Mucoadhesive Polymers and Their Mode of Action : A Recent Update

Article history: Received on: 17/02/2017 Accepted on: 23/04/2017 Available online: 30/05/2017 The potential of mucoadhesive delivery system for sustained delivery of drug has been established few decades back. Different polymeric systems such as single or combined, substituted, conjugated, pre-activated polymer (s) etc. are used to develop such delivery platform. To explain the mucoadhesion mechanism, several possible theories namely electronic theory, adsorption theory, wetting theory, diffusion theory, fraction theory and mechanical theory have been proposed. But none of these theories alone can explain the mechanism of mucoadhesion. Various mechanisms of mucoadhesion or bioadhesion between polymer and mucin such as H bonding, electrostatic interactions, di-sulfide linkage, van Der Waals attraction etc have been evidenced. Researches are focused to enrich such interaction between the mucous layer and the delivery platform by modifying the system. Wide varieties of polymers such as cationic, anionic, non-ionic, thiolated polymers etc have been used to design and develop mucoadhesive drug delivery system. Therefore reviewing and analyzing the mucoadhesive polymeric system and their mechanism of action is still relevant and necessary. The aim of this current review is to highlight the polymers which are being used under recent scientific researches with emphasis on their mechanism of mucoadhesion. The result of this critique will assist researchers to screen the mucoadhesive polymers for their designated purpose.


INTRODUCTION
Mucoadhesive formulation contains one or more hydrophilic polymers along with drug.When it comes in contact to saliva, due to the aqueous nature of saliva it becomes wet and the drug releases from the system.Simultaneously modified drug delivery system (MDDS) adheres to the mucous with some physical interaction.Mucous, secreted from salivary gland or epithelial glands is an aqueous based viscoelastic complex mixture of proteins, nucleic acid, immunoglobulins, enzymes, lipids and several ionic species (Russo et al., 2016).Functionally mucus membrane or mucosa provides a protective barrier, an adhesive function and lubricant effect (Bader and Putnam, .2013).The success of MDDS depends on the ability of the polymer/s to retain at the mucous layer and to sustain the drug release.
This indicates the importance of polymeric properties for successful development of mucoadhesive preparation.In general polymers consisting carboxyl, amine or hydroxyl groups with certain molecular weight have potential to prolong retention of the system with mucous layer (Bader and Putnam, 2013).Cellulose derivatives, chitosan, pectin, hyaluronic acids, alginates, thiolated derivatives are few examples of commonly applicable mucoadhesive polymers.In different published reviews the construction or composition of mucous layer, the theory of mucoadhesison has been addressed extensively (Smart, 2014).In this review different polymers that are used in recent times to design and develop MDDS are discussed with special emphasis on the mechanism of mucoadhesion exerted by respective polymer (s).

CHALLENGES BY MUCUS MEMBRANE TO DRUG DELIVERY
Mucus layer, also known as mucosal membrane creates challenges to the drug delivery system and drug absorption due to its physicochemical nature and composition.Mucus is a complex secretion of mucus layer which consist of water and mucin.It forms a gel like layer on the epithelial membrane of the oral cavity, nose or some other body cavities.Chemically mucin is glycoprotein which is composed of single chain amino acid backbones (mainly serine, threonine and proline) with branched oligosaccharide chains containing N-acetyl galactosamine, N acetyl glucosamine, fructose, galactose etc. (Bader and Putnam, 2013).The dynamic formation and fate of mucin has made a nonstagnant mucin composition in the body cavities.This dynamic nature influences the mucus composition which in turn creates a challenge to prolonged muacoadhesion by the drug delivery system and drug absorption.The formation and fate of mucus are a major biological factor behind the retention of delivery system on the mucus membrane (Russo et al., 2016).The mucus formation rate may also suffer from patient variation, fasted state-fed state, and disease conditions such as peptic ulcer, ulcerative colitis, bacterial or fungal infection etc.The thickness of gel like mucus layer also varies in such conditions.Therefore to design an optimized MDDS for all type of patients is really challenging.The soluble mucin molecule may react with the adhesive delivery system prior to attaching to the mucus membrane which may limit the bio-adhesion.Moreover, mucus layer itself causes decrease in drug absorption by reducing diffusion through it and by binding with the drug molecules (Khanvilkar et al., 2001;Lai et al., 2009).

