You are herePolymers in Mucoadhesive Drug Delivery System: A Brief Note

Polymers in Mucoadhesive Drug Delivery System: A Brief Note

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  [30]. Similarly, polyoxyethylene of 7,000,000 MW has exhibited excellent mucoadhesive  property and could be tried for the development of buccal delivery systems [31]. 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 [24]. 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 [33]. 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 [34]. 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 [36]. 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 [40].
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 [41]. 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 [36].

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  [42].  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 [46]. 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 [47]. 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  [45].  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 [48]. 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].

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  [51].  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 [24].
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 [24]. 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 [61]. 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 [62].



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