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Home , Bioadhesive, Mucoadhesion, Paste (rheology)

Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013

ISSN 2278 – 5221 www.ijpmbs.com Vol. 2, No. 1, January 2013 © 2013 IJPMBS. All Rights Reserved Review Article RECENT ADVANCES IN MUCOADHESIVE/ SYSTEM: A REVIEW

Phanindra B1*, B Krishna Moorthy1 and M Muthukumaran1

*Corresponding Author: Phanindra B,  [email protected]

The current article has been focused on the mucoadhesive drug delivery system may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. is commonly defined as the between two materials, at least one of which is a mucosal surface. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a is dependent upon a variety of factors, including the nature of the mucosal and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal) based on literatures were reported so far.

Keywords: Bioadhesive, Transmucosal, Bioavailability,

INTRODUCTION surfaces or a bond between a biological and a synthetic surface. In case of bioadhesive drug The oral mucosa has many properties which delivery, the term bioadhesion is used to describe make it an attractive site for drug delivery but also provides several challenges for researchers the adhesion between , either synthetic investigating novel delivery techniques to or natural and soft tissues or the gastrointestinal overcome many different formulations including mucosa. In cases where the bond is formed with sprays, tablets, , , pastes and the the term mucoadhesion may be used patches are presently used for delivery into and/ synonymously with bioadhesion. Buccal delivery or across the oral mucosa (Hearnde et al., 2011; involves the administration of the desired drug Mathiowitz, 2000). The term bioadhesion refers through the buccal mucosal membrane lining of to any bond formed between two biological the oral cavity. Unlike oral drug delivery, which

1 Montessori Siva Sivani Institute of Science&Technology College of Pharmacy, Mylavaram, Vijayawada, Andhra Pradesh-521230.

68 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 presents a hostile environment for drugs, phases, for example, platelet aggregation and especially and polypeptides, due to acid wound healing. hydrolysis and the hepatic first-pass effect, the • Type 2, adhesion of a biological phase to an mucosal lining of buccal tissues provides a much artificial substrate, for example, adhesion milder environment for drug absorption (Miller et to culture dishes and bio-film formation on al., 2005). A number of relevant mucoadhesive prosthetic devices and inserts. dosage forms have been developed for a variety of drugs. Several peptides, including thyrotropin- • Type 3, adhesion of an artificial material to a releasing hormone (TRH), insulin, octreotide, biological substrate, for example, adhesion of leuprolide, and oxytocin, have been delivered via synthetic hydro gels to soft tissues (Henriksen the mucosal route, albeit with relatively low et al., 1996) and adhesion of sealants to dental bioavailability (0.1-5%), (Veuillez et al., 2001) enamel. owing to their hydrophilicity and large molecular For drug delivery purposes, the term weight, as well as the inherent permeation and bioadhesion implies attachment of a drug carrier enzymatic barriers of the mucosa. system to a specified biological location. The biological surface can be epithelial tissue or the MUCOADHESION mucus coat on the surface of a tissue. If The term bioadhesion can be defined as the state attachment is to a mucus coat, the phenomenon in which two materials, at least one biological in is referred to as mucoadhesion. Leung and nature, are held together for an extended period Robinson (Leung and Robinson, 1988) described of time by interfacial forces (Good, 1983). In mucoadhesion as the interaction between a biological systems, bioadhesion can be classified mucin surface and a synthetic or natural . into 3 types: Mucoadhesion should not be confused with bioadhesion; in bioadhesion, the polymer is • Type 1, adhesion between two biological attached to the biological membrane and if the

Figure 1: Schematic Representation of Approaches to Oral Mucoadhesive Drug Delivery System