MUCOADHESION THEORIES AND MECHANISMS
There are several general theories that can explain mucoadhesion such as electronic theory, adsorption theory, wetting theory, diffusion theory, fraction theory and mechanical theory.For an overview, the theories explained by different researchers are summarized by Table 1.
Combination of all the possible theories together helps in explaining several mechanisms about mucoadhesion.The dosage form needs to become swell and spread on the mucus, which explains the wetting theory.
Next, within the mucus-polymer interface due to electric charges distribution (electronic theory) linkages might be created (adsorption theory).Following that, the polymer and protein chains diffuse together (diffusion theory) and entangle together, forming further bonding (electronic and adsorption theories) for longer adhesion.These mechanisms also can be categorized into two, which are contact stage and consolidation stage, explained by Fig 1.
During contact stage, wetting will occur between dosage form and mucus surface.During consolidation stage the plasticizing and adhesion activity of the polymers are activated by the moisture that promotes formation of hydrogen bonds and van Der Waals force.Diffusion theory also explains the consolidation phase where the glycoprotein of mucus layer and the polymer molecules inter-diffuses and form secondary bonds.This will strengthen and prolong the adhesion.It can be said that bioadhesion or mucoadhesion cannot be explained by a single theory rather it is better explained by combining all or some of the above mentioned mechanisms.Formation of electrostatic attraction from electron transfer between mucoadhesive polymer and mucous membrane that possess di fferent electronic charges [Smart,2014, Smart, 2005].

Adsorption theory
Adhesion between mucus and polymer that is achieved via intermolecular interactions [Smart, 2014].

Wetting theory
Capability of mucoadhesive polymer to spread on the mucus with respect to its surface tension [Smart, 2014].

Diffusion theory
Diffusion of polymer into the mucus and vice versa, resulting in formation of an interpenetration layer [Smart, 2014].

Fracture theory
Strength required detaching two surfaces after adhesion [Leung and Robinson, 1990].

Mechanical theory
Considers the effect of surface roughness, which favors the adhesion due to an increased contact area [Leung and Robinson, 1990].There are three major factors that affect mucoadhesion in a broader sense, which include environmental factor, physiological factor and polymeric factor.These factors are described in detail by different researchers earlier (Burgalassi et al., 2015).In this review, we have concentrated on the polymeric factors because polymer is the most important component of a mucoadhesive drug delivery system.Environmental factor such as pH at the mucoadhesion site affects ionizable functional group of ionic polymers that are used as an adhesive layer in the formulation such as a carboxylic group for anionic polymers.Ionic polymer provides a higher degree of mucoadhesion by interaction of the ionizable functional group with charged component of mucin layer thus promoting a strong adhesiveness.Polymer will be largely ionized if the pH at the mucoadhesion site is above the pKa value of the polymer whereas it will be largely unionized if pH at mucoadhesion site is below pKa (Shaikh et al., 2011).Other factor that can affect mucoadhesion is physiological factor specifically mucin turnover factor which has been discussed earlier in this article.Apart from environmental and physiological factors, major responsible factor from the formulation point of view is the polymeric nature that present in the formulation.Polymeric factors that may affect mucoadhesion include hydrogen bonding capacity and hydrophilicity, molecular weight, cross-linking, spatial conformation and concentration of polymer.

Hydrogen bonding capacity and hydrophilicity
Hydrophilic functional groups such as carboxyl and hydroxyl allow hydrogen bonding between the polymer and mucous membrane.More hydrophilic functional groups enable the formation of more hydrogen bonding.The degree of hydration of a polymer depends on its molecular structure.Hydration is important for polymer to swell on mucus layer, creating a maximal exposure for interpenetration between polymer and mucin as well as providing entanglement between them.However, excess hydration may reduce mucoadhesion and slippery mucilage will form instead (Perioli et al., 2004).

Molecular weight
In general, the interpenetration of polymer molecules is better in low molecular weight polymers, while higher molecular weight polymer can entangle better (Jain et al., 2012).For maximum mucoadhesion, optimum molecular weight of polymer is needed.However, it depends on the type of polymer used.Different type of polymer used will have different optimum molecular weight to achieve better bioadhesion (Edsman and Hägerström, 2005).

