Polymers in Mucoadhesive Drug Delivery System: A Brief Note
About Authors: NIDHI KARIA1*, RAKHI CHANDAK1, ARATI RATHI2
1. P.WADHWANI COLLEGE OF PHARMACY,YAVATMAL
2. ASST PROFFESER AT SUMANDEEP DEPARMENT OF PHARMACY, VADODARA
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 . 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 . 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) .
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.
THEORIES OF MUCOADHESION
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 . 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 .
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