INTRODUCTION:

The skin and mucus membrane are the foremost component s of the first line of defense in the human body. The mucus layer covers various body cavities as well as internal organs like a respiratory tract, gastrointestinal tract and reproductive organs. The mucus layer represents a hydrophilic barrier to protect different regions of the body from external infectious or toxic substances (1). Along with this, the mucus layer is highly vascularized and hence offers a great surface for drug absorption. The oral route of drug administration is the most popular and conventional route. Nevertheless, the hepatic first-pass metabolism and enzymatic degradation sometimes limit its application(2).

At the same time, the parenteral route is quite inconvenient and painful way of drug delivery. So, to avoid the challenges of oral and parenteral drug delivery system and enhance the drug efficacy the mucoadhesive drug delivery system has emerged as a simple, convenient and novel approach of drug administration (3).

The concept of Mucoadhesion has risen inthe early 1980s as an attractive novel drug delivery tool in pharmaceutical technology(4). In recent year delivery of therapeutic agent via mucoadhesive drug delivery system has become highly interesting. Adhesion may be defined as the bond produced by contact between a surface and a pressure sensitive adhesive. The American Society of Testing and Materials has defined it as the state in which two surfaces are held together by interfacial forces, which may consist of valence forces, interlocking action or both(5).

Mucoadhesion is referred as a process of binding of any material to the biological membrane (mucus membrane). Mucoadhesive drug delivery belongs to the controlled drug delivery system which increases the contact time of targeted tissue and the dosage form (6-8). Mucoadhesive behavior is achieved by incorporation of bioadhesive polymers into the pharmaceutical dosage form to increase the residence time of the dosage form at the site of application or absorption. It protects the drug from enzymatic degradation, enhances the bioavailabilityand improves the therapeutic efficacy of the drug (9, 10). Mucoadhesion is a sequential process which firstly involves the wetting of polymer followed by interpenetration of the polymeric chain and finally involves the formation of chemical bond between the biological layer and the polymeric chain(11).

In the present study, graduates have gathered the information from the available resources and compiled the article so that it can be available to them in published form. Although the subject is explored one, the intention for the publication of the present work is to seed the interest towards the publication so that they can learn the process thoroughly.

Advantages of mucoadhesive drug delivery system

Mucoadhesive drug delivery system offers various advantages over the oral and parenteral drug delivery system which includes;

· Because of the high vascularity of the mucusmembrane, it increases the drug absorption from the site of adhesion

· The bioadhesive polymer prolongs the drug resident time,and so increases the bioavailability.

· The drug is not entered into the GI tract. Hence it protects the drug from enzymatic degradation. The mucoadhesive system is suitable for the GI sensitive drug substances like protein, peptide,etc.

· It also limits the drug metabolism and clearance by avoiding the first pass metabolism.

· It offers rapid onset of action

· The controlled release system decreases the dose of the drug

· The site-specific application minimizes the side effect of drug

· The system also represents a patient-friendly drug delivery system as compared to the parenteral formulations.

Disadvantages

The major drawback of mucoadhesive drug delivery system includes;

· Ulcer or irritation at the contact surface due to continuous contact with the drug

· Sore or dry mouth in case of oral mucoadhesive system

· Eating or drinking is prohibited during drug administration period

· The rectal, vaginal, nasal and ocular mucoadhesive system may sometime produce irritation and discomfort to the contact area

· Taste of the dosage form is important parameter for oral mucoadhesive system

· The in vitro assessment is limited due to unavailability of the suitable model (12).

TYPES MUCOADHESIVE DRUG DELIVERY SYSTEM

By sites of mucoadhesion

The mucoadhesive drug delivery system can be delivered to various mucosal layers of the body. By different sites of application the mucoadhesive system is classified into the following categories;

1. Buccal drug delivery system: In this system, the mucoadhesive systemis placed in the buccal cavity for systemic as well as local delivery of the drug. The buccal mucosa is enriched in blood vessels which facilitates the drug absorption at a constant rate for a prolongedperiod. It is suitable for GI susceptible drug molecules like protein and peptides and avoids the first pass metabolism of the drug. The polymers used for the buccal mucoadhesive system includes chitosan, gellan, polyacrylic acid, hyaluronic acid, carboxymethylcellulose, hydroxypropyl cellulose, etc.(13)

2. Sublingual drug delivery system: Sublingual mucosa composed of smooth muscles and immobile mucosa which makes it more permeable than the buccal mucosa(14).

