Bioadhesive polymers: Novel tool for drug delivery

Abstract

Mucoadhesive drug delivery systems came into picture in the early 1980s and are one of the most studied novel delivery systems. Several researchers have focused on the investigations of the interfacial phenomena of mucoadhesion with the mucus. Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for an extended period of time by the help of interfacial forces. A number of polymers have shown characteristics of bioadhesion and have been used in the formulation of various conventional and novel drug delivery systems. Studies demonstrated that these carriers not only increase the local therapeutic activity, but also increase the systemic availability of the drugs by increasing the residence time at the site of application. The current review is an attempt to throw some light on the basics of the mucoadhesion: the mechanism of bioadhesion and the polymers that are used in the design of the bioadhesive delivery system with their properties that affect the bioadhesion.

Keywords::

• alginate
• bioadhesion
• chitosan
• drug delivery
• polymers

Introduction

Bioadhesion connotes attachment of a drug carrier system to a specific biological location, for example, epithelial tissue. If the biological site is a mucus coat, the phenomenon is known as mucoadhesion. The concept of mucoadhesion was introduced in the field of controlled-release drug delivery systems in the early 1980s (Peggs and Mackinnon 2003). Bioadhesive polymeric systems have been used since long time in the development of products for various biomedical applications including denture adhesives and surgical glues (Muthukumaran et al. 2011). In general, biopolymers show the bioadhesive properties and have been utilized for various therapeutic purposes (Horstedt et al. 1989). These bioadhesive polymers can be broadly classified into two groups: namely specific and nonspecific (Woodley 2001). Based on their properties, the specific bioadhesive polymers (e.g., lectins, and fimbrins) have the ability to adhere to specific chemical structures within the biological molecules while the nonspecific bioadhesive polymers (e.g., polyacrylic acid [PAA] and cyanoacrylates) have the ability to bind with both the cell surfaces and the mucosal layer. Mucoadhesive polymers have recently gained interest among pharmaceutical scientists as a means of improving drug delivery by increasing residence time and contact time with the mucous membranes. The present review describes mucoadhesion, mucoadhesive polymers, and use of these polymers in designing different types of mucoadhesives: gastrointestinal, nasal, ocular, vaginal, and rectal drug delivery systems.

Mucoadhesion

Good defined mucoadhesion as the state in which two materials, at least one biological in nature, are held together for an extended period of time by interfacial forces (Good 1992). It is also defined as the ability of a material (synthetic or biological) to adhere to a biological tissue for an extended period of time (Shaikh et al. 2011). Mucoadhesion is the attachment of the drug along with a suitable carrier to the mucous membrane. Mucoadhesion is a complex phenomenon which involves wetting, adsorption, and interpenetration of polymer chains. Schematic diagram depicting mechanism of mucoadhesion is demonstrated in Figure 1 (Andrews et al. 2009, Asane et al. 2008).

Figure 1. Mechanism of Mucoadhesion. The mucoadhesion takes place in two stages. (A) Contact stage: Intimate contact between a bioadhesive and a membrane (wetting or swelling phenomenon). (B) Interactive stage: Penetration of the bioadhesive into the tissue or into the surface of the mucous membrane (interpenetration).

Different theories have been described by the research to explain the mechanism of mucoadhesion. These include electronic theory, wetting theory, adsorption theory, diffusion theory, mechanical theory, and cohesive theory—as summarized in Table I.

Table I. Theories of mucoadhesion.

Theory	Mechanism
Electronic theory	Electron transfer among surfaces resulting in attractive forces (Lee et al. 2000).
Wetting theory	Affinity of the liquid to the substrate inversely dependent on contact angle (Bhalodia et al. 2010).
Adsorption theory	Adhesive interaction among substrate surface depends upon the intermolecular forces such as hydrogen bond, van der Waals forces, etc. (Kumar and Prabhakar 2010).
Diffusion theory	Diffusion of the polymer chains, present on the substrate surfaces, across the adhesive interface thereby forming a networked structure (Jasti et al. 2003).
Mechanical theory	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 (Smart 2005).
Cohesive theory	Bioadhesion due to the intermolecular forces among like molecules (Andrews et al. 2009).

Mucoadhesive polymers: Different polymers have been explained by the researchers for the drug delivery. However, polymers having mucoadhesive nature should possess same specific characteristics and act as drug delivery system.

