Polymers in Mucoadhesive Drug Delivery System: A Brief Note


Bioadhesion can be defined as the process by which a natural or a synthetic polymer can adhere to a biological substrate. When the biological substrate is a mucosal layer then the phenomena is known as mucoadhesion. The substrate possessing bioadhesive property can help in devising a delivery system capable of delivering a bioactive agent for a prolonged period of time at a specific delivery site. The current review  provides  a good insight on mucoadhesive polymers, the phenomenon of mucoadhesion and the factors which have the ability to affect the mucoadhesive properties of a polymer.

Reference Id: PHARMATUTOR-ART-1177

Bioadhesion can be defined as a phenomenon of interfacial molecular attractive forces amongst the surfaces of the biological substrate and the natural or synthetic polymers, which allows the polymer to adhere to the  biological surface for an extended period of time [1-4]. Bioadhesive polymeric systems have been used since long time in the development of products for various biomedical applications which include denture adhesives and surgical glue [5-8]. The adhesion of bacteria to the human gut may be attributed to the interaction of lectin-like structure (present on the cell surface of bacteria) and mucin (present in the biological tissues) [9-12]. In general, various  biopolymers  show  the  bioadhesive  properties  and  have  been  utilized  for  various therapeutic purposes in medicine [2, 13]. The bioadhesive polymers can be broadly classified into two groups, namely specific and nonspecific [14]. The specific bioadhesive polymers (e.g. lectins, fimbrin) have the ability to adhere to specific chemical structures within the biological molecules while  the nonspecific bioadhesive polymers (e.g. polyacrylic acid, cyanoacrylates) have the ability to bind with both the cell surfaces and the mucosal layer.
The use of mucoadhesive polymers for the development of pharmaceutical formulations dates back to 1947,  when attempts were made to formulate a penicillin drug delivery system for delivering the bioactive agent to  the oral mucosa using gum tragacanth and dental adhesive powders [15].  Improved  results were reported  when carboxymethylcellulose and petrolatum were  used  for  the  development  of  the  formulation.  Subsequent   research  resulted  in  the development  of  a  mucoadhesive  delivery vehicle  which  consisted  of  finely  ground  sodium carboxymethylcellulose (SCMC), pectin, and gelatin. The formulation was later marketed as Orahesive®. Another formulation which entered into the clinical trials is Orabase®, which is a blend of  polymethylene/ mineral oil base. This was followed by the development of a system where polyethylene sheet  was laminated with a blend of sodium carboxymethylcellulose and poly (isobutylene) which provided an added advantage of protecting the mucoadhesive layer by the polyethylene backing from the physical interference of the external environment [16-18].
Over the years, various other polymers (e.g. sodium alginate, sodium carboxymethylcellulose, guar gum, hydroxyethylcellulose, karya gum, methylcellulose, polyethylene glycol (PEG), retene and tragacanth) have been found to exhibit mucoadhesive properties. During the period of 1980s poly (acrylic acid), hydroxypropylcellulose,  and sodium carboxymethylcellulose were widely explored for the development of formulations having mucoadhesive properties. Since then the use of acrylate polymers for the development of mucoadhesive  formulations have increased many-fold, various authors have investigated the mucoadhesive properties of different polymers with varying molecular architecture [19-21]. After a lot of research, the researchers are of the view  that  a  polymer  will  exhibit  sufficient  mucoadhesive  property  if  it  can  form  strong intermolecular hydrogen  bonding with the mucosal layer, penetration of the polymer into the mucus network or tissue crevices, easy wetting of mucosal layer and high molecular weight of the polymer chain. The ideal characteristics of a mucoadhesive polymer matrix include the rapid adherence to the mucosal layer without any change in the  physical property of the delivery matrix, minimum interference to the release of the active agent, biodegradable without producing any toxic byproducts, inhibit the enzymes present at the delivery site and enhance the penetration of the active agent (if the active agent is meant to be absorbed from the delivery site) [22].

