Bioadhesive Polymers as a Platform for Drug Delivery: Possibilities and Future Trends

Raj Kumar Poddar*¹, Pankaj Rakha¹, SK Singh² and DN Mishra²

¹Rajendra Institute of Technology and Sciences, Sirsa

²Guru Jambheshwar University of Science and Technology, Hisar

ABSTRACT:

This paper aims to review the developments in the bioadhesive drug delivery systems to provide basic principles to the young scientists, which will be useful to circumvent the difficulties associated with the formulation design. Bioadhesion can be obtained by the building of either non-specific interactions with the mucosal surface, which are driven by the physicochemical properties of the particles and the surfaces, or specific interactions when a ligand attached to the particle is used for the recognition and attachment to a specific site at the mucosal surface. Starting with a review of the oral mucosa, mechanism of drug permeation, and characteristics of the desired polymers, this article then proceeds to cover the theories behind the adhesion of bioadhesive polymers to the mucosal epithelium. The primary goal of bioadhesive controlled drug delivery is to localize a delivery device within the body to enhance the drug absorption process in a site-specific manner. This article reviews desirable properties of bioadhesive polymers and the latest advancement in the field.

KEYWORDS: Bioadhesion, oral mucosa, drug permeation, bioadhesive polymers.

INTRODUCTION:

The use of bio (muco) adhesive drug delivery systems for systemic or local delivery of various drugs has attracted a great deal of attention in recent years. These systems are capable of adhering to mucosal membranes for extended periods of time and releasing their drug content with a slow and gradual manner. A number of drugs, and in particular proteins and peptides, have been recognized as potential candidates for use in these systems^1-5.

Mucoadhesion is a relatively new topic and emerging concept in the design of drug delivery systems. In the early 80’s, Professor Joseph R. Robinson pioneered the concept of mucoadhesion as a new strategy to prolong the residence time of various drugs on the ocular surface. Over the years, mucoadhesive polymers were shown to be able to adhere to various other mucosal membranes. The capability to adhere to the mucus gel layer which covers epithelial tissues makes such polymers very useful excipients in drug delivery⁶.

In biological systems, four types of bioadhesion could be distinguished⁷:

i. Adhesion of a normal cell on another normal cell.

ii. Adhesion of a cell with a foreign substance.

iii. Adhesion of a normal cell to a pathological cell.

iv. Adhesion of an adhesive to a biological substance.

Bioadhesion is defined as the attachment of synthetic or biological macromolecules to the biological surface for extended periods of time by interfacial forces. The biological surface can be epithelial tissue or the mucus coat on the surface of tissue. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion⁸. The capability to adhere to the mucus gel layer which covers epithelial tissues makes such polymers very useful excipients in drug delivery.

Table .1 Characteristics of some human mucosae¹³

Location	Thickness (pm)	Keratinization	Intercellular Lipids
Buccal Sublingual Gingival Palatal	500-600 100-200 200 250	No No Yes Yes	Polar Polar Non-polar Non-polar

Figure .1 Anatomy of the oral mucosa¹⁴

Mucus is negatively charged at neutral pH and uncharged at acidic pH. Numerous hydroxyl and carboxyl groups on mucin molecules have the potential to interact with other polymers that can form H-bonds. The major components of all mucus gels are mucin glycoproteins, lipids, inorganic salts and water, the latter accounting for more than 95% of its weight, making it a highly hydrated system¹⁵. Mucins contain approximately 70–80% carbohydrate, 12–25% protein and up to 5% ester sulphate¹⁶.

The term “mucoadhesion” is used specifically when the bond involves mucous coating and an adhesive polymeric device, while “cytoadhesion” is the cell-specific bioadhesion.

A further classification of bioadhesion is based on the presence or absence of nonbiological (artificial) materials in the adhesion process. The types of bioadhesion, which have been identified, are classified into three types. Type I refers to the adhesion of two biological substrates (e.g. cell aggregation), type II refers to the adhesion of a biological substrate to an artificial material (e.g. barnacle adhesion to a rock surface) and type III refers to the adhesion of artificial substances to biological substrates (e.g. the adhesion of polymers to mucosal epithelium). Type III bioadhesion has been investigated most by many research groups.

Over the last 30 years, the market share of transmucosal drug delivery systems has significantly increased with an estimated value of $6.7 million in 2006¹². According to a recent report published by Kalorama, worldwide revenue in this area is expected to increase approximately 3.5% a year to reach $7.9bn by 2010. This growth can be related to the ease with which transmucosal products may be designed and administered. For example, such dosage forms may be delivered via the nasal route using sprays, pumps and gels, via the oral/buccal route using mucoadhesives, quickly dissolvable tablets and solid lozenge formulations and via vaginal or urethral routes using suppositories, pessaries, vaginal rods and gels⁹.

