You are herePolymers in Mucoadhesive Drug Delivery System: A Brief Note
Polymers in Mucoadhesive Drug Delivery System: A Brief Note
FACTORS AFFECTING MUCOADHESION
Based on the theories of the adhesion, it can be summarized that the mucoadhesive property of a polymer can be tailored by changing the parameters which has the capacity to alter the interaction among the polymer and the mucosal layer. In this section, attempts will be made to analyze some of the parameters which can tailor the mucoadhesive property of a given polymer.
Polymers usually diffuse into the mucosal layer and thereafter adhere to the layer by forming intermolecular entanglements. With the increase in the molecular weight (MW) of the polymer chain there is an increase in the mucoadhesiveness of a polymer. In general, polymers having MW ≥ 100, 000 have been found to have adequate mucoadhesive property for biomedical applications. A typical example is polyethylene glycol (PEG). PEG of 20,000 MW shows negligible mucoadhesive property while PEG of 200,000 MW exhibits improved mucoadhesiveness and the PEG of 400,000 MW has got excellent mucoadhesiveness . Similarly, polyoxyethylene of 7,000,000 MW has exhibited excellent mucoadhesive property and could be tried for the development of buccal delivery systems . Dextrans of 19,500,000 and 200,000 MW, poly(acrylic) acid of ~750,000 MW and polyethylene oxide of 4,000,000 MW also exhibit good bioadhesive property . Polymer chain length plays an important role in bioadhesiveness. With the increase in the chain length of the polymers there is an increase in the mucoadhesive property of the polymer. Flexible polymer chains helps in the better penetration and entanglement of the polymer chains with that of mucosal layer thereby improving the bioadhesive property. The flexibility of the polymer chains is generally affected by the crosslinking reactions and the hydration of the polymer network. Higher the crosslinking density, lower is the flexibility of the polymer chains. Keeping this in mind, teethering of long flexible chains onto the polymer matrices, with high crosslinking density, appears to be an excellent idea to improve the bioadhesive property. In a recent study, this phenomenon was utilized to device tethered poly (ethylene glycol)–poly (acrylic acid) hydrogels with improved mucoadhesive properties [24, 32]. In addition to the reduced flexibility of the polymer chains, crosslinking results in the reduced diffusion of water into the crosslinked polymer matrix. But sufficient hydration of the polymer network is necessary for the complete opening of the interpolymeric pores within the polymer matrix in addition to the mobilization of the polymer chains . Hence highly crosslinked polymeric matrix limits the interpenetration of polymer and mucin chains amongst themselves which in turn results in the decrease in the mucoadhesive strength . Apart from the MW and chain length of the polymer chains, spatial arrangement of the polymer chains may also play an important role. As mentioned above, dextrans of 19,500,000 and 200,000 MW exhibit good mucoadhesive properties. The efficiency of both the dextrans and PEG (MW: 200,000) have been found to possess similar bioadhesive strength [24, 30, 35].
Formation of hydrogen-bonds amongst the functional groups of the polymers and mucosal layer also plays an important role. In general, stronger the hydrogen bonding stronger is the adhesion. The functional groups responsible for such kind of interaction include hydroxyl, carboxyl and amino groups. Various polymers which have the ability to form strong hydrogen bonds include poly (vinyl alcohol), acrylic derivates, celluloses and starch . Apart from the hydrogen bond formation, the presence of functional groups within the polymer structure may render the polymer chains as polyelectrolytes. The presence of charged functional groups in the polymer chain has a marked effect on the strength of the bioadhesion and can be demonstrated by cell- culture-fluorescent probe technique [37-38]. Anionic polyelectrolytes have been found to form stronger adhesion when compared with neutral polymers [13, 39].
In addition to the above facts, the concentration of the polymer also plays a significant role in the process of mucoadhesion. At lower concentrations of the polymer chains, there is an inadequate and unstable interaction amongst the polymer and the mucosal layer resulting in poor mucoadhesive properties. In general, polymer concentration in the range of 1-2.5 wt % may exhibit sufficient mucoadhesive property for biomedical applications. However for certain polymers, like poly (vinyl pyrrolidone) and poly (vinyl alcohol), solvent diffusion into the polymer network decreases at very high polymer concentration due to the formation of the highly coiled structure thereby limiting interpenetration of the polymer and mucin chains with the subsequent reduction in the mucoadhesive property .
Apart from the above-mentioned physico-chemical properties of the polymeric network, various environmental factors also play an important role in mucoadhesion. As mentioned previously, mucoadhesive property is dependent on the presence of functional groups which can ionize so as to give a charge distribution on the polymer chains. The ionization of the functional group is dependent on the pH of the external medium. Hence change in the pH of the external environment may play an important role in tailoring mucoadhesive property. As for example, chitosan (cationic polyelectrolyte) exhibit excellent mucoadhesive property in neutral or alkaline medium . The contact time amongst the polymer matrix and the mucosal layer can also govern the mucoadhesive property. With the initial increase in the contact time there is an increase in the hydration of the polymer matrix and subsequent interpenetration of the polymer chains. The physiology of the mucosal layer may vary depending on the patho-physiological nature of the human body. The physiological factors which play an important role in governing the mucoadhesive property of a polymer matrix include texture and thickness of mucosa .
EVALUATION OF MUCOADHESIVE PROPERTIES
Various in vivo and in vitro methods are used for testing the efficacy of the mucoadhesive nature of a polymer matrix. Commonly used in vitro/ ex vivo methods include tensile strength measurement, shear strength measurement and chip based systems whereas various imaging techniques are used for the evaluation of the delivery systems under in vivo conditions. This section will describe various methods used to study the mucoadhesive properties.