69 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 substrate is mucus membrane the term • Drug is protected from degradation in the mucoadhesion is used. acidic environment in the GIT Hydrocolloids are believed to adhere to • Improved patient compliance & ease of drug mucosa upon hydration, as the synthetic polymer administration molecules become more freely mobile and are • Faster onset of action is achieved due to able to orientate adhesive sites favorably with mucosal surface those of the substrate. As the level of hydration increases, adhesive strength was found to MECHANISM OF MUCOADHE- decrease, since mucoadhesive bonds become SION overextended. It is proposed that the hydrogen The mucoadhesive must spread over the bond-forming capacity of the polymer is important substrate to initiate close contact and increase in this effect, and may emphasize the well- surface contact, promoting the of its documented mucoadhesive properties of chains within the mucus. Attraction and repulsion polymers possessing numerous carboxyl groups such as carbopol and polycarbophil. However, the forces arise and, for a mucoadhesive to be greater swelling properties of the polymer successful, the attraction forces must be increased ionisation may lead to a reduction in dominated. Each step can be facilitated by the mechanical strength and concomitant reduction nature of the dosage form and how it is in mucoadhesive properties. Based on the administered. For example, a partially hydrated mucoadhesion theories, it may be concluded that polymer can be adsorbed by the substrate the most efficient mucoadhesive polymers have because of the attraction by the surface water physiochemical properties that are closely related (Lee et al., 2000). to those of the mucus substrate. Due to its relative complexity, it is likely that ADVANTAGES (Asane, 2007; Sudha- the process of mucoadhesion cannot be kar Yajaman and Ketousetuo Kuotsu, 2006) described by just one of these theories. Lee, Park, Robinson, 2000 had described the mechanism • Prolongs the of the dosage form at the site of absorption of mucoadhesion in four different approaches. • To avoid the first pass metabolism These include • Dry or partially hydrated dosage forms • Due to an increased residence time it contacting surfaces with substantial mucus enhances absorption and hence the layers (typically particulates administered into therapeutic efficacy of the drug the nasal cavity) • Excellent accessibility • Fully hydrated dosage forms contacting • Rapid absorption because of enormous surfaces with substantial mucus layers supply and good blood flow rates (typically particulates of many mucoadhesive • Increase in drug bioavailability due to first pass that have hydrated in the luminal contents on metabolism avoidance delivery to the lower )

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• Dry or partially hydrated dosage forms • Adsorption theory contacting surfaces with thin/discontinuous • Diffusion theory mucus layers (typically tablets or patches in Theory of Mucoadhesion the oral cavity or vagina) The wetting theory is perhaps the oldest • Fully hydrated dosage forms contacting established theory of adhesion. It is best applied surfaces with thin/discontinuous mucus layers to or low-viscosity bioadhesive. It explains (typically aqueous semisolids or adhesion as an embedding process, whereby administered into the esophagus or eye) adhesive agents penetrate into surface It is unlikely that the mucoadhesive process irregularities of the substrate and ultimately will be the same in each case (Chowdary and harden, producing many adhesive anchors. Free Srinivas, 2000). In the study of adhesion, movement of the adhesive on the surface of the generally, two stages in the adhesive process substrate means that it must overcome any supports the mechanism of interaction between surface tension effects present at the interface. mucoadhesive materials and a mucous The wetting theory calculates the contact angle membrane Thus, the mechanism of mucoad- and the thermodynamic work of adhesion (McBain hesion is generally divided in two stages, the and Hopkins, 1925). contact stage and the consolidation stage. The work done is related to the surface tension Stage 1: Contact stage: An intimate contact of both the adhesive and the substrate, as given (wetting) occurs between the mucoadhesive and by Dupre’s equation (Pritchard, 1970); mucus membrane. A = b + t – b ...(1) Stage 2: Consolidation stage: Various where A is the specific thermodynamic work of physicochemical interactions occur to adhesion and b, t, and bt represent, respectively, consolidate and strengthen the adhesive joint, the surface tensions of the bioadhesive polymer, leading to prolonged adhesion. the substrate, and the interfacial tension. The THERIOS OF MUCOADHESION adhesive work done is a sum of the surface tensions of the two adherent phases, less the Various therios exist to explain at least some of interfacial tensions apparent between both the experimental observations made during the phases (Wake, 1982). Figure 2 a drop of liquid bioadhesion process. Unfortunately, each bioadhesive spreading over a soft-tissue surface. theoretical model can only explain a limited A liquid bioadhesive spreading over a typical number of the diverse range of interactions that constitute the bioadhesive bond (Longer and soft tissue surface Robinson, 1986). However five main theories can Horizontal resolution of the forces gives the be distinguished. Young equation: • Wettability theory  ta   bt   ba cos ...(2) • Electronic theory where  is the angle of contact, bt is the surface