An ideal mucoadhesive polymer has the following characteristics (Vinod et al. 2012, Sudhakar et al. 2006):

1. It must be loaded substantially by the active compound.

2. It must swell in the aqueous biological environment of the site of absorption.

3. It must interact with mucus or its components for adequate adhesion.

4. It must allow controlled release of the active compound when swelled.

5. It must be excreted unaltered or biologically degraded to inactive, nontoxic oligomers.

6. It must posses sufficient quantities of hydrogen- bonding chemical groups.

7. It must possess high molecular weight.

8. It must possess high chain flexibility.

9. It must have the surface tension that may induce spreading into mucous layer.

Effect of polymer properties on mucoadhesive drug delivery system

Different polymers exhibit different mucoadhesive properties depending on their physical and chemical strength. For example, a more flexible polymer exhibits higher degree of mucoadhesive property (Gu et al. 1988). Mucoadhesive polymers possessing hydrophilic functional groups such as COOH, OH, NH₂, and SO₄H are more favorable candidates for the formulation of targeted drug delivery. These polymers bearing the desired functional group interact with mucus through physical entanglement as well as through chemical bonds resulting in formation of cross-linked network. For example, urea is a well-accepted hydrogen-bonding disruptor which decreases mucoadhesion of mucin/pectin samples. Other properties which may affect the mucoadhesive nature of the polymer include chain length, degree of hydration, degree of cross-linking, polymer concentration, charge, etc. (Table II).

Table II. Effect of polymer properties on mucoadhesion.

Properties	Effect
Functional group	COOH, OH, NH2, SO4H groups favor mucoadhesion (Capra et al. 2007).
Molecular weight	More is molecular weight (above 100,000) more is the bioadhesion (Sachan and Bhattacharya 2009).
Flexibility	Higher is the flexibility of the polymer more is the diffusion and hence more mucoadhesion (Chowdary and Srinivas 2000).
Chain length	With decrease in chain length interpenetration increases (Boddupalli et al. 2010).
Degree of hydration	Excessive hydration leads to decreased mucoadhesion (Sigurdsson et al. 2006).
Degree of cross-linking	Increased cross-linking decreased mucoadhesion (Imam et al. 2003).
Polymer concentration	For semisolid: increase in concentration decrease mucoadhesion. For solid dosage form: increase in concentration increase mucoadhesion (Ugwoke et al. 2005).
Charge	Nonionic polymers posses less mucoadhesion than ionic, and cationic polymers exhibits more mucoadhesion than anionic (Lehr et al. 1992).

Polymers used for mucoadhesive drug delivery

The rheology of the mucoadhesion is a typical topic and it deals with a number of forces, factors of the components, state of the material, and its derived properties. Different polymers and their mucoadhesive strength are listed in Table III. Based on the rheological aspects, we can categorize the mucoadhesive polymers into two broad categories: materials which undergo matrix formation or hydrogel formation by either a water swellable material or a water soluble material. These carriers are generally polymers and classified as given in Table IV.

Table III. Bioadhesive property of different polymers.

Polymer	Bioadhesive property
CMC sodium	Excellent
Carbopol	Excellent
Polycarbophil	Excellent
Tragacanth	Excellent
Sodium alginate	Excellent
HPMC	Excellent
Gum karaya	Very good
Gelatin	Very good
Guar gum	Very good
Pectin	Good
Acacia	Good
Chitosan	Good
Hydroxypropyl cellulose	Good

Table IV. Classification of bioadhesive polymers.

Polymers	Examples
Hydrophilic polymers	Methyl Cellulose, hydroxyethyl cellulose, HPMC, Na CMC, carbomers (Ludwig 2005).
Thiolated polymers	Chitosan–iminothiolane, PAA–cysteine, PAA–homocysteine, chitosan–thioglycolic acid, chitosan–thioethylamidine, alginate–cysteine, poly (methacrylic acid)–cysteine and sodium carboxymethylcellulose–cysteine (Schnürch 2005).
Lectin-based polymers	Lentil lectin, peanut agglutinin, ulex europaeus agglutinin (Haltner and Lehr 1997).
Polyox WSR	WSR N-10, WSR N-80, WSR N-205, WSR N-750.
Novel polymers	Tomato lectin, PAA-co-PEG, PSA (Shojaei and Xiaoling 1997).