Cross-linking
More cross-linking provides less flexibility of the chain, thus limiting interpenetration as well as entanglement hence reducing mucoadhesion.In addition, greater cross-linking density will provide lesser swelling (Laffleur, 2014).This will reduce area for interpenetration between polymer and mucin resulting weaker adhesion.Thus, for maximum mucoadhesion, lesser cross-linking density of polymer is favored with addition of higher hydration rate and flexibility which will promote greater swelling.

Spatial conformation
Conformation of polymer molecules may affect mucoadhesion because some of the conformation may hinder functional groups that responsible for bonding with mucin.For example, helical conformation (e.g.Dextran) of a polymer may require higher concentration to produce same mucoadhesive strength as liner conformation such as polyethylene glycol (Hombach and Bernkop-Schnurch, 2010).

Concentration of polymer
This factor depends on type of dosage form.In case of solid dosage form, the higher the concentration of polymer, the stronger the mucoadhesion.However, for liquid dosage form, maximum mucoadhesion is shown when there is an optimum polymer concentration (Duchene and Peppas, 1988).
Other factor that may affect mucoadhesion is pressure applied initially during application.By giving higher pressure, it will increase the depth of interpenetration and prolong initial contact between polymer and mucous membrane resulting stronger mucoadhesion (Hombach and Bernkop-Schnurch, 2010).

POLYMERS USED IN MUCOADHESIVE DRUG DELIVERY SYSTEM
Huge numbers of polymers have been used to design and develop MDDS which are categorized as cationic, anionic, nonionic, thiolated polymers etc.Among the chemical groups evaluated extensively for mucoadhesion, acrylate polymers, cellulose derivatives, chitosan, alginates are most prevalent.Different composite materials, chemically modified polymers and combination of two or more than polymers are also applied to design the system (Russo et al., 2016).Due to lack of any compendial assay method and wide variety of experimental evaluations it is very difficult to categorize the polymers based on their mucoadhesion strength.The polymers cannot be categorized based on the source also.Because the boundary between synthetic and semi-synthetic is very narrow and often is a matter of debate.Based on the mechanism of mucoadhesion also, the classification of polymers is very difficult because either the polymers act by more than one mechanisms or the mechanism is not fully understood.Based on these considerations in this review we have described the polymers used for mucoadhesive delivery system with respect to the main chemical groups.The mechanism of mucoadhesion for each type is especially emphasized.

Acrylic acid derivative/Poly acrylate
Chemically polyacrylate is cross linked polymers of acrylic acid with divinyl glycol or polyalkenylether substitution.Methyl group substituted acrylate is a common type of plastic available at present.Among the polyacrylates, polycarbophil and carbomer have been extensively studied for polymeric platform of MDDS.Polycarbophil and carbomer differs in the cross linked pattern and viscosity.Carbomer grades with non-residual benzene content like 934P, 971P etc are extensively studied for mucoadhesion nature (Singla et al., 2000).The functional carboxylic acid groups of carbomers become ionized at moderately higher pH (around 6.2).The resultant electrostatic repulsion causes uncoiling of polymeric chain.Such uncoiling promotes mechanical entanglement and interaction of polymers with the mucus glycoprotein.Presence of numerous carboxylic groups in carbomer create favorable macromolecular conformation and increase accessibility of H bond forming groups (Mortazavi, 2002).Polycarbophil is insoluble in aqueous medium but has high swelling capacity.It was also reported enhanced H bonding by polycarbophil with glycoprotein of mucus after relaxation in intestine by Zhu et al. (2013).This bonding promotes penetration and interlinking of the polymer with mucus network, causing better adhesion.
Despite excellent mucoadhesive properties polyacrylates swells upon hydration resulting patient inconveniences.To overcome this drawback polyacrylates were modified by methyl group substitution forming poly methacrylate or polymethyl methacrylate.Polymethyl methacrylate (Eudragit® S100) has shown no swelling with satisfactory bioadhesion after salification with sodium salt.Drug release pattern was governed by erosion from the patch and tablets prepared from those methacrylate salts (Elhady et al., 2003).
Another modification of polyacrylate was done by thiolation or cysteine conjugation targeting better bioadhesion.Thiolated polycarbophil is derived by neutralizing its carboxyl group with sodium hydroxide (NaOH) and covalent bonding with cysteine amino groups (Wasnik and Godse, 2014).The thiolated polymer forms disulfide bond (S=S) with cysteine moiety of subdomains of mucus glycoprotein by either thio/disulfide exchange or oxidation of thiol group, resulting increased mucoadhesion.These mucoadhesive features prevented all thiolated formulations from reaching and/or adhering to the epithelial cell membrane and inhibited their absorption-enhancing effects.Therefore, sustained drug release pattern might be achieved from this backbone.Sustained drug release from thiolated polyacrylate was also demonstrated by Wasnik et al. (2014) where they observed higher drug release retardant property of polyacrylate-cysteine conjugate compared to non-thioalted polyacrylte.It is to note that both type of polymers were used to deliver antiparkisonism drug via buccal mucoahesive patch.