• Fracture theory tension between the tissue and polymer, ba is

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Figure 2: Shows the Steps Involved establishment of the electrical double layer at the in the Mucoadhesion Process interface and a series of attractive forces responsible for maintaining contact between the two layers. Diffusion Theory of Mucoadhesion Diffusion theory describes that polymeric chains from the bioadhesive interpenetrate into mucin chains and reach a sufficient depth within the opposite matrix to allow formation of a semi permanent bond. The process can be visualized from the point of initial contact (Alur H the surface tension between polymer and air, and H et al., 1999). The existence of concentration gradients will drive the polymer chains of the ta is the surface tension between tissue and air. Equation 3 states that if the angle of contact,  is bioadhesive into the mucus network and the greater than zero, the wetting will be incomplete. glycoprotein mucin chains into the bioadhesive matrix until an equilibrium penetration depth is If the vector ta greatly exceeds bt + ba, that is (Wake, 1982):] achieved as shown in a. Schematic representation of the diffusion  ta   bt   ba ...(3) theory of bioadhesion. Blue polymer layer and red Then  will approach zero and wetting will be mucus layer before contact; (b) upon contact; (c) complete. If a bioadhesive material is to The interface becomes diffuse after contact for a successfully adhere to a biological surface, it period of time must first dispel barrier substances and then The exact depth needed for good bioadhesive spontaneously spread across the underlying bonds is unclear, but is estimated to be in the substrate, either tissue or mucus. The spreading m (Alur H H et al., 1999). The coefficient, S , can be defined as shown in range of 0.2-0.5  b mean diffusional depth of the bioadhesive polymer

Sb   ta   bt   ba  0 ...(4) segments, s, may be represented by which states that bioadhesion is successful if S b S  2tD ...(5) is positive, thereby setting the criteria for the where D is the diffusion coefficient and t is the surface tension vectors; in other words, contact time. Duchene et al. (1988) adapted bioadhesion is favored by large values of  or by ta Equation 5 to give Equation 6, which can be used small values of  and  bt ba to determine the time, t, to bioadhesion of a Electrostatic Theory of Mucoadhesion particular polymer: (Ahuja A et al., 1997) 2 l According to electrostatic theory, transfer of t  ...(6) electrons occurs across the adhesive interface Db and adhering surface. This results in the in which l represents the interpenetrating depth