Hydrophilic polymers contain carboxylic group and possess excellent mucoadhesive properties. Matrices developed with these polymers swell when put into an aqueous media with subsequent dissolution of the matrix, for example, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose, carbomers, chitosan, and plant gums. Polyelectrolytes extend greater mucoadhesive property when compared with neutral polymers (Ludwig 2005). Anionic polyelectrolytes, for example,PAA and carboxymethyl cellulose, have been extensively used for designing mucoadhesive delivery systems based on their ability to exhibit strong hydrogen bonding with the mucin present in the mucosal layer (Andrews et al. 2009). Chitosan, a cationic polymer, is widely used for its biodegradable and biocompatible properties and it undergoes electrostatic interactions with the negatively charged mucin chains thereby exhibiting mucoadhesive property (Portero et al. 2007). The ionic polymers may be used to develop ionic complex with the counter-ionic drug molecules so as to have a drug delivery matrix exhibiting mucoadhesive property. Nonionic polymers, for example, poloxamer, HPMC, methyl cellulose, polyvinyl alcohol (PVA), and polyvinylpyrrolidone (PVP), have also been used for mucoadhesive properties (Ludwig 2005). The hydrophilic polymers form viscous solutions when dissolved in water and hence may also be used as viscosity modifying/enhancing agents in the development of liquid ocular delivery systems so as to increase the bioavailability of the active agents by reducing the drainage of the administered formulations (Hui and Robinson 1985, Ludwig 2005).

Hydrogels: Hydrogels can be defined as three-dimensional cross-linked polymer chains which have the ability to hold water within its porous structure. The water-holding capacity of the hydrogels is mainly due to the presence of hydrophilic functional groups such as hydroxyl, amino, and carboxyl groups. These include hydrogels prepared by thermal crosslinking of PAA and methyl cellulose (Dubolazov et al. 2006), and hydrogels prepared by condensation reaction of PAA and sucrose (Warren and Kellaway 1998). In addition to the drug targeting, mucoadhesive hydrogel-based formulations improve the bioavailability of the poorly water-soluble drug.

Novel polymers: With the advancement in the technology a large number of novel polymers have come into picture. Tomato lectin showed that it has binding selectivity to the small intestinal epithelium (Carreno-Gomez et al. 1999). Shajaei and Xiaoling have designed and characterized a copolymer of PAA and polyethylene glycol (PEG) monoethyl ether mono methacrylate (PAA-co-PEG) for exhibiting optimal buccal adhesion (Shojaei and Xiaoling 1997). Lele Hoffman (2000) investigated novel polymers of PAA complexed with PEGylated drug conjugate (Lele and Hoffman 2000). A new class of hydrophilic pressure sensitive adhesives (PSA) has been developed by Corium Technologies. A complex has been prepared by noncovalent hydrogen-bonding cross-linking of a film forming hydrophilic polymer with a short chain plasticizer having reactive OH groups at chain ends. Similarly, Bogataj et al. (1999) prepared and studied mucoadhesive microspheres prepared using different polymers by solvent casting method for application in urinary bladder (Bogataj et al. 1999). Chen and Langer (1998) investigated the benefit of thiolated polymers for the development of buccal drug delivery systems (Chen and Langer 1998).

Some important bioadhesive polymers used in drug delivery

Chitosan

Chitosan is a biodegradable, nontoxic polymer obtained by deacetylation of the N-acetyl glucosamine units of chitin, generally by hydrolysis under alkali conditions at high temperature (Bagheri-Khoulenjani et al. 2009). Due to its positive charge it shows ionic interaction with the negative charge of the sialic acid residues of mucus thus possessing very good bioadhesive properties. It is a biocompatible, pH-dependent cationic polymer, which is soluble in water up to pH 6.2. Basification of chitosan aqueous solutions above this pH leads to the formation of a hydrated gel-like precipitate. Chitosan—being linear polymer—provides greater polymer chain flexibility (Chenite et al. 2000). Many chitosan derivatives have been synthesized with improved mucoadhesion such as thiolated polymers, quaternized chitosan, fatty acid derivatives and different copolymers of chitosan (Riva et al. 2011). Chitosan and its derivatives have been used in the formulation of various mucoadhesive-controlled drug delivery systems. Vershosaz and Karimzadeh (2007) developed cross-linked chitosan films for the delivery of lidocaine and reported that while increasing the cross-linking and molecular weight of chitosan, bioadhesion and tensile strength, as well as the drug flux, were considerably increased. Moreover, the release of lidocaine was prolonged in the buccal area (Varshosaz and karimzadeh 2007). Similarly, Palanisamy et al. (2009) developed chitosan microspheres encapsulating metoprolol succinate using a cross-linking technique. The resulting micro-particulate systems were found to be efficient in the delivery of drug in the system over extended period of time with minimal dose (Palanisamy et al. 2009). Similarly, Motwani et al. (2008) developed gatifloxacin-loaded chitosan–sodium alginate nanoparticles for ocular delivery of the antibiotic by ionic gelation method. Nanoparticles revealed a fast drug release during the first hour followed by a more gradual drug release during a 24-h period indicating prolonged ocular delivery of the drug (Motwani et al. 2008).