Table .2 Comparison of mucus content (% w/w of dry solids) between species and site of secretion¹⁷

Component	Human ocular	Bovine submaxillary	Ovine submaxillary
Protein Carbohydrate Lipid	mucosa 29 53 12	mucosa 31 58 11	mucus 33 53 14

Table .3 Typical bond types and energies, modified from Kinloch²⁴

Type	Bond energy (kJ mol_1)
Primary bonding Ionic Covalent Metallic Secondary bonding Hydrogen bonding Other dipole dipole Dipole-induced dipole Deybe forces Dispersion (London) forces	590–1050 63–710 113–347 10–42 4–21 <2 0.08–42

The theories of mucoadhesion are based on the classical theories of metallic and polymer adhesion. There are six general theories of adhesion that describe the possible mechanisms of mucoadhesion: the electronic, the adsorption, the wetting, the diffusion theory, the mechanical theory, and the fracture theory.

Figure. 2 Theories of mucoadhesion and material properties of mucoadhesives. The overlapping areas between the circles of the material properties and the mucoadhesive theories indicate how and to what extent the former are connected to the latter²⁵.

Mucoadhesive drug delivery systems have been investigated as potential drug delivery for oral administration. Mucoadhesive drug delivery systems have three distinct advantages when compared to conventional dosage forms:-

i. Improve and enhance the bioavailability of drugs

ii. Facilitate the intimate contact with underlying absorption surface resulting in a better absorption

iii. Prolong residence time at the site of application

Table .4 Different theories explaining the mechanism of bioadhesion²⁵

S. No. Theory Mechanism of bioadhesion Comments

1 Electronic theory Attractive electrostatic forces between glycoprotein Electron transfer occurs between the two forming

mucin network and the bioadhesive material a double layer of electric charge at the nterface

2 Adsorption theory Surface forces resulting in chemical bonding Strong primary forces: covalent bonds

Weak secondary forces: ionic bonds, hydrogen

bonds and van der Waal’s forces

3 Wetting theory Ability of bioadhesive polymers to spread Spreading coefficients of polymers must be positive

and develop intimate contact with the

mucus membranes

4 Diffusion theory Physical entanglement of mucin strands For maximum diffusion and best bioadhesive

and the flexible polymer chains strength: solubility parameters (δ) of the

bioadhesive polymer and the mucus

glycoproteins must be similar

5 Fracture theory Analyses the maximum tensile stress Does not require physical entanglement of

developed during detachment of the BDDS bioadhesive polymer chains and mucin strands,

from the mucosal surfaces hence appropriate to study the bioadhesion of

hard polymers, which lack flexible chains

6. Mechanical theory Adhesion arises from an interlocking of However, rough surfaces also provide an increased

a liquid adhesive (on setting) into irregularities area available for interaction along with an

on a rough surface enhanced viscoelastic and plastic dissipation

of energy during joint failure

Table .5 Factors affecting the performance of BDDS ( Bioadhesive drug delivery system)²⁶

S. No. Factors Comments

1 Polymer related factors

Molecular weight Low molecular weight polymer: favours the interpenetration of polymer molecules

High molecular weight polymer: favours physical entanglement

Optimum molecular weight: at least 100,000 (threshold)

Flexibility of polymer chains Required for interpenetration and entanglement

Highly cross-linked polymers: mobility of individual polymer chains decreases which leads

to decreased bioadhesive strength

Concentration of polymer Solid BDDS: more is the polymer concentration higher is the bioadhesive strength

Liquid BDDS: Optimum concentration is required for best bioadhesion

High concentration may result in coiling of polymer molecules and hence reduced

flexibility of the polymeric chains

2 Environment related factors pH Surface charge on mucus: varies with pH due to differences in dissociation of functional groups on the carbohydrate moiety and amino acids of the polypeptide backbone

Surface charge on polymer and degree of hydration: e.g. polycarbophil—shows bioadhesive properties at pH below 5, protonated carboxyl groups form hydrogen bonds with mucin strands than the ionised carboxyl groups

Interpolymer complexation: introduces a lag time in the drug dissolution and release, more

at acidic pH

Initial pressure applied at Affects the depth of interpenetration

contact site High pressure applied for a sufficiently long period promotes attractive interactions of

bioadhesive polymer with mucin

Initial contact time Determines the extent of swelling and interpenetration of polymer chains

Cannot be controlled for the BDDS in GIT

Disease states May alter the physicochemical properties of mucus, e.g.

dissolution and release, more

at acidic pH

Initial pressure applied at Affects the depth of interpenetration

contact site High pressure applied for a sufficiently long period promotes attractive interactions of

bioadhesive polymer with mucin

Initial contact time Determines the extent of swelling and interpenetration of polymer chains