72 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013

and Db the diffusion coefficient of a bioadhesive FACTORS AFFECTING through the substrate. MUCOADHESION (Chen J L and Once intimate contact is achieved, the Cyr G N, 1963; Ch’ng et al., 1985) substrate and adhesive chains move along their The mucoadhesion of a drug carrier system to respective concentration gradients into the the mucous membrane depends on the below opposite phases. Depth of diffusion is dependent mentioned factors. on the diffusion coefficient of both phases. Reinhart and Peppas (Reinhart and Peppas, Polymer Based Factors 1984) reported that the diffusion coefficient 1. Molecular weight of the polymer, concentration depended on the molecular weight of the polymer of polymer used of polymer chain. strand and that it decreased with increasing cross- 2. Swelling factor stereochemistry of polymer. linking density. Physical Factors Adsorption Theory of Mucoadhesion pH at polymer substrate interface applied According to the adsorption theory, after an initial strength, contact time contact between two surfaces, the materials Physiological Factors adhere because of surface forces acting between Mucin turnover rate diseased state the chemical structures at the two surfaces.[21] When polar molecules or groups are present, they IDEAL MUCO POLYMER reorient ate at the interface (Leung S H and CHARACTERSTICS Robinson J R 1988). Chemisorption can occur A mucoadhesion promoting agent or the polymer when adhesion is particularly strong. The theory is added to the formulation which helps to maintains that adherence to tissue is due to the promote the adhering of the active pharmaceu- net result of one or more secondary forces (van tical ingredient to the oral mucosa. The agent can der Waal’s forces, hydrogen bonding, and have such additional properties like swelling so hydrophobic bonding) (Huntsberger, 1967; as to promote the disintegration when in contact Kinloch, 1980; Yang and Robinson, 1998). with the saliva. As understood earlier, that various Fracture Theory of Adhesion physical and chemical exchanges can affect the This theory describes the force required for the polymer/ mucus adhesion, so as polymer should separation of two surfaces after adhesion. The be carefully selected with the following properties fracture strength is equivalent adhesive strength in mind (Deraguin B V and Smilga V P 1969). through the following equation. This theory is • Polymer must have a high molecular weight useful for the study of bioadhesion by tensile up to 100.00 or more this is necessary to apparatus. promote the adhesiveness between the   E   / L1 / 2 ...(7) polymer and mucus (Allur et al.,1990) where  is the fracture strength,  fracture energy, • Long chain polymers-chain length must be E young modulus of elasticity, and L the critical long enough to promote the interpenetration crack length (Ahuja et al., 1997). and it should not be too long that diffusion

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becomes a problem (Huang et al., 2000) charge. Hence the mucoadhesive strength can be attributed as anion>cation>non-ionic • High viscosity (Ugwoke et al., 2005). • Degree of cross linking- it influences chain • Optimum hydration- excessive hydration leads mobility and resistance to dissolution to decreased mucoadhesive strength due to • Highly cross linked polymers swell in presence formation of a slippery mucilage. of water and retain their structure. Swelling • Optimum pH – mucoadhesion is optimum at favors controlled release of the drug and low pH conditions but at higher Ph change in increases the polymer/mucus interpenetration. the conformation occurs into a rod like structure But as the cross linking increases, the chain making them more available for inter diffusion mobility decreases which reduces the muco and interpenetration. At very elevated pH adhesive strength values, positively charged polymers like • Spatial conformation (Huang et al., 2000) form polyelectrolyte complexes with • Flexibility of polymer chain- this promotes the mucus and exhibit strong mucoadhesive interpenetration of the polymer within the forces (Bernkop-Schnurch and Freudl, 1999; mucus network (Sudhakar et al., 2006) Hagerstrom et al., 2000; Sigurdsson et al., 2006; Lee et al., 2000). • Concentration of the polymer-an optimum concentration is required to promote the muco • High applied strength and initial contact time adhesive strength. It depends however, on the • It should non toxic, economic, biocompatible dosage form. For dosage form the preferably biodegradable adhesive strength increases with increase in the polymer concentration. But in case of semi POLYMERS USED FOR MUCO- solid dosage forms an optimum concentration ADHESIVE DRUG DELIVERY so essential beyond which the adhesive (Shojaei and Li, 1997) strength decreases (Imam et al., 2003) 1. PAA derivatives carbomer- carbopol • Charge and degree of ionization- the effect of noveon- polycarbophil polymer charge on mucoadhesion was clearly These are polymers of acrylic acid cross linked shown by Bernkop-Schnurch and Freudl. In with polyalkenyl ethers or divinyl glycol. They are this work, various chemical entities were produced from primary polymer particles of about attached to chitosan and the mucoadhesive 2-6 micron diameter. Each primary particle exists strength was evaluated. Cationic chitosan HCl as a network structure of polymer cahains showed marked adhesiveness when interconnected by cross links. Carbopol polymers compared to the control. The attachment of along with pemulen and noveon polymers are all EDTA an anionic group increased the cross linked. They swell in water upto 1000 times mucoadhesive strength significantly. DTPA/ their original volume to form a when exposed chitosan system exhibited lower mucoadhesive to a pH of 4.0 to 6.0 the glass transition tempera- strength than cationic chitosan and anionic ture is about 105°C. Due to presence of EDTA chitosan complexes because of low carboxylate group and an pKa of 6.0 to 0.5,