3. Vaginal and rectal drug delivery system: The vaginal and rectal mucosa has also been explored for drug administration to the body not only for local effect but also for systemic drug delivery. It offers the advantage of bypassing the first pass metabolism as well as rapid drug absorption from the mucosal surface. However, the drug administration sometimes causes inconvenience or embarrassment to the patient. The polymers used for this delivery route are poloxamer, polycarbophil, mucin, gelatin,etc. (15)

4. Ocular drug delivery system: ocular drug delivery suffers from the poor bioavailability and nasolacrimal drainage of the drug due to the tear formation and eye blinking. The mucoadhesive system overcomes this limitation of ocular drug delivery. Although irritation and blurred vision are the drawbacks associated with this system. Various polymers used for development of ocular mucoadhesive dosage form include PVP, poly(dimethylsiloxane), hydroxyl ethyl cellulose, methyl cellulose, poloxamer, poly(acrylic acid),etc. (16, 17)

5. Nasal drug delivery system: The nasal mucosa also offers a suitable site for administration of bioadhesive system. It provides a large surface area for drug absorption as compared to the buccal mucosa. The drug retention time in the nasal mucosa may vary from 15 to 30 minutes during this time a rapid mucociliary activity is observed due to the presence of foreign material. The polymer used for the preparation of nasal mucoadhesive formulation are methyl vinyl ether, carbopol, Eudragit, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,etc.(18)

Each site of mucoadhesion has its advantages and disadvantages along with the basic property of prolonged residence of dosage form at that particular site. In buccal and sublingual sites, there is an advantage of fast onset along with bypassing the first-pass metabolism, but these sites suffer from inconvenience because of taste and intake of food. Rectal and vaginal sites are the best ones for the local action of the drug,but they suffer from inconvenience of administration. Nasal and ophthalmic routes have another drawback of mucociliary drainage that would clear the dosage form from the site.

By nature of adhesive layers the bioadhesion phenomenon is of three types:

Type 1: Adhesion between two biological phase, e.g.,platelet aggregation and wound healing.

Type 2: Adhesion of a biological phase to an artificial substrate, e.g.,cell adhesion to culture dishes and biofilm formation on prosthetic devices and inserts.

Type 3: Adhesion of an artificial material to a biological substrate, e.g.,adhesion of synthetic hydrogels to soft tissues, adhesion of sealants to dental enamel.

CHARACTERISTICS OF BIOADHESIVE TABLETS

· The polymer and their degradation products should be nontoxic and non-absorbable from the gastrointestinal tract.

· Should be non-irritant to the mucous membrane.

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

· Adhere quickly to most tissue and should possess some site-specificity.

· Allow incorporation to the daily dose of the drug and offer no interrupt to its release.

· The polymer should not be decomposingin storage or during the shelf life of the dosage form.

· The cost of the polymer should not be high so that the prepared dosage form remains competitive.

THEORIES OF BIOADHESION

Mucoadhesion is a complex process,and numerous theories have been proposed to explain the mechanisms involved. The process of mucoadhesion is mainly based on the formation of two types of the bond between bioadhesive system and mucus membrane and they are:

I. Electronic theory

Attractive electrostatic forces between glycoprotein mucin network & the bioadhesive material. According to the electronic theory, there is the difference in the electronic structure of mucin surfaces and bioadhesive system which leads to reachingan electronic gradient. Due to the presenceof this electronic structure difference, when they come in contact with each the transfer of electrons occurs in these two systems (mucin surface and bioadhesive system). As a result of this electron transfer, there is the formation of an electronic bi-layer at the interface of the two surfaces. This interfacial bi-layer exerts an attractive force in the interface of two surfaces that may produce an effective Mucoadhesion.

II. Adsorption theory

Surface forces (covalent bond, ionic bond, hydrogen bond & van der Waals forces) resulting in chemical bonding. This theory describes the involvement of both type of chemical bond, that is, primary and secondary bond in the bio-adhesion mechanism. Both the surface that is drug delivery system and mucin has their surface energy. When they come in contact, the adhesion occurs due to the surface energy and results in the formation of two types of chemical bond. A primary chemical bond such as a covalent bond, which is strong, thus produces a permanent bonding, whereas secondary chemical bond involves Vander-Waals forces, hydrophobic interaction and hydrogen bonding, which are weak in nature, thus produces a semi-permanent bond.