Carbopol

Carbopol or carbomer are high molecular weight polymers of acrylic acid cross-linked with either allyl sucrose or allyl ethers of penta erythritol. These contain 56% and 68% of carboxylic acid groups calculated on the dry bases (Barry and Meyer 1979). These are used as suspending agent or viscosity increasing agent, dry and wet binder, as well as rate controlling agent in tablets, enzyme inhibitor of intestinal protease in peptide containing dosage form, etc. Carbomer is a pH-dependent polymer which stays in solution form at acidic pH but forms a low viscosity gel at alkaline pH. Carbopol offers the advantage of exhibiting excellent mucoadhesive properties in comparison with other polymers (e.g., cellulose derivatives and polyvinyl alcohol) (Davies et al. 1992). Different mucoadhesive formulations containing carbopol have been developed and it was found that these demonstrated excellent mucoadhesive property and release the drug in controlled manner for a longer period of time. Tan et al. (2000) developed a bioadhesive gel incorporating lidocaine using carbopol and PVP. The results indicated that an increase in carbopol concentration significantly increased gel compressibility, hardness, and adhesiveness, that is, the factors that effect ease of gel removal from container, ease of gel application onto mucosal membrane, and gel bioadhesion, respectively. Moreover, the resulting formulation provided a sustained release as compared with the conventional dosage forms (Tan et al. 2000). Similar results were obtained by Bilensoy et al. (2007). They developed 5-FU containing thermosensitive, mucoadhesive gel based on carbopol 934 and pluronic F12 for the treatment of HPV-induced cervical cancer (Bilensoy et al. 2007). The resulting formulation demonstrated better anticancer activity at lower doses avoiding unwanted side effects of the drug. In another study, Patel and Chavda (2009) prepared amoxicillin-loaded gastroretentive microspheres using carbopol-934 providing sustained release (Patel and Chavda 2009).

Alginate

Alginates are random anionic, linear polymers consisting of varying ratios of glucuronic and manuronic acid units. Salts of alginate are formed when metal ion reacts with glucuronic- or manuronic acid residue. Alginate has been used in many biomedical applications, including drug delivery systems, as they are biodegradable, biocompatible, and mucoadhesive (Rajaonarivony et al. 1993). These delivery systems are formed when they are in monovalent, water-soluble state. Alginate salts undergo an aqueous sol–gel transformation to water-insoluble salts due to the addition of divalent ions such as calcium, strontium, and barium (Kesavan et al. 2010). Mainly calcium alginate matrix is used for drug delivery systems including beads, gels, films, microparticles, and sponges. Alginates with a high glucuronic acid contents form more rigid, porous gel due to their orientation with in the egg-box structure and conversely gel with low glucuronic content are more randomly packed and less porous (Wee and Gombotz 1998). Motwani et al. (2008) prepared Sodium alginate nanoparticles incorporating gatifloxacin (Motwani et al. 2008). The resulting formulation shows prolonged ocular residence time. Nayak et al. (2010) developed mucoadhesive beads of glicazide using sodium alginate along with isaphghula using calcium chloride as counter ion. The resulting formulation showed good mucoadhesion with drug entrapment of more than 70% thus improving the action of glicazide (Nayak et al. 2010).

Sodium carboxymethyl cellulose (Na CMC)

It is a low-cost, commercial, soluble, and polyanionic polysaccharide derivative of cellulose that has been employed in medicine, as an emulsifying agent in pharmaceuticals, and in cosmetics. The solution characteristics depend upon the average chain length and degree of polymerization. High and medium viscosity solutions of Na CMC possess thixotropic behavior (Elliot and Ganz 1974). The bioadhesive properties of the Na CMC are remarkable and it has been used in the development of various bioadhesive formulations such as matrix tablets (Mamatha et al. 2012), microspheres (Arya et al. 2010a), buccal patches (Chattopadhyay and Verma 2012), and nanoparticles. Going to the literature, a vast study has been carried out on Na CMC and various formulations have been prepared. As reported, Famotidine-loaded microspheres were prepared by Arya et al. (2010b). The microspheres were prepared by w/o emulsification solvent evaporation method using mucoadhesive polymers, Na CMC, and a release controlling polymer, sodium alginate. It was found that with increase in the Na CMC concentration the mucoadhesion increases and the rate of drug release decreased with the increasing sodium alginate concentration (Arya et al. 2010b). Also mucoadhesive, buccal-patch containing metoprolol succinate was prepared by solvent casting method using Na CMC showed drug release of 81.9% for 6 h (Chattopadhyay and Verma 2012). Similarly, Arya et al. (2010a) prepared double-walled microspheres loaded with pantoprazole. The primary wall was composed of mucoadhesive polymer, that is Na CMC and sodium alginate, showing good mucoadhesion (Arya et al. 2010a).