Before discussing  about  the commonly used  mucoadhesive  polymers,  the different  theories which have been  proposed to explain the phenomenon of mucoadhesion will be discussed. Furthermore, different factors affecting mucoadhesion, methods of evaluation of mucoadhesive properties  of  polymers  and  the  potential  biological  sites  where  mucoadhesion  can  play  an important role will be taken up for discussion.

The phenomena of bioadhesion occurs by a complex mechanism. Till date, six theories have been proposed  which can improve our understanding for the phenomena of adhesion and can also  be  extended  to  explain  the  mechanism  of  bioadhesion.  The  theories  include:  (a)  the electronic theory, (b) the wetting theory, (c) the adsorption theory, (d) the diffusion theory, (e) the mechanical theory and (f) the cohesive theory. The electronic  theory proposes transfer of electrons amongst the surfaces resulting in the formation of an electrical double layer  thereby giving rise to attractive forces. The wetting theory postulates 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. The adsorption theory proposes the presence of intermolecular forces,  viz. hydrogen  bonding and  Van der Waal’s forces, for the adhesive interaction amongst the substrate surfaces. The diffusion theory assumes  the  diffusion  of  the  polymer  chains,  present  on  the  substrate  surfaces,  across  the adhesive interface thereby forming a networked structure. The mechanical theory explains the diffusion of the liquid adhesives into the micro-cracks and irregularities present on the substrate surface thereby forming an  interlocked structure which gives rise to adhesion. The cohesive theory  proposes  that  the  phenomena  of  bioadhesion  are  mainly  due  to  the  intermolecular interactions amongst like-molecules [23-24].
Based on the above theories, the process of bioadhesion can be broadly classified into two categories, namely chemical (electronic and adsorption theories) and physical (wetting, diffusion and cohesive theory) methods [25-26]. The process of adhesion may be divided into two stages. During the first stage (also known as contact  stage), wetting of mucoadhesive polymer and mucous membrane occurs followed by the consolidation stage,  where the physico-chemical interactions prevail [27-28].
As mentioned above, bioadhesion may take place either by physical or by chemical interactions. These  interactions  can  be  further  classified  as  hydrogen  bonds,  Van  der  Waals  force  and hydrophobic bonds which  are considered as physical interactions while the formation of ionic and covalent bonds are categorized as chemical interactions. Hydrogen bonds are formed due to the interaction of the electronegative and electropositive atoms though there is no actual transfer of electrons. Example of this kind of interaction includes formation of  gelled structure when aqueous solutions of polyvinyl alcohol and glycine are mixed. Van der Waals forces are either due to presence of the dipole-dipole interactions in polar molecules or due to the dispersion forces amongst non-polar substrates. Hydrophobic bonds are formed due to the interaction of the non-polar groups when  the polymers are dispersed in an aqueous solution. Freeze-thawing of polyvinyl alcohol solution in water exhibits this kind of interaction.  Ionic bonds are formed due to the electrostatic interactions amongst the polymers (e.g.  instantaneous formation of gelled structure when alginate and chitosan solutions in water are mixed) while  covalent bonds are formed due to the sharing of electrons amongst the atoms (e.g. crosslinking reaction amongst genipin and amino groups).
The term “mucoadhesion” was coined for the adhesion of the polymers with the surface of the mucosal layer [29]. The mucosal layer is made up of mucus which is secreted by the goblet cells (glandular columnar epithelial cells) and is a viscoelastic fluid. It lines the visceral organs, which are exposed to the external environment. The main components constituting the mucosa include water and mucin (an anionic polyelectrolyte), while the other components include proteins, lipids and mucopolysaccharides. Water and mucin constitute > 99% of the total  composition of the mucus and out of this > 95% is water. The gel-like structure of the mucus can be attributed to the intermolecular   entanglements   of   the   mucin   glycoproteins   along   with   the   non-covalent interactions (e.g. hydrogen, electrostatic and hydrophobic bonds) which results in the formation of a hydrated gel-like structure and explains the viscoelastic nature of the mucus [24].


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