74 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 repulsion between the negative charges occurs • Are least effected by mucus turn over rates. leading to is swelling and hence increased • Site specific drug delivery is possible. mucoadhesive strength of the polymer (Park and Robinson, 1984). Lectins Lectins are naturally occurring proteins that are Today, a large number of companies are using useful in biological recognition involving cells and carbopol polymers because of the following proteins. Lectins are a class of structurally diverse merits. proteins and glycoprotein that bind reversibly to • Good tableting formulation, flowability specific residues (Onishi and • Long drug release profiles Machida, 1999). After binding to the cell the lectins • Can give drug releases profiles similar to may either remain on the cell surface or may be carbopol 971 NF, with better handling taken inside the cell via endocytosis. They hence characteristics. allow a method for site specific and controlled drug delivery. The lectins have many advantages • Are safe and effective for but they also have the disadvantage of being • Are bioadhesive and providing increased immunogenic. bioavailability • Are approved by many of the world. Thiolated Polymers Pharmacopoeias These are thiomers which are derived from hydrophilic polymers such as polyacrylates, • Protect and peptides from degradation chitosan or deacetylated gallan gum. The presence and hence increase the bioavailability of of the thiol group increases the residence time by proteins or peptide based formulations promoting covalent bonds with the cystiene 2. Chitosan residues in mucus. The disulphide bonds may also It is a cationic polymer () (Jian- alter the mechanism of drug release from the Hwa et al., 2003),it is produced by the deactivation delivery system due to increased rigidity and cross of chitin. Chitosan is gaining importance in the linking (Clark et al., 2000). development of mucoadhesive drug delivery E.g. chitosan iminothiolane system because of its good biocompatibility, biodegradability and non toxic nature. It binds to PAA homocystiene the mucosa via ionic bonds between the amino PAA cystiene group and sialic acid residues. Chitosan being Alginate cystiene linear provides greater polymer chain flexibility. Polyox WSRA Onishi and Machida showed that chitosan and Class of high molecular weight polyethylene its metabolized derivatives are quickly eliminated molecular weight polyethylene oxide homo by the kidney (He et al., 1998). polymers having the following properties (Lehr , 3. Newer second generation polymers 2000), They have the following advantages • Water soluble. • More site specific hence called cytoadhesives. • Hydrophilic nature.

