MUCOADHESIVE DRUG DELIVERY SYSTEMS

1.0 Definition Adhesion can be defined as the bond produced by contact between a pressuresensitive adhesive and a surface.10 The American society of testing and materials has defined it as the state in which two surfaces are held together by interfacial forces, which may consist of valence forces, interlocking action or both. The term bio-adhesion is defined as the attachment of a synthetic or natural macromolecule to mucus and/or an epithelial surface. Adherence of a polymeric material to biological surfaces is known as bio-adhesion or to the mucosal tissue is known as mucoadhesion.

1.2 Concepts of Mucoadhesion Bio-adhesion (or mucoadhesion) is generally understood to define the ability of a biological or synthetic material to stick to a mucous membrane, resulting in adhesion of the material to the tissue for a protracted period of time. For a material to be bioadhesive, it must interact with mucus, which is a highly hydrated, viscous anionic hydrogel layer protecting the mucosa. The mucin is composed largely of flexible glycoprotein chains, which are crosslinked as shown in figure 1.

Figure 1: Schematic representation of the mucus

The formation of non-covalent bonds such as hydrogen bonds and ionic interactions or physical entanglements between the mucus gel layer and polymers provides a good mucoadhesion. The residence time of dosage forms on the GI-mucosa should be prolonged, which allows a sustained drug release at a given target site to maximize the therapeutic effect which is mediated by mucoadhesive polymers. For the purpose of local therapy or of drug

liberation at the absorption window mucoadhesive drug delivery systems can be localized on a certain surface area representing the GI-segment, where drug absorption takes place. Mucoadhesive polymers like poly (acrylates) such as carbomers are believed to bind via hydrogen bonds, whereas chitosans seem to bind via ionic interactions between their primary amino substructures and sialic acid and sulfonic acid substructures of the mucus. Mucoadhesive polymers significantly prolong the residence time of dosage forms on the mucosa and hence the sustained drug release at a given target site. In biological systems, four types of bio-adhesion could be distinguished Adhesion of a normal cell on another normal cell Adhesion of a cell with a foreign substance Adhesion of a normal cell to a pathological cell Adhesion of an adhesive to a biological substance

For drug delivery purpose, the term bio-adhesion implies attachment of a drug carrier system to a specific biological location.

1.3 Theories of Mucoadhesion The mucosal surfaces are covered with a mucus layer, in which mucins are the major component. Mucins are highly glucosylated glycoproteins with a large peptide backbone and oligosaccharides as side chains. Their protein backbone is characterized by the presence of repeating sequences rich in serine, threonine and proline residues. Many of the O-linked oligosaccharide side chains are often terminated in sialic acid, sulfonic acid, or L- fructose. As a result, mucins are negatively charged at physiological pH. Mechanisms of polymer attachment to mucosal surfaces are not yet fully understood. Four theories have been suggested to play a major role in bio-adhesion, namely, adsorption, diffusion, electronic, and wetting theories.

i.

Adsorption theory In the adsorption theory, primary and secondary chemical bonds of the covalent and non-covalent (electrostatic and Vander Waals forces, hydrogen, and hydrophobic bonds) types are formed upon initial contact between the mucus and the mucoadhesive polymer. Most of the initial interfacial bonding forces are attributed to non-covalent forces. The formation of secondary chemical bonds greatly depends on properties of the polymer.

ii.

Diffusion theory The basis of the diffusion theory is chain entanglement between glycoproteins of the mucus and the mucoadhesive polymer. This is a two way diffusion process with penetration rate being dependent upon the diffusion co-efficients of both interacting polymers. Upon initial contact between these polymers, diffusion of the bioadhesive polymer chain into the mucus network creates an entangled network between the polymers. Sufficient polymer chain flexibility, adequate exposure for the surface contact of both polymers, similar chemical structures, and the diffusion coefficient of the bioadhesive polymer are among the factors which influence the inter-diffusion of the macromolecule network. Figure 2, represents schematic representation of the diffusion theory of adhesion.

