Mucoadhesion

A mucoadhesive drug delivery system is the system which utilizes the property of bio adhesion of certain polymers which become adhesive on hydration and can be used for targeting a drug to a particular region of the body for extended periods.  The term “mucoadhesion” was coined for the adhesion of the polymers with the surface of the mucosal layer. Bio adhesions are a phenomenon in which two materials at least one of which is biological and are held together using interfacial forces. In biological systems, bio adhesion can be classified into 3 types: 

1. Adhesion between two biological phases, for example, platelet aggregation and wound healing. 
2. Adhesion of a biological phase to an artificial substrate, for example, cell adhesion to culture dishes and biofilm formation on prosthetic devices and inserts. 
3. Adhesion of artificial material to a biological substrate, for example, adhesion of synthetic hydrogels to soft tissues and adhesion of sealants to dental enamel. 

For drug delivery purposes, the term bio adhesion implies the attachment of a drug carrier system to a specified biological location. The biological surface can be epithelial tissue or the mucus coat on the surface of a tissue. If the adhesive attachment is to a mucus coat, the phenomenon is referred to as mucoadhesion/ mucoadhesion as the interaction between a mucin surface and a synthetic or natural polymer. In bio adhesion, the polymer is attached to the biological membrane. 

Table.1: Composition of Mucous Membrane 

Sr. No.	Composition	% Amount
1.	Water	95
2.	Glycoprotein and Lipids	0.5-5.0
3.	Mineral salts	1
4.	Free proteins	0.5-1.0

Advantages of Mucoadhesive Systems 

Mucoadhesive systems have three distinct advantages when compared to conventional dosage forms: 

1. Readily localized in the region applied to improve and enhance the bioavailability of drugs. E.g. testosterone and its esters, vasopressin, dopamine, insulin and gentamycin, etc. 
2. Facilitate intimate contact of the formulation with the underlying absorption surface. This allows modification of tissue permeability for absorption of macromolecules. E.g. peptides and proteins. 
3. Prolong residence time of the dosage form at the site of application and absorption to permit once or twice a day dosing.

Stages of Mucoadhesion 

1. Contact Stage
2. Consolidation Stage 

Mechanism of Mucoadhesion 

Theories of Mucoadhesion 

The concept of mucoadhesion has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption. The mechanisms responsible for the formation of bio-adhesive bonds are not fully known. However, most research has described bioadhesive bond formation as a three-step process: 

• Step 1: Wetting and swelling of the polymer. 
• Step 2: Interpenetration between the polymer chains and the mucosal membrane. 
• Step 3: Formation of Chemical bonds between the entangled chains. 

Step 1: The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane to develop intimate contact with the substrate. This can be readily achieved. For example, by placing a bioadhesive formulation such as; a tablet or paste within the oral cavity or vagina. Bioadhesives can adhere to or bond with biological tissues with the help of the surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occurs because the components within the polymers have an affinity for water. 

Step 1: The wetting and swelling.

Step 2: The surface of mucosal membranes is composed of high molecular weight polymers known as glycoproteins. In this step, interdiffusion and interpenetration take place between the chains of mucoadhesive polymers and the mucous gel network creating a great area of contact. The strength of these bonds depends on the degree of penetration between the two polymer groups. To form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure. 

Step 3: In this step, entanglement and formation of weak chemical bonds as well as secondary bonds between the polymer chains mucin molecule. The types of bonding formed between the chains include primary bonds such as covalent bonds and weaker secondary interactions such as van der Waals interactions and hydrogen bonds. Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed.

A complete understanding of how and why certain macromolecules attach to a mucus surface is not yet available, but a few steps involved in the process are generally accepted, at least for solid systems. Several theories have been proposed to explain the fundamental mechanism of adhesion.

The phenomena of bio adhesion occur by a complex mechanism. Six theories have been proposed, which will explain the mechanism of bio adhesion. The theories are as follows:

(a) Electronic theory: Involves the formation of an electric double layer at the mucoadhesive interface by the transfer of electrons between the mucoadhesive polymer and the mucin glycoprotein network. For example: Interaction between positively charged polymers chitosan and negatively charged mucosal surface which becomes adhesive on hydration and provides intimate contact between a dosage form and absorbing tissue.