Cellulose derivative
Cellulose derivatives such as hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), hydroxyl ethyl cellulose (HEC), carboxy methyl cellulose (CMC) are considered as first generation mucoadhesive polymers (Bader Putnam, 2013).The mechanism of adhesion involves formation of H bond between caroboxylic acid group of cellulosic polymers and glycoprotein of mucin.Stronger H bond causes deeper and stronger attachment of the delivery system with the mucous layer.
HPMC are extensively used not only for mucoadhesison properties but also for its controlled release mechanism.It has been applied to deliver various drugs via different type of dosage forms.The list includes but not limited to delivery of mebeverine HCl by thermoresponsive mucoadheisve gel incorporating poloxamer in the system (Baloğlu et al., 2010), delivery of valsartan by mucoadheisve microsphere (Pardeshi et al., 2012), delivery of carvedilol by mucoadhesive patch (Meher et al., 2013)etc.In the last mentioned example, the researchers have combined HPMC K4M, HPMC K15M, eudragit, carbopol and methyl cellulose together to achieve better mucoadhesion along with sustained release profile.However the combination of so many polymers in a dosage form has been rarely observed.
CMC, more specifically sodium salt of CMC (Na-CMC) is also very extensively used as mucoadhesive polymer.Some recently published researches on mucoahdesive delivery system with Na-CMC include localized delivery of imiquimod by the buccal patch (Ramineni et al., 2013), delivery of lysozyme by gelatin-CMC mucoadhesive films (Dekina et al., 2016).In terms of mucoadhesion, CMC possesses better property than HPMC.HPMC is a non-ionic polymer and lacking of proton donating carboxylic group which causes lesser H bonding than CMC.CMC is anionic polymer which causes higher H bonding than nonionic cellulose polymers.But the mucoadhesion nature depends on the pH of the medium used for testing.In a published report, Prajapati et al (2008) demonstrated that mucoadhesive microcapsule prepared with gelatin showed almost the same period (hour) of adhesion to rat intestinal tissue when tested in pH 7.4 phosphate buffer solutions (Prajapati et al., 2008).However, in 0.1 N HCl solution the HPMC microcapsules showed a little higher period of mucoadhesison than Na-CMC capsule.The reason behind this was not explained by the author.But it can be assumed that at higher pH, anionic polymer like CMC was not ionized and hence could not form sufficient number of H bond with tissue glycoprotein.Thiolation of CMC shows better mucoadhesion due to disulfide bond formation like thiolated polyacrylate.Thiolated CMC, prepared by cysteine conjugation showed 1.6 folds improved mucoadhesion in buccal cavity compared to non-thiolated one (Flavia & Alexie, 2016).