Figure 2: Schematic representation of the diffusion theory of adhesion In the figure; (a) Top (polymer) layer and bottom (mucus) layer before contact; (b) Top layer and bottom layer immediately after contact; (c) Top layer after contact for a period of time.

iii.

Electronic theory Because of different electronic properties of the mucoadhesive polymer and the mucus glycoprotein, electron transfer between these two surfaces occurs. Electron transfer contributes to formation of a charged double layer at the interface of the mucus and the polymer, which results in forces of attraction in this region and inter-diffusion of the two surfaces.

iv.

Wetting theory The wetting theory describes the ability of a bioadhesive polymer to spread on biological surfaces This theory postulates that the adhesive component penetrates surface irregularities, hardens and anchors itself to the surface. This process defines the energy

required to counter the surface tension at the interface between the two materials allowing for a good mucoadhesive spreading and coverage of the biological substrate. Therefore the contact angle (), which may be easily determined experimentally, is related to interfacial tension () of both components using equation 1 and 2
SG = SL + LG Cos 1 S = SG (SL - LG) ..2

Figure 3: Schematic representation of the wetting theory of adhesion

1.4 Mechanism of Mucoadhesion As stated, mucoadhesion is the attachement 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. Mucoadhesion has the following mechanism, a) intimate contact between a bioadhesive and a membrane( wetting or swelling phenomenon) b) penetration of the bioadhesive into the tissue or into the surface of the mucous membrane(interpenetration)

1.5 Factors Affecting Mucoadhesion The mucoadhesion of a drug carrier system to the mucous membrane depends on the below mentioned factors. Polymer based factors weight of the polymer of polymer used polymer chains stereochemistry of polymer molecular concentration flexibility of swelling factor Physical factors substrate interface pH at polymer applied strength contact time

 Physiological factors Mucin turnover rate diseased state

1.6 Advantages of Oral Mucoadhesive Prolongs the residence time of the dosage form at the site of absorption, hence increases the bioavailability. Excellent accessibility, rapid onset of action. Rapid absorption because of enormous blood supply and good blood flow rates Drug is protected from degradation in the acidic environment in the git Improved patient compliance

1.7 Disadvantages of Mucoadhesive occurrence of local ulcerous effects due to prolonged contact of the drug possessing ulcerogenic property one of the major limitations in the development of oral mucosal delivery is the lack of a good model for in vitro screening to identify drugs suitable for such administration. Patient acceptability in terms to taste, irritancy and mouth feel is to be checked

1.8 Polymers Used For Mucoadhesive Drug Delivery These polymers are classified as, Hydrophillic polymers Contains carboxylic group and possess excellent mucoadhesive properties.These are, PVP(Poly vinyl pyrrolidine) MC(Methyl cellulose) SCMC(Sodium carboxy metyhyl cellulose) HPC(Hydroxyl propyl cellulose)

Hydrogels These swell when in contact with water and adhere to tne mucus membrane . these are further classified according to their charge Anionic polymers- carbopol, polyacrylates Cationic polymers- chitosan Neural/ non ionic polymers- eudragit analogues

1.9 Methods Of Evaluation Mucoadhesive polymers and drug delivery systems can be evaluated by testing their adhesion strength by both in vitro and in vivo tests. I. In vitro tests / exvivo methods determining tensile strength methods determining shear stress adhesion weight method fluorescent probe method flow channel method mechanical spectroscopic method falling liquid film method colloidal gold staining method viscometer method thumb method adhesion number electrical conductance swelling properties in vitro drug release studies mucoretentability studies

II. In vivo methods use of radioisotopes use of gamma scintigraphy use of pharmacoscintigraphy use of electron paramagnetic resonance(EPR) oximetry X ray studies Isolated loop technique

2.0 Design Considerations for Therapeutic Drugs Via Trans-Mucosal Drug Delivery Drug selection for oral trans-mucosal delivery is limited by the physicochemical properties of the drugs themselves. To be delivered trans-mucosally, drugs must have unique physicochemical properties, i.e. a proper balance between solubility and lipophilicity. Factors that influence drug release from a system are also to be considered.