(b) Wetting Theory: States that if the contact angle of liquids on the substrate surface is lower, then there is a greater affinity for the liquid to the substrate surface. If two such substrate surfaces are brought in contact with each other in the presence of the liquid, the liquid may act as an adhesive amongst the substrate surfaces. 

(c) Adsorption Theory: According to this theory, after initial contact between two surfaces, the material adheres because of surface force acting between the atoms in two surfaces. 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 like electrostatic forces, Vander Walls forces, hydrogen, and hydrophobic bonds.

(d) Diffusion Theory: According to this theory, the polymer chains and the mucus mix to a sufficient depth to create a semi-permanent adhesive bond. The exact depth to which the polymer chain penetrates the mucus depends on the diffusion coefficient and the time of contact. The diffusion coefficient in terms depends on the value of molecular weight between cross-linking and decreases significantly as the cross-linking density increases. 

(e) Mechanical Theory: Explains the diffusion of the liquid adhesives into the microcracks and irregularities present on the substrate surface thereby forming an interlocked structure that gives rise to adhesion. 

(f) Cohesive Theory: Proposes that the phenomena of bio adhesion are mainly due to the intermolecular interactions amongst like-molecules. Based on the above theories, the process of bio adhesion can be broadly classified into two categories.

• Chemical: Electronic and adsorption theories.
• Physical: Wetting, diffusion and cohesive theory. 

The process of adhesion may be divided into two stages. During the first stage (also known as the contact stage), wetting of mucoadhesive polymer and mucous membrane occurs followed by the consolidation stage, where the physicochemical interactions take place. 

Application of Mucoadhesive Microspheres

• Vaccine delivery for treatment of diseases like; hepatitis, influenza, pertussis, ricin toxoid, diphtheria, birth control. Microsphere in vaccine delivery has specific advantages like improved antigenicity by adjuvant action, modulation of antigen release, stabilization of antigen.
• Passive targeting of leaky tumour vessels, active targeting of tumour cells, antigens, by intra-arterial/ intravenous application. The concept of targeting i.e. site-specific drug delivery is well established because the placement of the micro-particles in discrete anatomical compartments leads to their retention either because of physical properties of the environment or biophysical interaction of the particles with the cellular content of the target tissue.
• Chemoembolization is an endovascular therapy, which involves the selective arterial embolization of a tumour together with simultaneous or subsequent local delivery of the chemotherapeutic agent. The theoretical advantage is that such embolizations will not only provide vascular occlusion but will bring about sustained therapeutic levels of chemotherapeutics in the areas of the tumour. Chemoembolization is an extension of traditional percutaneous embolization techniques.
• Imaging: The microspheres have been extensively studied and used for targeting purposes. Various cells, cell lines, tissues and organs can be imaged using radio-labelled microspheres. The particle size range of microspheres is an important factor in determining the imaging of particular sites. The particles injected intravenously apart from the portal vein will become entrapped in the capillary bed of the lungs. This phenomenon is exploited for the scintigraphic imaging of the tumour masses in lungs using labelled human serum albumin microspheres.
  1. Release of proteins, hormones and peptides over an extended period. 
  2. Gene therapy with DNA plasmids and also delivery of insulin.
• Topical porous microspheres: Micro sponges are porous microspheres having a myriad of interconnected voids of particle size range 5-300 µm. These micro-sponges having the capacity to entrap a wide range of active ingredients such as emollients, fragrances, essential oils, etc., are used as the topical carries system.
• Surface modified microspheres: Different approaches have been utilized to change the surface properties of carriers to protect them against phagocytic clearance and to alter their body distribution patterns. The most studied surface modifiers are; Antibodies and their fragments, Proteins, Mono-oligo- and polysaccharide, Chelating compounds (EDTA, DTPA or desferrioxamine), synthetic soluble polymers. Such modifications are provided with the surface of microspheres to achieve the targeting of the discrete organs.

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