Hydroxypropyl methyl cellulose

HPMC, a semisynthetic, inert, viscoelastic polymer, used as an ophthalmic lubricant, emulsifier, suspending agent, thickening agent, and controlled-delivery component in oral medicaments, is found in a variety of commercial products. Also known as hypermellose, it is a thermosenstive polymer whose aqueous solution sets into gel when heated up to critical temperature (Silva and Olver 2005). It also shows good bioadhesive property due to its ability to exhibit strong hydrogen bonding with the mucin present in the mucosal layer. Various films, tablets, and gels formulations have been formulated using HPMC as mucoadhesive polymer. The formulation shows very good mucoadhesion and provided sustained release. Koland et al. (2010) prepared a film loaded with losartan potassium, using HPMC and retardant polymers such as ethyl cellulose (EC) and Eudragit RS 100 by solvent casting method. Film showed better therapeutic efficiency by controlling drug release thereby improving patient compliance and increased bioavailability with decreased dosing and fewer side effects (Koland et al. 2010). Similarly, Patel et al. (2011) formulated mucoadhesive famotidine tablets using HPMC K4M and tragacanth with an aim to prolong gastric residence time. It was found that the formulation showed good mucoadhesive strength and desirable release profile (Patel et al. 2011). Singh et al. (2010) prepared microspheres incorporating amoxicillin trihydrate using Eudragit RS 100 as matrix and HPMC K4M as mucoadhesive polymer by solvent evaporation method. The resulting formulation showed good mucoadhesion with increased residence time and decreased frequency of administration (Singh et al. 2010).

Evaluation of mucoadhesive drug delivery systems

Mucoadhesive drug delivery systems can be evaluated by testing their adhesion strength. Various in vitro and in vivo tests (Figure 2) are available to determine the adhesion strength of the mucoadhesive polymers. Brief description of these tests is as follows:

Figure 2. Different methods for evaluation of mucoadhesive polymers.

In vitro/ex vivo methods

In vitro/ex vivo tests are important in the development of a controlled-release bioadhesive systems because they contribute to studies of permeation, release, compatibility, mechanical and physical stability, superficial interaction between formulation and mucous membrane, and strength of the bioadhesive bond. These tests can imitate a number of administration routes including oral, buccal, periodontal, nasal, gastrointestinal, vaginal, and rectal. Few in vitro and ex vivo tests most prevalent in the literature are reported below.

Tensile-strength measurement: Texture analyzer is generally used to measure tensile strength. The force required to remove the formulation from a model membrane is measured. This test is done by dipping a filter paper in 8% mucin dispersion. Thereafter, the mucin-coated filter paper is placed in contact with the hydrated polymeric samples (in physiological solutions) for a definite period of time, followed by the determination of the maximum force required to detach the filter paper and polymer surfaces after the mucoadhesive bonding (Eouani et al. 2011).

Detachment force measurement: The mucoadhesion force is measured in the terms of shear strength. This test measures the force required to separate two parallel glass slides covered with a polymer and a mucus film. In this method a glass plate is suspended by a microforce balance and immersed in a sample of mucus under controlled temperature. The force required to pull the plate out of the sample is then measured under constant experimental conditions (Chowdary and Rao 2004).

Falling liquid film method: It is a quantitative in situ technique in which the percentage of particles which get retained on a mucosal tissue is calculated. Briefly, a suspension of the microspheres is allowed to flow down a plastic slide at an inclined position of 45° relative to the horizontal plane as shown in Figure 3. The adhered microsphere amount was estimated from the difference between the applied microspheres and the flowed microspheres amount. The ratio of the adhered microparticles was computed as percentage mucoadhesion (Shahi et al. 2011). The quantification can also be done by the aid of coulter current method (Takeuchi et al. 2005).

Figure 3. Falling liquid film technique for measurement of mucoadhesion.

