeric materials that significantly affect the effectiveness of mucoadhesive drug delivery systems, different environmental factors also contribute an important part in mucoadhesion property.^[17]

pH of polymer-substrate interface:

The pH of polymer-mucin interface should be same as it is possible, because, the difference in pH amongst the two systems may results in the transfer of charge due tothe higher pH gradient. This may affect the mucoadhesion.^[11]

Moistening:

Moistening is required to allow the mucoadhesive polymer to spread over the surface. It creates a network of polymer chains of sufficient pore size. Through these pores, the interpenetrationof polymer and mucin molecules takes place that results in increasing the mobility of polymer chains for the proper diffusionof mucoadhesive polymer in mucin layer^.[11]

Physiological factors:

In addition to physiological factors they also play very essential role in the mucoadhesive ability of a polymer matrix include texture and thickness of mucosa.^[11]

Mucin turnover:

The mucin turnover is expected to limit the residence time of the mucoadhesive on the mucus layer. No matter how high the mucoadhesive strength is.^[17]

Tissue movement:

Tissue movement occurs on consumption of liquid and food, speaking, peristalsis in the GIT and it affects the mucoadhesive system especially in case of gastro retentive dosage forms ^[11]

EVLUATIONS:

In vitro/ex vivo tests^[19]

· Tensile strength

· Shear stress

· Fluorescent probe method

· Falling liquid film method

· Colloidal gold staining method

· Viscometer method

· Thumb method

· Adhesion number

· Swelling properties

· Stability studies

In vivo methods^[19]

· Use of radio opaque markers

· Use of gamma scintigraphy

· X ray studies

· Isolated loop technique

· Use of electron paramagnetic resonance

DIFFERENT DOSAGE FORM OF MDDS^[2]:

The dosage form of oral drug delivery system are as follows:

· Buccal tablets

· Bioadhesive film\patches

· Buccal liposomes

· Buccal gels and ointments

· Bioadhesive lozenges

· Medicated Chewing gum

Example-Buccastem, Susgard, Corsodyl Gel

Ophthalmic/occular dosage form are as follows:

· Ocular nanoparticles

· Ocular liposomes

· Ocular microspheres

· Ocular inserts

Example- Nyogel, Hyotears, PiloGel

Nasal dosage form are as follows:

Nasal microspheres

Nasal liposomes

Example- Rhincort, Nasacart

Gastrointestinal dosage form are as follows:

Gastric floating tablets

Gastric floating capsules

Floating pills

Swellable tablets

Example- Coreg CR, Liquid Gaviscon, Nucarnit M

Vaginal dosage form are as follows:

Pessaries

Vaginal topical administration

Vaginal tablets

Vaginal microspheres

Example- Crinone, Acid Gel

CONCLUSION:

Mucoadhesive drug delivery systems, are gaining popularity day by day Extensive research efforts throughout the world have resulted in significant advances in understanding the various aspects of mucoadhesion here is no doubt that mucoadhesion has moved into a new area with these new specific targeting compounds (lectins, thiomers, etc.) The mucoadhesive dosage forms offer prolonged contact at the site of administration, low enzymatic activity, and patient compliance. The formulation of mucoadhesive drug delivery system depends on the selection of suitable polymer with excellent mucoadhesive properties and biocompatibility. This review focused on the study of different aspects of mucoadhesion. The structure of mucus membrane gives the better understanding of mucus membrane, mucoadhesive theories, mucoadhesion formulations. Also the remarkable advancement has been made in the field of mucoadhesion but still there are many difficulties ahead. However, the novel mucoadhesive formulations were developed for the treatment of both systemic and topical diseases.

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Received on 29.10.2019 Modified on 05.11.2019

Res. J. Pharmacognosy and Phytochem. 2019; 11(4):251-257.

DOI: 10.5958/0975-4385.2019.00042.6