III. Wetting theory

The ability of bioadhesive polymers to spread & develop intimate contact with the mucous membrane. This theory is basedupon the mechanism of spreadability of dosage form across the biological barrier. This theory is mainly applicable to liquids or low viscous mucoadhesive system. According to this theory, the active components penetrate into the surface irregularities and gets harden it that finally results in Mucoadhesion.

IV. Diffusion interlocking theory

Physical entanglement of mucin strands and flexible polymer chains. This theory describes the involvement of a mechanical bond between the polymeric chain of drug delivery system and polymeric chain of mucus membrane, that is, glycol proteins. When two surfaces are in intimate contact, the polymeric chain of drug delivery system penetrates into the glycoprotein network. According to this theory, the bio-adhesionbasically depends on the diffusion coefficient of both polymeric chains. The other factors that may influence the inter-movement of the polymeric chain are chain flexibility, molecular weight, cross linking density and temperature in order to achieve a good bio adhesion, the bio adhesive medium should have a similar solubility with glycoprotein resulting in effective Mucoadhesion.

V. Fracture theory

Analyses the maximum tensile stress developed during detachment of the BDDS from mucosal surfaces. The fracture theory is mainly based on the fact that, the force required separating the polymeric chain from the mucin layer is the strength of their adhesive forces. This strength may also be called as fracture strength. The fracture strength can be determined by using the formula given below:

G= (E. e/L) ½

G-Fracture strength,

E-Young’s modules of electricity,

E-Fracture energy,

L-Critical crack length(19)

MECHANISM OF BIOADHESION

The mechanisms responsible for the formation of bioadhesive bonds are not completely clear. To develop ideal bioadhesive drug delivery systems, it is important to describe and understand the forces that are responsible for adhesive bond formation. Most of the research has focused onanalyzing the bioadhesive interactions between soft tissue and polymeric hydrogels. The process involved in the formation of such bioadhesive bonds has been described in three steps:

· Wetting and swelling of polymer to permit intimate contact with biological tissue,

· Interpenetration of bioadhesive polymeric chains and entanglement of polymer and mucin chains,

· Formation of week chemical bonds between entangled chains.

Step 1- Contact stage

An intimate physical contact (wetting or swelling) occurs between the mucoadhesive and mucous membrane.

Step 2-Consolidation stage

Various physicochemical interactions occur to consolidate and strengthen the adhesive joint, leading to prolongedadhesion (interpenetration)(20).

FACTOR AFFECTING MUCOADHESIONS

The bioadhesive power of a polymer is affected by the nature of the polymer and also by the nature of the surrounding media.

1. Polymer-Related Factors

a) Molecular Weight

The adhesion property depends on the molecular weight of selected bioadhesive polymer. Bioadhesion is successful if the molecularweight is 100,000 and more.

Example: Polyethylene glycol (PEG) with a molecular weight of 20,000 has little adhesive character, whereas PEG with 200,000 molecular weight has improved, and a PEG with 400,000 has superior adhesive properties. The bioadhesive nature improves with increasing molecular weight for linear polymers.

Adhesiveness of a nonlinear structure follows the different trend.

Example: The adhesive strength of dextran, with a very high molecular weight of 19,500,000 is similar to that of PEG, with amolecular weight of 200,000. The reason for this similarity may bethat the helical conformation of dextran may shield many of theadhesive groups, which are primarily responsible for adhesion,unlike the conformation of PEG.

b) The concentration of active polymers

If there is an optimum concentration of bioadhesive polymer, produce maximum bioadhesion. In highly concentrated systems,beyond the optimum level, the adhesive strength drops significantlybecause the coiled molecules become separated from the medium sothat the chains available for interpenetration become limited.

c) The flexibility of polymer chains

If the polymer chains decrease, the effective length of the chain that can penetrate into mucous layer decreases, which reducesbioadhesive strength. It is critical for interpenetration andentanglement.

d) Spatial conformation

Besides molecular weight or chain length, the spatialconformation of a molecule is also important.