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• High molecular weight. RECENT APPLICATIONS IN • Functional group for hydrogen bonding. AN ORAL MUCOADHESIVE • Biocompatible and non toxic. DRUG DELIVERY • Can be formulated into tablets, films, gels, Oral mucoadhesive drug delivery has widespread microcapsules, . applications for many drugs which on oral administration result in poor bioavailability and are NOVEL POLYMERS rapidly degraded by the oral mucoadhesive drug • Tomato lectin showed that it has binding delivery provides advantages of high accessibility selectivity to the small intestine epithelium and low enzymatic activity. (Bottenberg et al., 1991). Earlier the hydrophilic polymers like SCMC, • Shajaei and Li have designed and HPC and polycarbophil were used for the characterized a co polymer of PAA and PEG treatment of periodontal diseases, but now the monoethylether mono methacrylate (PAA-co- trend is shifting towards the effective utilization PEG) for exhibiting optimal buccal adhesion of these systems to the delivery of peptides, (Carreno-Gomez et al., 1999). proteins and (Park K and • Leleetal, investigated novel polymers of PAA Robinson J R, 1984). complexed with PEGylated drug conjugate The buccal cavity has additional advantages (Shojaei and LI, 1997). of high patient compliance. Orabase, a first • A new class of hydrophilic pressure sensitive generation mucoadhesive has been used (PSA) has been developed by as barrier system for mouth ulcers. Semisolids corium technologies. Complex have been offer more ease in administration, but tablets have prepared by non covalent hydrogen bonding also been formulated. Tablets include matrix cross linking of a film forming hydrophilic devices or multilayered systems containing a polymer with a short chain plasticizer having mucoadhesive agent. The is kept under the reactive OH groups at chain ends. upper lip to avoid clearance mechanism of the • Bogataj et al., prepared and studied salivary gland. Buccostem, an adhesive Mucoadhesive microspheres for application in antiemetic tablet containing prochloroperazine is (Lele and Hoffman, 2000). usually administered in this manner (Patel V M et al., 2007 and Peppas N A and Buri P A, 1985). • Langath N et al. investigated the benefit of thiolated polymers for the development of Buccal mucoadhesive dosage forms may be buccal drug delivery systems (Alur et al., 1999) classified into three types, • Alur et al. Studied the transmucosal sustained • A single layer device with multidirectional drug delivery of chlorphenazine maleate in rabbits release. using a novel natural mucoadhesive gum from • A dosage form with impermeable backing layer hakea as an excipient in buccal tablets. The which is superimposed on top of a drug loaded gum provided sustained release and sufficient bioadhesive layer, creating a double layered mucoadhesion (Langoth et al., 2003). device and preventing loss from the top

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surface of the dosage form into the oral cavity. • X ray studies • Unidirectional release device, the drug is • Isolated loop technique released only from the side adjacent to the buccal mucosa. CURRENTLY USED FORMULATIONS METHODS OF EVALUATION Representative drugs with transmucosal dosage Mucoadhesive polymers can be evaluated by former with type of release and manufacturer are testing their adhesion strength by both in vitro and shown in table. Many novel formulations have in vivo tests. been advanced to various stages of development and approval and have met with varying IN VITRO METHODS manufacturing and marketing successes. The importance is laid on the elucidation of the exact mechanisms of bioadhesion. These a. Tablets (Alur et al., 1999) methods are (Botagataj et al., 1999), Lozenges, troches and tablets for systemic • Methods determining tensile strength delivery across the oral mucosa are currently commercially available for drugs including • Methods determining shear nitroglycerin and fentanyl. Solid formulations such • Adhesion weight method as tablets and lozenges dissolve into the saliva • Fluorescent probe method utilizing the whole surface area of the oral cavity • Flow channel method for absorption. • Mechanical spectroscopic method Drawbacks of tablets and lozenges include • Filling liquid film method variation due to differences in saliva production • Colloidal gold staining method and sucking intensity, accidental swallowing and short exposure time, usually no greater than 30 • Viscometer method min. Mucoadhesive tablet formulations are better • Thumb method in this respect as they adhere to the mucosa- • Adhesion number increasing exposure time. One example of this • Electrical conductance is a mucoadhesive tablet under development • Swelling properties shown to deliver therapeutic doses of flurbiprofen • In vitro drug release studies to the saliva for 12 h. This mucoadhesive tablet • Muco retentability studies allowed patients to eat and speak without discomfort and caused no irritation, bad taste or In Vivo Methods pain. When compared to delivery of the same • Use of radioisotopes (Sam et al., 1989) drug via lozenges such as Benactiv® or orally in • Use of gamma scintigraphy Froben® the daily dosage requirement was • Use of pharmacoscintigraphy reduced as the drug release was sustained within the oral cavity. Striant™ is a commercially available • Use of electron paramagnetic resonance mucoadhesive tablet for testosterone replace- (EPR) oximetry