Chitosan
Among all mucoadhesive agents, chitosan is the most abundant polysachharide after cellulose in the world.It is one of the extensively studied polymers under countless scientific reports since early 80s (He et al., 1998).Chitosan, a cationic mucoadhesive agent is basically a polysachharide derived from chitin by means of deacetylation.This is a co-polymer of glucosamine and N-acetyl-glucosamine. Chitosan is insoluble in water but soluble in dilute weak acid (Lehr et al., 1992).The biocompatibility, biodegradation and low toxic nature probably has made chitosan an attractive polymeric component (He et al., 1998).The mucoadhesion nature of chitosan is attributed to several mechanisms.The abundant mechanism is H bonding with glycoprotein of mucin due to presence of -OH and -NH 2 groups.
The conformational flexibility of the linear chitosan molecule also contributes to the mucoadhesion property (Alhalaweh et al., 2011).Besides this, electrostatic interaction between positively charged amines of chitosan and negatively charged sialic acid residue of the mucin is considered a factor for adhesion (Jacobsen et al., 2014).All these interactions cause strong mechanical fusion of polymeric chain into the mucous layer.The interaction of chitosan with mucous and its mucoadhesive phenomena is affected by both physiological factor and physicochemical properties of chitosan.The extent of mucin adsorption by chitosan increases with increasing sialic acid in mucin (Sandri et al., 2012).Since the amounts of sialic acid in mucosal secretions vary, the force of adhesion of chitosan to mucus may also vary depending on the mucosa considered.
Chitosan is used for successful development of the different mucoadhesive delivery system.However, the oral delivery with chitosan containing devices is not very popular because at higher pH (6-6.5)chitosan precipitates.So in the distant region of the gastrointestinal tract chitosan may lose its mucoadhesive and permeation enhancing property (Sandri et al., 2012).But chitosan is very popular in some other routes of delivery.Ocular delivery of cyclosporine A by chitosan nanoparticle showed improved drug delivery to the ocular mucosa and also enhances drug permeation to the inner eye (Hermans et al., 2014).Sound mucoadhesion along with permeation enhancing nature has made chitosan a promising component for buccal delivery also as retardation of the delivery system in the buccal mucosa increases sustainability of drug action.For instance, trimethylated chitosan was shown to deliver hydrophilic macromolecule successfully to the buccal cavity (Sandri et al., 2005).Apart from these routes, nasal delivery or vaginal delivery using chitosan as a component of the system is also reported (El-Kamel et al., 2002;Na et al., 2010).

Modified chitosan
Thiolated chitosan (TC) is a disulfide substituted chitosan that might be prepared by reacting chitosan with thioglycolic acid or by cysteine conjugation.It is evidenced from many scientific literatures that TC possesses improved mucoadhesion and permeation properties compared to chitosan (Peh et al., 2000).Advantages of TC over chitosan include more hydrophilicity due to disulfide bonds, more efficient uptake process for macromolecules delivered, enzyme inhibitory activity, opening of tight cellular junction for improved drug permeation etc (Anitha et al., 2011).Thiolated chitosan is extensively evaluated for use in buccal or oral cavity with prolonged mucoadhesion and hydration effect (Laffleur et al., 2015).Apart from this route, a cysteine conjugated thiolated chitosan nanoparticle was developed and studied by Yin et al. for oral delivery of insulin (Yin et al., 2009).The authors reported 1.8-2.6 folds of improvement of insulin transport through rat intestine compared to insulin solution.In a recent research, a pH responsive thiolated chitosan nanoparticle is developed and successfully applied to deliver low molecular weight heparin orally with improved bioavailability (Fan et al., 2016).
Apart from thiolation, different substituted or crosslinked chitosan is also used by the researchers in order to improve its mucoadhesion efficiency such as N-trimethyl chitosan which is a partially quaternized chitosan made from reaction of chitosan and EDTA (Sandri et al., 2005) or cross-linked catecholized chitosan hydrogel for buccal delivery of lidocaine (Xu et al., 2015).

Alginates
Alginate is a natural and biodegradable anionic polymer that is typically obtained from brown seaweed.It has low toxicity and relatively low cost thus making it extensively being investigated in numerous studies to prepare microparticles, beads with excellent bioadhesive features (Lee and Mooney, 2012).Mostly sodium or calcium salt of alginate is used in pharmaceutical research (Tønnesen and Karlsen, 2002).Alginate has good mucoadhesion property due to the presence of carboxylic acid moiety which causes H bonding with the glycoprotein of mucin (Patil and Sawant, 2009).In acidic pH alginate does not swell much resulting much coiling of the polymeric chain.Uncoiling of polymeric chains raises possibilities of entanglement with mucous layer and hence more mucoadhesion occurs.Therefore alginate gives comparatively less mucoadhesion in acidic pH (Kesavan et al., 2010).In most of the cases alginate is used to formulate beads or microsphere by crosslinked with divalent cation commonly Ca ++ .But if concentration of Ca ++ is increased more alginate becomes crosslinked with Ca ++ and polymer chain flexibility reduces.This in turn reduces mucoadhesion strength (Patil and Sawant, 2009).
Combination of alginate with different other bioadhesive carrier to design drug delivery system is very popular in pharmaceutical researchers, for example; chitosan-alginate bead for vaginal delivery of chlorhexidine digluconate (Abruzzo et al., 2013), jackfruit seed starch-alginate microsphere of metformin HCl (Nayak and Pal, 2013), tamarind seed polysachharide-alginate beads for gliclazide oral delivery (Pal and Nayak, 2012) etc. Strength of mucoadhesion by alginate depends on its molecular weight.It has been shown that low molecular weight alginate chain remains comparatively rigid than high molecular weight alginate.This nature makes low molecular weight alginate less susceptible to bridge with mucin molecule resulting lower bioadhesion than high molecular weight alginate (Menchicchi et al., 2015).