Example: High molecular weight of19,500,000 for dextrans, they have the similar adhesive strength to thepolyethylene glycol with a molecular weight of 200,000. The helicalconformation of dextran may shield many adhesively active groups,primarily responsible for adhesion, unlike PEG polymers which havea linear conformation(21).

2. Environment Related Factors

a) Applied strength

To place a solid bioadhesive system, it is necessary to apply a defined strength. Whatever the polymer, poly acrylicacid/vinylbenzene or carbopol 934, the adhesion strength increases with theapplied strength or with the duration of its application. If highpressure is applied for a sufficiently longperiod, polymersbecome mucoadhesive even though they do not have attractiveinteraction with mucin.

b) pH

Bioadhesion can be influenced by the charges present on the surfaceof mucus as well as certainionizable bioadhesive polymers. Mucuswill have a different charge density depending on pH due tothe difference in dissociation of functional groups on the carbohydratemoiety and the amino acids of the polypeptide backbone. pH of themedium is important for the degree of hydration.

Example: Poly acrylic acid, showing consistently increased hydration from pH 4 to 7 and then decrease as alkalinity and ionic strength increases.

c) Initial Contact Time

Contact time between the bioadhesive and mucus layer determinesthe extent of swelling and interpenetration of the bioadhesivepolymer chains. Moreover, bioadhesive strength increases as theinitial contact time increases.

d) Swelling

It depends on the polymer concentration, ionic concentration, aswell as the presence of water. Overhydration results in theformation of a slippery mucilage without adhesion(22).

3. Physiological Variables

a) Mucin Turnover

The natural turnover of mucin molecules is important for at least two reasons. First, the mucin turnover is expected to limit theresidence time of the mucoadhesive on the mucus layer. If theadhesive strength is high, mucoadhesive is detached from thesurface due to mucin turn over. Second, mucin turnover results insubstantial amounts of soluble mucin molecules. These moleculesinteract with the mucoadhesive before they have a chance tointeract with the mucus layer. Mucin turnover may depend on otherfactors such as the presence of food.

b) Disease States

The physiochemical properties of mucus are known to Change during disease conditions such as common cold, gastric ulcers, andulcerative colitis, and cystic fibrosis, bacterial and fungal infectionsof the female reproductive tract(23, 24).

MUCOADHESIVE POLYMERS

Mucoadhesive polymers can be water-soluble and water-insoluble polymers, which form a network, connected by cross-linking agents by the processes such as wetting, mutual adsorption,and interpenetration of polymer and mucus(25). Mucoadhesive polymers that adhere to the mucin-epithelial surface can be conveniently divided into three broad classes

· When polymers placed in water, it becomes sticky.

· Polymers that adhere to nonspecific, non-covalent interactions that are primarily electrostatic (although hydrogen and hydrophobic bonding may be significant).

· Polymers that bind to a specific receptor site on self-surface.

1) Natural polymers

a) Protein-based polymers: collagen, albumin, gelatin

b) Polysaccharides: Alginates, Cyclodextrines, Chitosan, Dextran, Agarose, Hyaluronic acid, Starch, Cellulose

2) Synthetic polymer

a) Biodegradable polymers

i. Polyesters: Polylactic acid, Polyglycolic acid, Polyhydroxyl butyrate, Polycaprolactone, Poly Doxanones

ii. Polyanhydride: Polyadipic acid, Polyterphthalic acid, Polysebacic acid and Various copolymers

iii. Polyamides: Poly iminocarbonates, Poly amino acids.

iv. Phosphorous Based polymers: Polyphosphates, Polyphosphonates,

Polyphosphazenes.

v. Others: Poly cyanoacrylates, Polyurethanes, Poly ortho esters, Polyacetals.

b) Non-biodegradable polymers

i. Cellulose derivatives: Carboxymethylcellulose, Ethyl cellulose, Cellulose acetate HPMC.

ii. Silicones: Polydimethyl siloxanes, Collodial silica, Polymethacrylates

Others: PVP, EVA, Poloxamines.

EVALUATION OF MUCOADHESIVE DRUG DELIVERY SYSTEMS

1. Measuring the force of attachment: The adhesive strength at bonding interface can be measured by measuring the force requiredto detach one entity from the other through the application of anexternal force. Hence the destruction of the adhesive bond is usuallyunder the application of either a shearing, tensile or peeling force.