In vitro tensile strength measurement 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 . Similarly, ex vivo experimentations are also done with the exception that the mucin coated filter-paper is replaced with excised mucosal tissues (e.g. buccal mucosa, intestinal mucosa, vaginal mucosa) [43-45]. The mucoadhesive properties can also be determined by incubating the hydrated polymer matrix surface kept in contact with a viscoelastic 30 % (w/w) mucin solution in water with the subsequent determination of the maximum detachment force required to separate the polymer matrix and mucin solution surfaces after the adhesion . Wash-off test may also be used to determine the mucoadhesive property of delivery systems. In the test, the mucosal tissue is attached onto a glass slide with the help of a double-sided cyanoacrylate tape. Thereafter, the delivery system is put on the surface of the tissue (exposed mucosal surface) with the subsequent vertical attachment of the system into the USP tablet disintegrator apparatus, which contains 1 L of physiological solution maintained at 37oC. The operation of the equipment gives an up-and-down movement to the tissue-delivery matrix system. In this study, the time for the complete detachment of the delivery system from the mucosal layer is determined . For the relative measurement of mucoadhesive nature of powder polymer samples modified Du Noüy tensiometer may be used, while in the shear strength determination method the force required to slide the polymer matrix over the mucus layer is determined . Recently mucoadhesion studies have been reported by using BIACORE® integrated chip (IC) systems. The method involves immobilization of the polymer (powder) on to the surface of the IC with the subsequent passage of the mucin solution over the same. This results in the interaction of the mucin with that of the polymer surface. The polymer- mucin interaction is measured by an optical phenomenon called Surface Plasmon Resonance (SPR), which measures the change in the refractive index when mucin binds on the polymer surface . The in vivo experiments involve the administration of radioactive labeled delivery system with the subsequent measurement of radioactivity in the tissues, at regular intervals of time, where the delivery system is supposed to adhere. The higher the radioactivity, the higher is the mucoadhesive property of the designed delivery system [48-50].
SITES FOR MUCOADHESIVE DRUG DELIVERY SYSTEMS
The common sites of application where mucoadhesive polymers have the ability to delivery pharmacologically active agents include oral cavity, eye conjunctiva, vagina, nasal cavity and gastrointestinal tract. The current section of the review will give an overview of the above- mentioned delivery sites.
The buccal cavity has a very limited surface area of around 50 cm2 but the easy access to the site makes it a preferred location for delivering active agents. The site provides an opportunity to deliver pharmacologically active agents systemically by avoiding hepatic first-pass metabolism in addition to the local treatment of the oral lesions. The sublingual mucosa is relatively more permeable than the buccal mucosa (due to the presence of large number of smooth muscle and immobile mucosa), hence formulations for sublingual delivery are designed to release the active agent quickly while mucoadhesive formulation is of importance for the delivery of active agents to the buccal mucosa where the active agent has to be released in a controlled manner. This makes the buccal cavity more suitable for mucoadhesive drug delivery . The various mucoadhesive polymers used for the development of buccal delivery systems include cyanoacrylates, polyacrylic acid, sodium carboxymethylcellulose, hyaluronic acid, hydroxypropylcellulose, polycarbophil, chitosan and gellan [24, 52]. The delivery systems are generally coated with a drug and water impermeable film so as to prevent the washing of the active agent by the saliva .
Like buccal cavity, nasal cavity also provides a potential site for the development of formulations where mucoadhesive polymers can play an important role. The nasal mucosal layer has a surface area of around 150-200 cm2. The residence time of a particulate matter in the nasal mucosa varies between 15 and 30 min, which have been attributed to the increased activity of the mucociliary layer in the presence of foreign particulate matter. The polymers used in the development of formulations for the development of nasal delivery system include copolymer of methyl vinyl ether, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carbopol-934P and Eudragit RL-100 [53-54].
Due to the continuous formation of tears and blinking of eye lids there is a rapid removal of the active medicament from the ocular cavity, which results in the poor bioavailability of the active agents. This can be minimized by delivering the drugs using ocular insert or patches . The mucoadhesive polymers used for the ocular delivery include thiolated poly(acrylic acid), poloxamer, celluloseacetophthalate, methyl cellulose, hydroxy ethyl cellulose, poly(amidoamine) dendrimers, poly(dimethyl siloxane) and poly (vinyl pyrrolidone) [55-57].
The vaginal and the rectal lumen have also been explored for the delivery of the active agents both systemically and locally. The active agents meant for the systemic delivery by this route of administration bypasses the hepatic first-pass metabolism. Quite often the delivery systems suffer from migration within the vaginal/rectal lumen which might affect the delivery of the active agent to the specific location. The use of mucoadhesive polymers for the development of delivery system helps in reducing the migration of the same thereby promoting better therapeutic efficacy. The polymers used in the development of vaginal and rectal delivery systems include mucin, gelatin, polycarbophil and poloxamer [58-60].
Gastrointestinal tract is also a potential site which has been explored since long for the development of mucoadhesive based formulations. The modulation of the transit time of the delivery systems in a particular location of the gastrointestinal system by using mucoadhesive polymers has generated much interest among researchers around the world . The various mucoadhesive polymers which have been used for the development of oral delivery systems include chitosan, poly (acrylic acid), alginate, poly (methacrylic acid) and sodium carboxymethyl cellulose .
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