Colloidal gold staining: This technique was developed by Park (1989), where mucin-gold conjugates interacted with a hydrogel surface resulting in a red coloration. This method was developed for the quantitative comparison of mucoadhesive properties of various hydrogels. The technique employs red colloidal gold particles which are stabilized by the adsorbed mucin molecules (mucin-gold conjugates). Upon interaction with mucin-gold conjugates, mucoadhesive hydrogels develop a red color on the surface. Thus, the mucoadhesive properties of hydrogels can be compared quantitatively by measuring the intensity of the red color. The pH-dependent stability of mucin-gold conjugates was examined and optimum conditions for mucin-gold staining were determined.

There are various other in vitro tests used for the determination of mucoadhesion strength. Fluorescent probes can be used to determine the effect of various polymer and mucin interaction. This technique involved the labelling of the lipid bilayer of cultured human conjunctiva cells with the fluorescent probe pyrene. The adhesion caused a change in the degree of fluorescence which is proportional to the polymer binding (Andrews et al. 2009).

Biacore system: The biacore instrument is based on the principle of an optical phenomenon called surface plasmon resonance (SPR). The SPR response is a measurement of the refractive index, which varies with the solute content in a solution that contacts a sensor chip. When a detected molecule is attached to the surface of the sensor chip, or when the analyte binds to the detected molecule, the solute concentration on the sensor chip surface increases, leading to an SPR response (Strumia 2007). In the detection of the mucoadhesive property of polymers using BIACORE, each polymer was immobilized on the surface of the sensor chip CM5 and the mucin suspension was passed through the sensor chip. When the analyte (mucin particle) binds to the ligand molecule (polymer) on the sensor chip surface, the solute concentration and the refractive index on that surface change, increasing the RU (resonance unit) response; when they dissociate, the RU (resonance unit) response will fall (Sikavitsas et al. 2002).

Confocal laser scanning microscopy (CLSM) method: Confocal laser scanning microscopy (CLSM or LSCM) is a technique for obtaining high-resolution optical images with depth selectivity. The key feature of confocal microscopy is its ability to acquire in focus images from selected depths, a process known as optical sectioning. CLSM design combined the laser scanning method with the 3D detection of biological objects labelled with fluorescent markers. Fluorescencent marker such as, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindo carbocyanine perchlorate was used to determine mucoadhesive strength of liposomes. CLSM observation may be a promising method to characterize the mucoadhesive properties of fine particle drug delivery systems and to explain their effectiveness in the oral administration of drugs (Varum et al. 2011).

In vivo methods

Gamma Scintigraphy: Gamma scintigraphy is an elegant way to gain insights of the actual in vivo distribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables the in vivo determination of the target of the formulation administered through a large number of routes (Meseguer et al. 2004). Scintigrams are used to determine formulation activities in the regions of interest (ROIs). ROIs relating to the site of mucoadhesion were drawn on gamma images for each time point, and counts relating to ROIs are calculated using xeleris software (Pund et al. 2011).

X-ray studies: The GI transit time can be measured by using one of the many radio opaque markers such as barium sulphate which is coated to the bioadhesive dosage form so as to assess the GI transit by means of x-ray inspection. In a study by Senthil et al. on mucoadhesive slow-release tablets of theophylline, barium sulphate-loaded tablet was used to determine mucoadhesion in vivo. Two healthy rabbits weighing 2.5 kg were selected and administered orally with the tablet. X-ray photograph was taken at different time intervals. (Senthil et al. 2010).

Isolated loop technique: Isolated ileal loop model in the rat was used in order to study the intestinal transit of the microspheres. Bioadhesive property is evaluated by recording the mean residence time of the microspheres when injected into the in situ perfused gut segment (Lehr et al. 1990).

Application of mucoadhesvie polymers in drug delivery

Mucoadhesive formulations have been widely used for targeted and controlled release delivery to many mucosal membrane-based organs. Such formulations may deliver active ingredients for local or systemic effect, while bioavailability limiting effects such as enzymatic or hepatic degradation can be avoided or minimized. Till date a large number of mucoadhesive polymers have been used to design various formulations such as tablets, hydrogels, microspheres, nanoparticles, patches, films, beads, etc. each providing sustained and controlled release. A brief of the studies carried out using the mucoadhesive polymers is summarized in the Table V.

Table V. Compilation of studies performed for drug delivery using bioadhesive polymers.