The release kinetics of a given drug from a system could be governed predominantly by the polymer morphology and excipients present in the system. Ideal formulation and its degradation products should be non-toxic, non irritant and free from leachable impurities. It should not aid in development of secondary infections and prevent the effects of local drug irritation at the site of application. An ideal trans-mucosal drug delivery system must meet several prerequisites to be successful. The first prerequisite for a trans-mucosal drug delivery system is that it should rapidly attach to the mucosal surface and maintain a strong interaction to prevent displacement. Spontaneous adhesion of the system at the target site is critical and can be achieved through bio-adhesion promoters that use tethered polymers. Contact time should also be sufficiently long at the target site, normally longer than that needed for complete drug release. The second prerequisite for a successful and effective trans-mucosal drug delivery system is that the bioadhesion performance should not be impacted by surrounding environmental pH. Other desirable characteristics of a trans-mucosal drug delivery system include high drug loading, complete drug release, and convenient administration. Drug release from a polymeric material takes place either by the diffusion or by polymer degradation or by their combination. Polymer degradation usually takes place by the enzymes or hydrolysis. This may happen in the form of bulk erosion or surface erosion. It is also important to consider factors influencing drug release from a polymer. The release kinetics of a given drug from a polymeric matrix could be governed predominantly by the polymer morphology and excipients present in the system. Critical barriers such as mucus covering the GI epithelia, high turnover rate of mucus, variable range of pH, transit time with broad spectrum, absorption barrier, degradation during absorption, hepatic first pass metabolism, rapid luminal enzymatic degradation, longer time to achieve therapeutic blood levels, and intra-subject variability, are all possible issues with oral route. The idea of bioadhesive clears the need to localize a drug at a certain site in the GI tract. Therefore a primary objective of using bioadhesive systems orally would be achieved by obtaining a substantial increase in residence time of the drug for local drug effect and to permit once daily dosing. Mucoadhesive drug delivery system offers a unique carrier system for many pharmaceuticals and can be tailored to adhere to any mucosal tissue, found in gastrointestinal tract.

2.1 Pharmaceutical Consideration And Formulation Design For Successful GastroIntestinal Mucosal Drug Delivery System Drug selection for gastrointestinal mucosal delivery is limited by the physicochemical properties of the drugs themselves. To be delivered trans-mucosally, drugs must have unique physicochemical properties, i.e. a proper balance between solubility and lipophilicity. Presently, new classes of drugs are typically not developed specifically for oral trans-mucosal delivery. It is also important to consider factors influencing drug release from a system. The release kinetics of a given drug from a system could be governed predominantly by the polymer morphology and excipients present in the system. An ideal gastrointestinal mucosal drug delivery system must meet several prerequisites to be successful. The first prerequisite for a gastrointestinal mucosal drug delivery system is that it should rapidly attach to the mucosal surface and maintain a strong interaction to prevent displacement. Spontaneous adhesion of the system at the target site is critical and can be achieved through mucoadhesive polymers. Contact time should also be sufficiently long at the target site, normally longer than that needed for complete drug release. The second prerequisite for a successful and effective gastrointestinal mucosal drug delivery system is that the bio-adhesion performance should not be impacted by surrounding environmental pH. Other desirable characteristics of a gastrointestinal mucosal drug delivery system include high drug loading, complete drug release, and convenient administration. Drug release from a polymeric material takes place either by the diffusion or by polymer degradation or by their combination. Polymer degradation usually takes place by the enzymes or hydrolysis. This may happen in the form of bulk erosion or surface erosion. It is also important to consider factors influencing drug release from a polymer. The release kinetics of a given drug from a polymeric matrix could be governed predominantly by the polymer morphology and excipients present in the system.

