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Mucus layer thickness can vary from 50-450 µm in the stomach to less than 1 µm in the oral cavity21. Mucus contains high molecular weight glycoprotein macromolecular constituent (0.2 and 10 million Dalton) called as mucin. Mucin contains one or more domains which are highly glycosylated. The glycosylated domains are enriched in serine and threonine residues which serve as anchoring points for oligosaccharide side chains. These O-linked oligosaccharide side chains are complex both in terms of composition and length22. Mucin contains 68 and 81% by weight fraction carbohydrate23. Mucin also contains "naked domains" which are present in the N-terminal and C-terminal part of the protein, slightly glycosylated or non glycosylated and abundantly contains cysteine residues. The cysteine residues can form intermolecular bonds24.
The glycosylated regions of mucin interact favorably with water and force the molecule to an extended random coil conformation, and the high molecular weight enables individual mucin molecules to overlap and entangle at relatively low concentrations. These characteristics are ideal with respect to the formation of hydrogel and investigations have shown that reconstructed mucous gels from mucin have similar rheological properties as native mucous gels at physiological concentrations25.
Mucins are responsible for the viscoelastic properties of the mucus secretions. Mucins are negatively charged molecules because of the presence of sialic acid and sulphated sugars residues on their surfaces. This produces attraction forces between mucin and positively charged drug carriers in delivery system26. Thus adhesive properties of mucin generate keen interest in the development of gastro retentive drug delivery systems through the use of bio/mucoadhesive polymers27.
1.4 Mechanisms and theories of mucoadhesion
The binding of polymers to the mucin epithelial surface can be studied through28-29 hydration mediated adhesion, receptor mediated adhesion and bonding mediated adhesion. Hydration mediated adhesion is produced when hydrophilic polymers tend to absorb large amount of water and become sticky, thereby acquiring mucoadhesive properties. Receptor mediated adhesion occurs when polymers bind to specific receptor sites on the surface of cells which enhances the gastric retention of dosage forms. Plant lectins e.g. tomato lectins interact specifically with the sugar groups present in mucus or on the glycocalyx. Bonding mediated adhesion occurs when the adhesion of polymers to a mucus or epithelial cell surface involves physical bonding and chemical bonding. Physical bonds can result from the insertion of the adhesive material into the crevices or folds of the mucosa. Chemical bonds may be either covalent (primary) or ionic (secondary) in nature. Secondary chemical bonds consist of van der Waals' interactions and stronger specific interactions such as hydrogen bonds. The hydrophilic functional groups responsible for forming hydrogen bonds are the hydroxyl and carboxylic groups.
1.4.1 Steps of Mucoadhesion
Wetting and swelling is subjected to spreading of the polymer over mucosal membrane in order to develop an intimate contact with the substrate. The components available within the polymers have an affinity for water which leads swelling of polymers.
Mucoadhesive bond formation is subjected to mucoadhesive bond formation between the mucoadhesive polymer chains and the mucosal polymer chains (glycoproteins) where they intermingle and entangle to form semi permeable adhesive bonds. The strength of these bonds depends on the degree of penetration between the two polymer groups. In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure.
Formation of weak chemical bonds between the entangled polymer chains subjected to the formation of weak chemical bonds between the entangled polymer chains. 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 mucoadhesive formulations in which strong adhesions between polymers are formed.
Adhesion of drug delivery system onto mucous membrane can be affected by the mucociliary clearance system. It is a natural defense mechanism of the body against the deposition of substances onto the mucous membrane which can also remove the drug delivery system. Thus, it is possible to retain the delivery system at the site of action and to allow the drug to absorb at specific site or tissue, by using mucoadhesive polymers. Other advantage associated with the development of prolonged release mucoadhesive drug delivery systems is to decrease the drug administration frequency and to increase the patient compliance to the therapy6.
1.4.2 The mucoadhesive/mucosa interaction
Mucoadhesive are synthetic or natural polymer, which interact with the mucus layer covering the mucosal epithelial surface, and mucin molecules constituting a major part of mucus12, 21, 30, 31. For adhesion to occur, molecules must bond across the interface. These bonds can arise in the following way.
Ionic bonds-where two oppositely charged ions attract each other via electrostatic interactions to form a strong bond (e.g. in a salt crystal).
Covalent bonds-where electrons are shared, in pairs, between the bonded atoms in order to fill the orbitals in both. These are also strong bonds.
Hydrogen bonds-here a hydrogen atom, when covalently bonded to electronegative atoms such as oxygen, fluorine or nitrogen, carries a slight positive charge and is therefore is attracted to other electronegative atoms. The hydrogen can therefore be thought of as being shared, and the bond formed is generally weaker than ionic or covalent bonds.
Van der Waals' bonds-these are some of the weakest forms of interaction that arise from dipole-dipole and dipole-induced dipole attractions in polar molecules, and dispersion forces with non-polar substances.
Hydrophobic bonds-more accurately described as the hydrophobic effect, these are indirect bonds (such groups only appear to be attracted to each other) that occur when non-polar groups are present in an aqueous solution. Water molecules adjacent to non-polar groups form hydrogen bonded structures, which lowers the system entropy. There is therefore an increase in the tendency of non-polar groups to associate with each other to minimize this effect.