Cannot be controlled for the BDDS in GIT

Swelling Depends on polymer concentration and presence of water

Allows easy detachment of BDDS after the release of active ingredients

3 Physiological factors

Mucin turnover Limits the residence time of BDDS on the mucous layer

In GI mucosa: depends on presence of food

Intranasal mucociliary clearance: inhibited by chitosans

Disease states May alter the physicochemical properties of mucus, e.g. common cold, gastric ulcers,

ulcerative colitis, cystic fibrosis, bacterial and fungal infections and inflammation

Table .6 Properties and characteristics of some representative bioadhesive polymers²⁷

Bioadhesives Properties Characteristics

Polycarbophil • Insoluble in water, but swell to varying degrees in • Swellable depending on pH and ionic

common organic solvents, strong mineral acids, and strength.

bases. • Swelling increases as pH increases.

Carbopol/ carbomer • Pharmaceutical grades: 934 P, 940 P, 971 P and 974 P • Synthesized by cross-linker of allyl sucrose

• White, fluffy, acidic, hygroscopic powder with a slight or allyl pentaerythritol.

characteristic odour. • Incompatible with Phenols, cationic

polymers, high concentrations of electrolytes and resorcinol.

Sodium carboxymethyl • It is an anionic polymer made by swelling cellulose • In general, stability with monovalent salts is

Cellulose with NaOH and then reacting it with monochloroacetic good; with divalent salts good to marginal;

acid. with trivalent and heavy metal salts poor,

resulting in gelation or precipitation.

Hydroxypropyl cellulose • White to slightly yellowish, odorless powder. • It is inert and showed no evidence of skin

• Soluble in water below 38 °C, Insoluble in hot water. Irritation or sensitization.

Hydroxypropylmethyl • Methocel E5, E15, E50, E4M, F50, F4M, K100, K4M, • Suspending, viscosity-increasing, film

Cellulose K15M, K100M. forming agent, tablet binder and adhesive

• Odorless, tasteless, white or creamy white fibrous or ointment ingredients .

granular powder.

Hydroxyethyl Cellulose • Available in grades ranging from2 to 8,00,000 cps at2%.. • Polyvalent inorganic salts will salt out HEC

• Light tan or cream to white powder, odorless and at lower concentrations than monovalent salts.

tasteless. It may contain suitable anticaking agents.

Xanthan gum • Anionic polysaccharide derived from the fermentation of • Solutions show very good viscosity stability

the plant bacteria Xanthamonas campestris. the pH 2 to 12 range and good tolerance of

It is soluble in hot or cold water and gives visually water miscible solvents.

hazy, neutral pH solutions.

Guar gum • Obtained from the ground endosperms of the seeds of • Stable in solution over a pH range of 1.0–10.5.

Cyamposis tetyragonolobus (family leguminosae). • Used as thickener for lotions and creams, as

Tablet binder, and as emulsion stabilizer.

Chitosan • Prepared from chitin of crabs and lobsters by N- • Mucoadhesive agent due to either secondary

deacetylation with alkali. chemical bonds such as hydrogen bonds or

ionic nteractions between the positively charged amino groups of chitosan and the

negatively charged sialic. acid residues of

mucus glycoproteins or mucins.

Carrageenan • Available in sodium, potassium, magnesium, calcium • Excellent thermoreversible properties.

and mixed cation forms. • Used also for microencapsulation.

Sodium Alginate • Purified carbohydrate product extracted from brown • Safe and nonallergenic.

seaweed by the use of dilute alkali. • Biocompatible.

Occurs as a white or buff powder, which is odorless

and tasteless.

Poly (hydroxy butyrate), • Properties can be changed by chemical modification, • Used as a matrix for drug delivery systems,

Poly (e-caprolactone) copolymerization and blending. Cell microencapsulation.

and copolymers

Poly (ortho esters) • Surface eroding polymers. • Application in sustained drug delivery and

ophthalmology

Poly (cyano acrylates) • Biodegradable depending on the length of the alkyl • Used as surgical adhesives and glues

chain. • Potentially used in drug delivery.

Polyphosphazenes • Can be tailored with versatile side chain functionality. • Can be made into films and hydrogels.

Poly (vinyl alcohol) • Biocompatible • Gels and blended membranes are used in drug

delivery and cell immobilization.

Poly (ethylene oxide) • Highly biocompatible. • Its derivatives and copolymers are used in

various biomedical applications.

Poly (hydroxytheyl • Biocompatible • Hydrogels have been used as soft contact

methacrylate) lenses, for drug delivery, as skin coatings, and

for immunoisolation membranes.