2. Fluorescent probe method: In this method, the membrane lipid bilayered and membrane proteins were labeled with pyrene and fluorescein isothiocyanate, respectively. The cells were mixed with the mucoadhesive agents,and changes in fluorescence spectra were monitored. This gave a direct indication of polymer binding and its influence on polymer adhesion.

3. Thumb test: The adhesiveness is measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time. Although the thumb test may not be conclusive, it provides useful information on peel strength of the polymer.

4. In vitro residence time study: The mucoadhesive properties of tablets were evaluated by in vivo residence time. A 1-cm by a 1-cm piece of the porcine buccal mucosa was tied onto a glass slide (3-inch by 1-inch) using thread. Tablet was stuck onto the wet, rinsed, tissue specimen, by applying light force with a fingertip for 30 seconds. The prepared slide was hung onto one of the groves of a USP tablet disintegrating test apparatus. The disintegrating test apparatus was operated such that the tissue specimen was given regular up and down movements in a beaker containing the dissolution medium (0.01 N HCl). At the end of 3 hours, the detachment of tablet from tissue was checked and the time of detachment was recorded as the in vivo residence time.

5. GI transit study using radio-opaque markers: It is a simple procedure involving the use of radio-opaque markers, e.g., barium sulfate, encapsulated in bioadhesive to determine the effects of bioadhesive polymers on GI transit time. Feces collection (using an automated feces collection machine) and X-ray inspection provide a non-invasive method of monitoring total GI residence time withoutaffecting normal GI motility(22).

CONCLUSION:

The mucoadhesive drug delivery system is cumulative for delivering the drugs which have narrow absorption window at the target site to optimize their usefulness. The oral route is the most ancient as well as preferred by the patient being convenient to take similarly in Mucoadhesive dosage forms has inclined patient towards due to ease of drug administration and Painless administration. Studies on Mucoadhesive system have focused on a broad array of aspects as distended from the simple oral mucosal delivery to the nasal, vaginal, ocular and rectal drug delivery systems. In all, it was good to see that the students were propelled towards the said target and they have now known the basics of the publication process. Henceforth, this article will prove to be a milestone in their future research carrier.

AKNOWLEDGMENT:

The author wants to show a sincere gratitude to the Rungta College of Pharmaceutical Sciences and Research for providing necessary facilities for the completion of work.

CONFLICT OF INTEREST:

None.

REFERENCES:

1. Netsomboon K, Bernkop-Schnurch A. Mucoadhesive vs. mucopenetrating particulate drug delivery. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV. 2016;98:76-89.

2. Silva BM, Borges AF, Silva C, Coelho JF, Simoes S. Mucoadhesive oral films: The potential for unmet needs. International journal of pharmaceutics. 2015;494(1):537-51.

3. Montenegro-Nicolini M, Morales JO. Overview and Future Potential of Buccal Mucoadhesive Films as Drug Delivery Systems for Biologics. AAPS PharmSciTech. 2017;18(1):3-14.

4. Shinkar DM, Dhake AS, Setty CM. Drug delivery from the oral cavity: a focus on mucoadhesive buccal drug delivery systems. PDA journal of pharmaceutical science and technology. 2012;66(5):466-500.

5. Laffleur F. Mucoadhesive polymers for buccal drug delivery. Drug development and industrial pharmacy. 2014;40(5):591-8.

6. Duggan S, Cummins W, O OD, Hughes H, Owens E. Thiolated polymers as mucoadhesive drug delivery systems. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2017;100:64-78.

7. Cook MT, Khutoryanskiy VV. Mucoadhesion and mucosa-mimetic materials--A mini-review. International journal of pharmaceutics. 2015;495(2):991-8.

8. Gilhotra RM, Ikram M, Srivastava S, Gilhotra N. A clinical perspective on mucoadhesive buccal drug delivery systems. Journal of biomedical research. 2014;28(2):81-97.

9. Bruschi ML, de Francisco LM, A SdTL, Borghi FB. An overview of recent patents on composition of mucoadhesive drug delivery systems. Recent Pat Drug Deliv Formul. 2015;9(1):79-87.