Pectin
Pectin is a natural, biodegradable, biocompatible, nontoxic heterogenous polysaccharide that is extracted from citrus peel or apple pomace.It contains linear chains of (1-4)-linked a-D-galacturonic acid residues that have carboxyl groups (Sharma and Ahuja, 2011).Mucoadhesion mechanism of pectin has been explained in two ways; formation of H bond with mucin and electrostatic interaction between pectin and mucin molecule (Sriamornsak et al., 2010).H bonding occurs due to the presence of carboxylic acid group in pectin.If pectin is mixed with mucin in aqueous solution it showed formation of aggregates which increase with increasing amount of pectin (Russo et al., 2016).This established increasing adhesion with mucin molecule.Mucin and pectin both are negatively charged.Therefore increasing concentration of pectin in aqueous medium causes increase in electrostatic repulsion with mucin.This repulsion causes uncoiling of polymer chain facilitating more entanglement and adhesion.Interesting fact is that the theories of physical adsorption by formation of H bonding and electrostatic repulsion are contradictory to each other.But both are described by different researchers.Better mucoadhesion was reported by Jorgensen et al (2011) with low molecular weight pectin compared to high molecular weight (Joergensen et al., 2011).The author explained low molecular weight pectin can penetrate mucin layer easily and form intermolecular bonding better than high molecular weight pectin.
To characterize pectin the degree of amidation (DA) and the degree of esterification (DE) is very important.Sometimes the carboxylic acid groups of galacturonic acid are substituted by methyl group naturally or are reacted with ammonia to form carboxamide group.A study was made to prepare and evaluate the pectin-based mucoadhesive buccal disc containing carbenoxolone sodium for treatment of aphthous ulcers (Wattanakorn et al., 2010).The pectin buccal discs were prepared by direct compression.The discs were categorized into two main categories following DE which were low-DE (38%) pectin and high-DE (70%) pectin.It was found that low-DE pectin showed higher mucoadhesion strength compared to high-DE pectin.It might be due to the difference in molecular weight of esterified pectin and presence of methoxy groups.A higher MW and the presence of hydrophobic moieties in pectin structure may result in the lower thermodynamic work of adhesion (Wattanakorn et al., 2010).Not only as a single mucoadhesive component, pectin was also combined with other polymers to exploit the mucoadhesion property by many researchers, for example: pectin-gellan gum beads (Prezotti et al., 2014), modified pectin-acrylate combined carrier, pectin -jackfruit seed starch beads (Pal and Nayak, 2012) etc. Thiolation of pectin was shown to possess superior mucoadhesion than normal pectin.In a study by Sharma and Ahuja (2011), a comparison between metformin loaded gel beads made up of pectin esterified by thioglycolic acid and normal pectin showed that the former had 2.5 folds higher strength of bioadhesion with respect to ex-vivo bioadhesion study.The mechanism lies behind is the stronger disulfide linkage between -SH group of thiolated pectin and mucin compared to H bonding between -OH group of pectin and mucin (Sharma and Ahuja, 2011).

Hyaluronic acid
Hyaluronic acid (HA), an anionic biopolymer with high molecular weight is composed of alternating disaccharide units of D-glucuronic acid and N-acetyl-Dglucosamine with β (1→4) inter-glycosidic linkage (Oh et al., 2010).This is biodegradable as well as highly biocompatible in nature.The random coil structure in solution might be behind the bioadhesive property of HA by entanglement with the mucous layer (Russo et al., 2016).Low molecular weight HA was shown to form superior mucoadhesion compared to the high molecular weight (Mayol et al., 2008) A thermosensitive and mucoadhesive polymeric platform was designed by Mayol et al. (2008) by incorporating low molecular weight HA with poloxamer.The model showed good mucoadhesion behavior with sustained drug release (Mayol et al., 2008).
Sodium hyaluronate was used as component of MDDS in order to deliver drugs to the brain via intra-nasal administration.In a recent study a comparison is done between HA, thiolated HA and pre-activated thiolated HA (pre-activation by mercaptonicotinamide) with respect to bioadhesion to vaginal mucosa (Nowak et al., 2015).The order of adhesion time is as follows; HA<thiolated HA<pre-activated thiolated HA.Presence of disulphide bonds between thiolated HA and glycoprotein of mucin is attributed to the stronger adhesion than normal HA where the formation of H bonding is the responsible factor for adhesion.In contrast to HA and thiolated HA, preactivated thiolated HA did not detach from the mucosa during the whole experiment.This can be explained by the moderate swelling behavior and by preactivation with MNA which led to higher stability because of less oxidation of thiol groups and higher attendance to form disulfide bonds with the mucus (Nowak et al., 2015).