Bioadhesive polymer	Drug	Dosage form	Result	Reference
CMC	Pantoprazole	Microspheres	With increase in CMC concentration the mucoadhesive strength and percent drug release increased up to 8 h.	(Arya et al. 2010b).
Gelatin + Na CMC	Aceclofenac	Buccal patch	Sustained release of 88. 4% for 8 h and greater mucoadhesive strength for about 268 min.	(Khairnar, 2009)
CMC	Famotidine	Microspheres	Drug release was increased to 90% in 8 h, and the percent mucoadhesive strength was up to 82% which increased with increase in polymer concentration.	(Arya et al. 2010a)
PEG+ Carbopol+ PVP	Lidocaine	Bioadhesive gel	Addition of carbopol and PVP provides more sustained release.	(Tan et al. 2000)
Carbopol+ HPMC	5-FU	Thermosenstive vaginal gel	Higher anti-cancer activity with controlled release of drug.	(Bilensoy Erem 2007)
Carbopol-934P	Amoxicillin	Microspheres	Gastro retentive with mucoadhesion percent of greater than 80% after 1 h and sustained release for about 12 h.	(Patel and Chavda 2009)
Carbopol-934P	Sumatriptan	Thermosenstive nasal gel	Prolonged nasal residence time and enhanced drug permeation.	(Majithiya et al. 2006)
Polycarbophil	Moxifloxacin	Hydrogel	98% of drug was released 12 h from the hydrogel providing sustained release.	(Dholakia et al. 2012)
HPMC	Losartan potassium	Film	Sustained drug release in the range of 90.10–97.40% for a period of 6 h, slowerpermeation of the drug for 6–7 h.	(Koland et al. 2010)
Tragacanth+ HPMC K4M	Famotidine	Tablets	Increased mucoadhesive property and continuous release of drug at a predetermined rate and for apredetermined time were observed.	(Sankar et al. 2011)
HPMC K4M	Amoxicillin trihydrate	Microspheres	Prolonged gastric residence time and enhanced gastric stability due to mucoadhesive nature of microspheres.	(Singh 2010)
Chitosan	Lidocaine	Films	Sustained release in the range of 90.10–97.40% for a period of 6 h, and ex vivo permeation studies show slow permeation of the drug for 6–7 h.	(Varshosaz and Karimzadeh 2007)
Chitosan	Miconazole	Buccal films	Significant enhancement of miconazole: in vitro release from about 60% (reference) to 94% (optimized film) and superior antifungal activity as compared with miconazole oral gel.	(Bazigha and Abdul 2010)
Chitosan	Carvedilol	Tablet containing drug loaded microspheres	Pharmacokinetic studies showed significantly higher C(max) (71.26 ± 6.45 ng/mL), AUC (0–10) (AUC, area under the curve 390.75 ± 5.23 ng/mL/h) and AUC (0–∞) (664.72 ng/mL/h) than carvedilol oral tablet hence, enhanced bioavailability and sustained release	(Yedurkar et al. 2012)
Sodium Alginate+ Isaphgula	Glicazide	Beads	Drug release was from 73–92% in 10 h and mucoadhesive strength was found to be 66–70% and 38–43% in HCl and PBS, respectively, ex vivo.	(Nayak et al. 2010)
Sodium alginate + chitosan	Gatifloxacin	Nanoparticles	Prolonged ocular residence time for more than 24 h.	(Motwani et al. 2008)

Mucoadhesive dosage forms are potential candidates for drug delivery to the different application sites including oral, gastrointestinal, nasal, ocular, vaginal, and rectal. A brief discussion about these routes is presented in the following paragraphs. Buccal region appears to be more suitable for sustained delivery of therapeutic agents using mucoadhesive systems due to the presence of a smooth and relatively immobile surface for placement of a mucoadhesive dosage form. Different types of mucoadhesive dosage forms such as gels, patches, films, tablets, and ointments can be used for drug delivery across buccal mucosa. Generally the drugs with a short biological half-life, poor permeability, poor solubility, sensitivity to enzymatic degradation, and requiring a sustained release effect may be good candidates to be delivered via the oral cavity (Pranshu and Madhav 2011). Fini et al. (2011) developed mucoadhesive gel loading chlorhexidine using HPMC, carboxymethyl- (CMC), and hydroxypropyl- (HPC) cellulose, alone (3% w/w) or in binary mixtures (5% w/w). All the gel systems proved suitable for Chlorhexidine buccal delivery, providing prolonged release and reduced transmucosal permeation as well as reduced toxicity (Fini et al. 2011). Bhanja et al. (2010) formulated mucoadhesive buccal tablets using Carbopol 934p, Polyethylene oxide, and HPMC in different ratios loading Timolol maleate by direct compression method. The tablets were tested for weight variation, hardness, surface pH, drug content uniformity, swelling index and bioadhesive strength, and in vitro drug dissolution study. The formulation containing the drug, carbopol 934p and HPMC K4M in the ratio of 1:2.5:10, was best exhibiting 7-h sustained drug release, that is, 98.18% with desired therapeutic concentration (Bhanja et al. 2010). Various marketed formulations based on bioadhesive polymers are available in the market. These are Buccastem, Suscard, Miconaczole Lauriad tablets, Orabase, Corcodyl gel, Gaviscon Liquid, etc. (Puratchikody et al. 2011).