77 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 ment therapy. effectiveness. More recently, the use of antimicrobial mouthwashes have also been b) Sprays (Palermo et al., 2011) proposed for reduction of viral contamination (HIV- Glyceryltrinitrate is a small molecule that can be 1 and HSV-1) of bio-aerosols during the delivery rapidly delivered across the sublingual oral of dental care. The management of vesiculo- mucosa using a spray for angina relief. The ulcerative conditions frequently involves the Generex Biotechnology Corporation has topical delivery of various steroid preparations and developed a RapidMist™ spray which is capable antimicrobials in form. Numerous of delivering large molecules, such as insulin other studies have utilized mouthwash vehicles across the oral mucosa. The Generex Oral-lyn™ to deliver established therapeutic agents in the spray uses micelles and generally recognised as management of various conditions, some of these safe GRAS like surfactants as permeability have been referenced however extensive review enhancers to improve the permeability of the of these is outside the scope of this review. drugs across the buccal epithelium. The product d) Gels (Peppas and Sahlin, 1996) is currently available for purchase in India and Gels have been investigated as a means of Ecuador and awaiting approval elsewhere in the controlled drug delivery since the 1980s. The world. Other applications of the RapidMist™ primary goal of bioadhesive controlled drug system in development include vaccination delivery is to localise a delivery device within the against influenza and cancers, pain management body to enhance the drug absorption process in and weight loss. a site-specific manner. Bioadhesion is affected by the synergistic action of the biological c) Mouthwashes (Battino et al., 2002) environment, the properties of the polymeric The current literature on mouthwashes and oral controlled release device, and the presence of rinses predominantly focuses on their use in the the drug itself. Overall, more than half of the local delivery of antimicrobial agents. therapeutic agents and vehicles being formulated Chlorhexidine gluconate is one such antimicrobial are in the development stage (bioavailability, with literature supporting its use in the distribution, safety and adherence stages). Others management of gingival and periodontal disease, are at the stage of animal or ex-vivo studies. Few caries and as prophylaxis for oral candidiasis in clinical trials have been performed and those that the immunosuppressed. The substantivity allows have are often small in size. None-the-less, gels significant antibacterial effect up to 7 h after the applied to the oral mucosa have been trilleds for mouth rinse. Several naturally occurring the delivery of systemic analgesics, anti- antimicrobials such as lactoperoxidases, hypertensive’s and drugs for treating lysozymes and lactoferrin have also been cardiovascular disease as well as topical delivery investigated in a mouthwash form. The of antifungal agents, anti-inflammatories and effectiveness of essential oil containing mucoprotective agents to the oral mucosa. antimicrobial mouthwashes is thought to relate to their antioxidant properties with current e) Pastes (Ortega et al., 2007) literature demonstrating variable levels of The use of pastes as a drug delivery vehicle is a

78 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 relatively under investigated method with most gingival crevice surrounding teeth in the treatment current literature focussing on the intra-canal of periodontal disease. Allen et al. investigated delivery of antimicrobial pastes in endodontics; the topical delivery of an antiviral agent in paste however this is beyond the scope of this review. form. The drug was delivered topically to oral and One currently commercially available muco- genital lesions. Only genital lesion response was adhesive paste is Orabase® an oral adhesive measured and was found to have some effect. paste that is available as a carrier alone or One might consider topical oral delivery for the containing 0.1% triamcinoloneacetonide (Kenalog treatment of oral HSV lesions. in Orabase®) for treating immunologically f) Patches (Gibson et al., 2007) mediated oral mucosal conditions. Several different patch systems that adhere to have been investigated as drug delivery carriers both as a and in a paste formulation. One the oral mucosa and are designed to deliver drugs study suggests that encapsulated have been developed. There are basically three corticosteroids applied topically in a paste form different types of oro-adhesive patches: patches may enhance symptom remission in the with a dissolvable matrix for drug delivery to the treatment of oral lichenplanus and an anti- oral cavity. These patches are longer acting than inflammatory paste incorporating amlexanox has solid forms such as tablets and lozenges and been found to accelerate healing of aphthous can produce sustained drug release for treating ulcers. Pastes have been utilised in the delivery oral candidiasis and mucositis. They slowly and of antimicrobial agents for improved extraction completely dissolve during use leaving nothing socket healing after tooth extractions in patients to remove. However significant amounts of drug with HIV disease and for the delivery of controlled will be lost to the oral cavity. They are better used, release triclosan in oral care formulations. Pastes therefore, for delivering drugs more generally into are also being used for the local delivery and the oral cavity than into the oral mucosa to which retention of slow release minocycline in the they are applied. Non-dissolvable backing patches