Use of polymers in newer MDDS
Conventionally mucoadhesive polymers are used to design and develop different drug delivery platforms such as gel, patch, microspheres, beads etc via buccal, nasal, vaginal, oral etc routes.Examples of such systems are widely available under current scientific domain.Other than these, few relatively newer delivery systems are also reported and becoming popular among the researchers.The most prevalent is mucoadhesive nano-carriers.As a recent example; Luo, Teng, Li and Wang designed and developed a solid lipid nanoparticle coated with chitosan.Due to chitosan the nanoparticle showed improved mucoadhesive property following oral delivery (Luo et al., 2015).In another recent work, Oh and Borros (2016) studied mucoadhesion as well as mucous permeability of thiolated chitosan made nanoparticle and observed significant results with respect to both properties (Oh and Borrs, 2016).A nanogel was prepared using conjugated chitosan and carboxymethyl chitosan by electrostatic interaction (Feng et al., 2015).It was shown that the nanogel adhered to the intestinal mucosa for prolonged duration of time which in turn results into better drug action in colorectal cancer.In a recent review by Sosnik et al. (2014) the usage of mucoadheisve polymers for non-parenteral delivery system has been described.As per the authors, all the three types of polymers such as natural (pectin, alginate, chitosan, hyaluronic acid etc), synthetics (acrylic acid derivatives) and semi-synthetic (cellulose derivatives) are used for the nanoparticulate mucoadhesive delivery system.In another interesting work Abd-Elbarry et al (2016) has explained the formulation of HPMC coated buccal sponge loaded with carvedilol nanoemulsion.Carvedilol by their developed delivery system showed more sustained release profile and 1.5 folds higher relative bioavailability in human volunteer compared to conventional tablet.In another non-conventional mucoadhesive approach, an in-situ ocular mucoadhesive gel was developed by Horvat et al (2015) where the authors have used thiolated poly aspartic acid which can also be considered as a non-conventional mucoadhesive carrier.The thio groups of poly aspartic acid are able to from disulphide linkage with mucin glycoprotein and hence cause mucoadhesion.
The delivery system showed promising drug release up to 24 hrs (Horvát et al., 2015).Apart from these few more researches on newer type of MDDS are highly prevalent in the pharmaceutical or bio-engineering field for example; delivery of insulin via intestinal device (Gupta et al., 2016) or floating bioadhesive multiparticulate delivery via hollow structure (Zhang et al., 2016).

CONCLUSION
This review presents the mucoadhesive or bioadhesive polymers, both conventional and substituted or conjugated emphasizing their mechanism of mucoadhesion.It can be concluded from the current study that research with conventional MDDS with conventional polymer is already a past trend.The reason is the maximum mucoadhesion occupancy with a single conventional polymer is already being achieved or studied.It is found from the current study that use of composite material, combined polymer systems, substituted or conjugated polymers are more popular to design a MDDS with desired criteria.Among the substituted polymers, it can be assumed, although not exclusively, that thiolated polymer is more prevalently explored by the researchers than other substituted mucoadhesive polymers.The reason is prolonged mucoadhesion due to the presence of the thiol group.
Thiolated chitosan is one of the most abundant mucoadhesive polymers among the substituted or conjugated system.Mucoadhesive platform loaded with nanoparticulate dosage form is one of the recent advancements of mucoadhesive research.But the physiological challenges and the constraints on in-vivo pharmacokinetic studies are required to overcome in order to make mucoadhesive delivery platform more successful in future.
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Fig. 1 :
Fig. 1: Mechanism of mucoadhesion.(a) Polymer layer and mucosal layer before contact: (b) Both layers upon contact (starting to create bonds): (c) Interpenetration and entanglement (bonds created for a period of time).