2.2 Technologies In Gastro-Intestinal Mucoadhesive System Advances in oral gastrointestinal drug delivery focus on the development of drug delivery systems that not only achieve the therapeutic aims of delivery but also overcome the unfavorable gastric environmental conditions. Creative approaches that incorporate a combination of these strategies to create a balance between patient convenience and clinical benefits have been used in newer technologies in gastrointestinal mucoadhesive systems. Mucoadhesive carrier is a viable option to develop a non-invasive carrier platform for the controlled release of bioactive. To improve oral gastrointestinal mucoadhesive delivery of

drugs, various novel dosage forms like bioadhesive tablets, bilayered or multilayered systems hydrogels, adhesive films, nanoparticles, microspheres etc have been developed.

2.3 Gastro-Intestinal Mucoadhesive Patch System (GIMAPS) Gastrointestinal patch systems with integrated multi-functions surmount the challenges associated with conventional drug delivery. GIMAPS is mainly designed to achieve the difficult task of performing multiple functions using a single platform, namely drug protection, unidirectional release and bio-adhesion. Although lower amounts of drug can be held in an individual micro-patch, a comparable drug dose could be achieved by increasing the number of micro-patches administered. Furthermore, because they are capable of traversing between intestinal undulations, micro-patches maximize utilization of the absorptive intestinal surface area. GIMAPS provides add on smart characteristics to this innovative therapeutic platform by self regulated release and cell-specific targeting of the system. GIMAPS is an approach for inducing greater levels of absorption and stability at the intestinal epithelium is the use of a multilayered patch system. GIMAPS comprise layers of thin, flexible membranes: an impermeable backing; a drug reservoir; a rate-controlling membrane; and an adhesive. On application of this patch, the drug flows through the skin into the bloodstream at a rate regulated by the membrane that is preprogrammed to keep the drug at an effective level. GI patch systems that have three key attributes: (i) Bioadhesive properties for retention of the dosage form; (ii) Controlled and unidirectional drug release towards the intestinal epithelium and (iii) Drug protection.

i.

Drug-in-adhesive patch

Figure A: A capsule containing gastrointestinal mucoadhesive patch systems Figure B: A microsphere patch design

ii.

Insulin patch for oral delivery

Figure: Intestinal patches for insulin delivery (a) A capsule containing insulin patches. (b) A close up of the insulin patches.

iii.

Gated hydrogel patch

Drug release from the assembled gated hydrogel patch at pH 7.3 and 25C. The diameter of the device is 5.0 mm, the thickness of bilayered gate is 60m and the thickness of the drug reservoir is 1.0 mm.

Figure: Gated hydrogel patch In figure: a. Dry assembled device. b. Release at 40 min. c. Release at 80 min. d. A schematic depicting drug release from an assembled device as the hydrogel gate opens.

iv.

Micropatches

Small particles of < 5 m have an increased adherence in the whole gut; they are more likely to induce a localized inflammatory response followed by phagocytosis by macrophages. This leads to an increased risk of the carrier system being degraded after internalization, resulting in a loss of activity.

Figure: Polymer- and silicon-based micro patches In figure (a): Silicon dioxide micro devices with different 35 m diameter reservoirs inside a 100 m diameter body 2 m thick. Bar represents 100 m. (b): Scanning electron micrograph of poly- methyl methacrylate micro devices with 80 m diameter reservoirs in a 150 m diameter body 5 m thick.

References

Gandhi R.B., Robinson J.R., Bioadhesion in drug delivery. Ind. J. Pharm. Sci., 50(3):145 -152, (1988). C.M. Lehr, J.A. Bowstra, H.E. Bodde, H.E. Junginger. A surface energy analysis mucoadhesion: Contact angle measurements on polycarbophil and pig intestinal mucosa in physiology relevant fluids. Pharm Res, 9: 70-75, (1992). Mathiowitz E, Chickering III D.E., Definitions, Mechanisms, and Theories of Bioadhesion, In: Bioadhesive Drug Delivery Systems, Fundamentals, Novel Approaches, and Development, Mathiowitz E, Chickering III D.E., Lehr C.M., (eds.), Marcel Dekker Inc. New York, 2010, pp. 4-8. S.Kockisch, G.Rees, S.Young, J.Tsibouklis, J.Smart, a direct staining method to evaluate the mucoadhesion of polymers from aqueous dispersion, J. Control. Release, 77: 1-6, (2001).