Table 1: Shows Some Commercially Available Oral Mucoadhesive Drug Delivery Systems

79 Int. J. Pharm. Med. & Bio. Sc. 2013 Phanindra B et al., 2013 systems for systemic drug delivery that offer technology and sustained local drug release also protection from saliva. The patches deliver a have the potential for reducing the systemic side controlled concentrated dose of the drug into the effects from ingested or injected therapies, where oral mucosa for 10–15 h. Drawbacks include that an oral mucosal disease is the target of therapy. the patch can only deliver to a small area of the mucosa, limiting the dose which can be delivered, REFERENCES and the patch has to be removed by the patient 1. Ahuja A, Khar R K and Ali J ()1997, after the dose is delivered. “Mucoadhesive Drug Delivery Systems”, Drug Dev Ind Pharm., Vol. 23, pp. 489-515. g) Wafers/Films (IntelGenxCorp., 2006) 2. Allur H H, Johnston T P and Mitra A K (1990), Thin strips of polymeric films, capable of loading in Swarbrick J and Boylan J C (Eds.), up to 20 mg of drugs, dissolve on the tongue in Encyclopedia of Pharmaceutical less than 30 s and deliver drugs(which are able to cross the permeability barrier) directly to the Technology, Vol. 20, No. 3, pp. 193-218, blood supply for rapid treatment of conditions Marcel Dekker, New York. such as impotence, migraines, motion sickness, 3. Alur H H, Pather S I, Mitra A K and Johnston pain relief and nausea. Similar wafer technology T P (1999), “Transmucosal Sustained – is already used in the treatment of migraines and Delivery of Chlorpheniramine Maleate in it is hoped the fast dissolution of the wafers, the Rabbits using a Novel, Natural Muco- self-administrable nature of the technology and adhesive gum as an Excipient in Buccal the high blood supply of the oral mucosa will Tablets”, Int. J. Pharm., Vol. 88, No. 1, pp. enable fast effective treatments for many more 1-10. conditions in the future. 4. Asane G S (2007), Mucoadhesive Gastro CONCLUSION Intestinal Drug Delivery System : An overview, Vol. 5 No. 6, http// www.pharma The phenomenon of mucoadhesion can be used info.net. Accessed on 06/07/2010. as a model for the controlled drug delivery approaches for a number of drug candidates. The 5. Battino M, Ferreiro M S, Fattorini D and various advantages of the oral mucoadhesive Bullon P (2002), “In Vitro Antioxidant Activities drug delivery systems like prolongation of the of Mouthrinses And Their Components”, J. residence time of the drug which in turn increases Clin. Periodontol., Vol. 29, pp. 462-467. the absorption of the drug are important factors 6. Bernkop-Schnurch A and Freudl J (1999), in the oral bioavailability of many drugs. With the “Comparative In Vitro Study Of Different appropriate technologies, delivery techniques and Chitosan Complrxing Agent Conjugates”, the choice of the polymer for the oral mucosa Pharmazie, Vol. 54, pp. 369-371. could, in the future, be utilized for the treatment of many diseases both mucosal and systemic 7. Botagataj M, Mrhar A and Korosec L (1999), and the catalogue of drugs which can be delivered “Influence of Physicochemical and Biological via the mucosa could be greatly increased. Parameters on Drug Release from Further advances in muco-buccal adhesive Microspheres Adhered on Vesicular and

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