Nasal cavity is another important site for mucoadhesive formulations. The nasal mucosal layer has a large surface area of around 150–200 cm². Presence of any foreign particulate matter increases activity of the mucocilliary layer, hence the residence time of a particulate matter in the nasal mucosa varies between 15 and 30 min. Thus by using means of mucoadhesive formulations the residence time of the drug can be increased. The polymers used in the development of formulations for nasal delivery system include copolymer of methyl vinyl ether, HPMC, sodium carboxymethylcellulose, carbopol-934P, and Eudragit RL 100 (Semalty et al. 2008). Uttarwar (2012) formulated in situ gelling system for nasal administration for an antiemetic drug Ondansetron hydrochloride by using Pluronics 127P and Pluronics 68, providing the systemic delivery of drug through the nasal route and thereby reducing the dose of drug, avoiding its first-pass metabolism (Uttarwar 2012).

Topical application of drugs to the eye is the most-popular and well-accepted route of administration for the treatment of various eye disorders. The bioavailability of ophthalmic drugs is however very poor due to efficient protective mechanisms of the eye. Blinking, baseline and reflex lachrymation, and drainage remove rapidly foreign substances, including drugs, from the surface of the eye. Moreover, the anatomy, physiology, and barrier function of the cornea compromise the rapid absorption of drugs. This drawback can be overcome by the use of mucoadhesive polymers such as thiolated PAA, poloxamer, celluloseacetophthalate, methyl cellulose, hydroxy ethyl cellulose, polyamidoamine (PAMAM) dendrimers, polydimethylsiloxane and PVP. (Wagh et al. 2008). The delivery of therapeutic agents to the eye may be achieved using various types of dosage forms including liquid drops, gels, ointments, and solid ocular inserts (both degradable and nondegradable). Choy et al. (2008), formulated mucoadhesive microdiscs loading proparacaine HCl, and the resulting formulation was found to have prolonged residence time on the preoccular surface. Thus, it was concluded that the mucoadhesive formulations are highly applicable for drug delivery across ocular mucosa (Choy et al. 2008).

Mucoadhesive formulations have also proved for drug delivery through vaginal and rectal routes. These routes offer many advantages; the avoidance of hepatic first-pass metabolism, a decrease in hepatic side effects, and avoidance of pain, tissue damage, and infection commonly observed in parenteral drug delivery routes of administration. Besides large surface area, rich blood supply, and high permeability, drug residence time at these sites is comparatively small. Mucoadhesive formulations have helped a lot to reduce the migration of the drug and increase therapeutic efficacy (Song et al. 2004). The polymers used in the development of vaginal and rectal delivery systems include mucin, gelatin, polycarbophil, and poloxamer. Various rectal and vaginal formulations include creams, ointments, in situ gels, emulgels, tablets, etc. Patel et al. (2012) formulated mucoadhesive vaginal tablet of sertaconazole for vaginal candidiasis using a combination of mucoadhesive polymers such as Carbopol 934P, chitosan, Na CMC, sodium alginate, methyl cellulose, HPMC, and HPC to enhance its solubility and release characteristics and therefore its feasibility for vaginal delivery to treat local fungal infections. From the ex vivo retention study it was found that the mucoadhesive polymers hold the tablet for more than 24 h inside the vaginal tube (Patel et al. 2012).

Conclusion

The focus of pharmaceutical research is being steadily shifted from the development of new chemical entities to the development of novel drug delivery system (NDDS) of existing drug molecule to maximize their effect in terms of therapeutic action and patient protection. Mucoadhesive polymers may provide an important tool to improve the bioavailability of the active agent by improving the residence time at the delivery site. The most widely studied and accepted polymers for mucoadhesion have been the hydrophilic, high molecular weight, anionic molecules such as carbomers. Recently the focus has been on the novel second generation polymers such as the thiolated polymers, lectins, and lecithins. Many potential mucoadhesive systems are being investigated which may find their way into the market in near future.

Conflict of interest

Authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.