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RECENT ADVANCES IN ORAL MUCOADHESIVE DRUG DELIVERY SYSTEMS: A REVIEW Pranshu Tangri1*, N.V.Satheesh Madhav1,
1

Pranshu Tangri

DIT- Faculty of Pharmacy, Mussoorie Diversion road, Dehradun-248001, Uttarakhand, India. Email:patilraj05@gmail.com

ABSTRACT The current article focuses on the principles of mucoadhesive drug delivery systems based on adhesion to biological surfaces that are covered by mucus. An overview of the last decades discoveries on mucoadhesion and applications of mucoadhesive hydrogels as drug carriers is given. Techniques that are frequently used to study the adhesion forces and physicochemical linteractions between hydrogel, mucus, and the underlying mucosa are reviewed. Typical examples of applications of mucoadhesive hydrogels to mucosal routes of delivery are given. Finally, the perspectives of the application of these polymers in drug delivery are discussed. Mucoadhesion can be defined as a state in which two components, of which one is of biological origin are held together for extended periods of time by the help of interfacial forces 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 The mucoadhesive polymers can be categorized into two broad categories, materials which undergo matrix formation or hydrogel formation by either a water swellable material or a water soluble material. Mucoadhesive drug delivery systems is one of the most important novel drug delivery systems with its various advantages and it has a lot of potential in formulating dosage forms for various chronic diseases. Key Words: mucoadhesion, bioadhesion, oral mucosa, mucin. INTRODUCTION The term bioadhesion refers to any bond formed between two biological surfaces or a bond between a biological and a synthetic surface. In case of bioadhesive drug delivery, the term bioadhesion is used to describe the adhesion between polymers, either synthetic or natural and soft tissues or the gastrointestinal mucosa. In cases where the bond is formed with the mucus the term mucoadhesion may be used synonymously with bioadhesion. Mucoadhesion can be defined as a state in which two components, of which one is of

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biological origin are held together for extended periods of time by the help of interfacial forces. Generally speaking, bioadhesion is an term which broadly includes adhesive interactions with any biological or biologically derived substance, and mucoadhesion is used when the bond is formed with a mucosal surface[1]. 2. 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,[2] 1. intimate contact between a bioadhesive and a membrane( wetting or swelling phenomenon)[3,4] 2. penetration of the bioadhesive into the tissue or into the surface of the mucous membrane(interpenetration)[3,4] Residence time for most mucosal routes is less than an hour and typically in minutes, it can be increased by the addition of an adhesive agent in the delivery system which is useful to localize the delivery system and increases the contact time at the site of absorption.[5] The exact mechanism of mucoadhesion is not known but an accepted theory states that a close contact between the mucoadhesive polymer and mucin occurs which is followed by the interpenetration of polymer And mucin. The adhesion is prolonged due to the formation of van der vaals forces, hydrogen bonds and electrostatic bonds.[1] 2.1 Theories of mucoadhesion[2] Wettability theory Electronic theory Fracture theory

Adsorption theory Diffusion theory 3. FACTORS AFFECTING MUCOADHESION[6,7] The mucoadhesion of a drug carrier system to the mucous membrane depends on the below mentioned factors. polymer based factors molecular weight of the polymer , concentration of polymer used of polymer chains swelling factor stereochemistry of polymer physical factors pH at polymer substrate interfaceapplied strength, contact time physiological factors mucin turn over rate diseased state 4. ADVANTAGES[8] prolongs the residence time of the dosage form at the site of absorption. Due to an increased residence time it enhances absorption and hence the therapeutic efficacy of the drug Excellent accessibility Rapid absorption because of enormous blood supply and good blood flow rates increase in drug bioavailability due to first pass metabolism avoidance Drug is protected from degradation in the acidic environment in the git Improved patient compliance- ease of drug administration faster onset of action is achieved due to mucosal surface

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5. ORAL MUCOSA 5.1 Oral mucosa Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable.[9] 5.1Oral histology The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium [10]. The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The turnover time for the buccal epithelium has been estimated at 5-6 days[11], and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 m, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure at about 100-200 m. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosae of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosae of the soft palate, the sublingual, and the buccal regions, however, are not keratinized [11]. The keratinized epithelia contain neutral lipids like

ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide. They also contain small amounts of neutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia have been found to be considerably more permeable to water than keratinized epithelia [12,13,14].

6. POLYMERS USED FOR MUCOADHESIVE DRUG DELIVERY[2,6] The rheology of the mucoadhesion is a typical topic and it deals with a number of forces, factors of the components, state of the material, its derived properties. Based on the rheological aspects, We can categorise the mucoadhesive polymers into two broad categories, materials which undergo matrix formation or hydrogel formation by either a water swellable material or a water soluble material.These carriers generally polymers are classified as, Hydrophillic polymers Hydrogels 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

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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 polymerseudragit analogues[15-18] They can also be classified as,[1] Synthetic polymers Natural polymers Synthetic polymerscellulose derivatives, carbopols, etc. Natural polymers- tragacanth, pecyin, gelatin sodium alginate, acacia.