Poly (ethylene • Surfactants with amphiphilic properties • Used in protein delivery and skin treatments.

oxide-b-propylene oxide)

To develop an ideal mucoadhesive system, one must have a thorough understanding of mucosa, mucous-polymer interactions, and bioadhesive polymers. The mucosa layer lines the regions of the body including gastrointestinal (GI) tract, urogenital tract, airways, ear, nose and eyes. Hence, the mucoadhesive drug delivery systems could be designed for buccal, oral, vaginal, rectal, nasal and ocular routes of administration.

MUCOSA: STRUCTURE, FUNCTION AND COMPOSITION:

The mucosa or mucus membrane is the moist tissue that lines organs and body cavities such as mouth, gut, nose and lungs. Three distinctive layers of the oral mucosa are the epithelium, basement membrane, and connective tissues (fig.1). The thickness of this mucus layer varies on different mucosal surfaces, from 50 to 450 Am in the stomach^10-11, to less than 1 Am in the oral cavity¹². Mucosal surface may be eye, nose, mouth, gastro-intestinal tract, vaginal, anus or lungs. The main mechanisms responsible for the penetration of various substances include simple diffusion (paracellular, transcellular), carrier-mediated diffusion, active transport, and pinocytosis or endocytosis.

The epithelium, as a protective layer for the tissues beneath, is divided into (a) non-keratinized and (b) keratinized epithelium. The epithelia may be either single layered (e.g. the stomach, small and large intestine and bronchi) or multilayered/stratified (e.g. in the oesophagus, vagina and cornea). The basement membrane forms a distinctive layer between the connective tissues and the epithelium. It provides the required adherence between the epithelium and the underlying connective tissues, and functions as a mechanical support for the epithelium. The underlying connective tissues provide many of the mechanical properties of oral mucosa.

MECHANISMS INVOLVED IN MUCOADHESION:

To date, no individual theory has been accepted to explain mucoadhesion as a phenomenon occurring via one singular mechanism but several of these theories can be combined to obtain a picture of the mucoadhesive process. Some of these theories are founded on physical interactions, while some others are based on chemical interactions. In general, it is agreed that the process involved in the mucoadhesion phenomenon can be described in three steps: first of all, the wetting and swelling of the polymer should allow an intimate contact with the tissue, secondly interpenetration of the polymer chains and entanglement between the polymer and the mucin chains should be attained and finally, the formation of weak chemical bonds should be possible^{18, 19}. There exist three main types of interactions between a polymer and the mucous layer: physical or mechanical bonds, secondary chemical bonds and covalent chemical bonds^20-23.

Interrelation between mucoadhesive theories:²⁶

The interrelation between the theories of mucoadhesion and properties of mucoadhesive materials are shown in fig.1. The overlapping areas between the circles indicate how and to what extent the mucoadhesive theories are connected to the material properties.

FACTORS AFFECTING MUCOADHESION IN THE ORAL CAVITY:

Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. A variety of factors affect the mucoadhesive properties of polymers, such as

Polymer related factors (Molecular weight, Flexibility of polymer chains, Concentration of polymer), Environment related factors (Initial pressure, Initial contact time, Swelling), and Physiological factors (Mucin turnover), which are briefly addressed below.

MUCOADHESIVE POLYMERS:

Some of commonly used polymers for mucoadhesive drug delivery systems are carbomer and polycarbophil, cellulose derivatives, chitosan, and sodium alginate.

CONCLUSION:

Bioadhesion is a method which has great potential for pharmaceutical technology and pharmaceutical dosage form design. Mucosal (local) and transmucosal (systemic) delivery of drugs via the mucus route is still very challenging. The main obstacles derive from the limited absorption area and from the barrier properties of the mucosa, particularly in the case of drugs intended for a transmucosal delivery. The primary goal of bioadhesive controlled drug delivery is to improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. A multidisciplinary approach will therefore be required to overcome these challenges and to employ bioadhesive polymers as a cutting edge technology for site targeted controlled release drug delivery of new as well as existing drugs. Bioadhesive polymers offer unique carrier system for many pharmaceuticals and can be tailored to adhere to any mucosal tissue, including those found in eyes, oral cavity and throughout the respiratory, urinary and gastrointestinal tract. Mucoadhesive polymers are very promising candidates for systemic and local vaginal drug delivery. The recent improvement in the area of targeted drug delivery holds great promise. Taking the great potential of mucoadhesive polymers into consideration, this class of polymers will certainly further alter the landscape of drug delivery and contribute towards the development of more efficient therapeutic systems. There is still ongoing research dealing with muco (bio) adhesive formulations that are capable of delivering the active agent for an extended period at a predictable rate.

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Received on 23.09.2009

Accepted on 19.11.2009

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Research Journal of Pharmaceutical Dosage Forms and Technology. 2(1): Jan. – Feb. 2010, 1-6