6.1 Ideal muco polymer Characteristics A mucoadhesion promotoing agent or the polymer is added to the formulation which helps to promote the adhering of the active pharmaceutical ingredient to the oral mucosa. The agent can have such additional properties like swelling so as to promote the disintegration when in contact with the saliva. As understood earlier, that various physical and chemical exchanges can effect the polymer/ mucus adhesion, so as polymer should be carefully selected with the following properties in mind.[19] 1) polymer must have a high molecular weight upto 100.00 or more this is necessary to promote the adhesiveness between the polymer and mucus.[19] 2) long chain polymers-chain length must be long enough to promote the interpenetration and it should not be too long that diffusion becomes a problem.[20] 3) High viscosity

4) Degree of cross linking- it influences chain mobility and resistance to dissolution. Highly cross linked polymers swell in presence of water and retain their structure. Swelling favours controlled release of the drug and increases the polymer/mucus interpenetration. But as the cross linking increases, the chain mobility decreases which reduces the mucoadhesive [20] strength. 5) Spatial conformation 6) Flexibility of polymer chain- this promotes the interpenetration of the polymer within the mucus network.[21] 7) Concentration of the polymer- an optimum concentration is required to promote the mucoadhesive strength. It depends however, on the dosage form. For solid dosage form the adhesive strength increases with increase in the polymer concentration. But in case of semi solod dosage forms an optimum concentration os essential beyond which the adhesive strength decreases.[22] 8) Charge and degree of ionization- the effect of polymer charge on mucoadhesion was clearly shown by Bernkop-Schnurch and Freudl. In this work , various chemical entities were attached to chitosan and the mucoadhesive strength was evaluated. Cationic chitosan hcl showed marked adhesiveness when compared to the control. The attachement of EDTA an anionic group increased the mucoadshesive strength significantly. DTPA/chitosan system exhibited lower mucoadhesive strength than cationic chitosan and anionic EDTA chitosan complexes because of low charge. Hence the mucoadhesive strength can be attributed as anion>cation>nonionic.[23] 9) Optimum hydration- excessive hydration leads to decreased mucoadhesive strength due to formation of a slippery mucilage.[24,25,26]

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10) Optimum Ph mucoadhesion is optimum at low pH conditions but at higher pH values a change in the conformation occurs into a rod like structure making them more available for inter diffusion and interpenetration.[27] At at very elevated pH values, positively charged polymers like chitosan form polyelectrolyte complexes with mucus and exhibit strong [28] mucoadhesive forces. 11) High applied strength and initial contact time 12 it should non toxic ,economic ,biocompatible preferabliy biodegradable [29]

Can give drug releases profiles similar to carbopol 971oNF, with better handling characterstics. Are safe and effective for oral administration Arebioadhesive and providing increased bioavailability Are approved by many pf the world pharmacopoeias Protect protien and peptides from degradation and hence increase the bioavailability of proteins or peptide based formulations

6.2 Polymers used for oral mucoadhesive drug delivery[30] 6.2.1 PAA derivatives carbomer- carbopol 934 noveon- polycarbophil These are polymers of acrylic acid cross linked with polyalkenyl ethers or divinyl glycol. They are produced from primary polymer particles of about .2 - .6 micron diameter. Each primary particle exists as a network structure of polymer cahains interconnected by cross links. Carbopol polymers along with pemulen and noveon polymers are all cross linked. They swell in water upto 1000 times their original volume to form a gel when exposed to a pHof 4.0 to 6.0. the glass transition temperature is about 105c. due to presence of carboxylate group and an pka of 6.0 to 0.5, repulsion between the negative charges occurs leading to increased swelling and hence increased mucoadhesive strength of the polymer.[31] Today, a large number of companies are using carbopol polymers because of the following merits[31] good tabletting formulation flowability. Long drug release profiles

6.2.2 ChitosanIt is an cationic polymer(polysaccharide),[32] it is produced by the deacetylation of chitin. Chitosan is gaining importance in the development of mucoadhesive drug delivery system because of its good biocompatibility, biodegradability and non toxic nature. It binds to the mucosa via ionic bonds between the amino group and sialic acid residues. Chitosan being linear provides greater polymer chain flexibility. Onishi and Machida showed that chitosan and its metaboloized derivatives are quickly eliminated by the kidney.[33] 6.2.3 Newer second generation polymers[2] They have the following advantages[2] - more site specific hence called cytoadhesives. - Are least effected by mucus turn over rates., - Site specific drug delivery is possible. a) LectinsLectins are naturally occurring proteins that are useful in biological recognition involving cells and proteins. Lectins are a class of structurally diverse proteins and glycoprotein that bind reversibly to specific carbohydrate residues.[34] After binding to the cell the lectins may either remain on the cell surface or may be taken

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inside the cell via endocytosis., they hence allow a method for site specific and controlled drug delivery. The lectins have many advantages but they also have the disadvantage of being immunogenic. b) Thiolated polymersThese are thiomers which are derived from hydrophilic polymers such as polyacrylates, chitosan or deacetylated gallan gum. The presence of the thiol group increases the residence time by promoting covalent bonds with the cystiene residues in mucus. The disulphide bonds may also alter the mechanism of drug release from the delivery system due to increased rigidity and cross linking.[35] e.x. chitosan iminothiolane PAA homocystiene Paa cystiene Alginate cystiene c) polyox WSRA class of high molecular weight polyethylene molecular weright polyethylene oxide homopolymers having the following properties,[36] -water soluble -hydrophillic nature - high molecular weight - functional group for hydrogen bondimg - biocompatible and non toxic - can be formulated into tablets, films, gels, microcapsules, syrups. 6.2.4 Novel polymers Tomato lectin showed that it has binding selectivity to the small intestine epithelium.[37] Shajaei and Li have designed and characterized a co polymer of PAA and PEG monoethylether mono methacrylate(PAA-co-PEG) for exhibiting optimal buccal adhesion [38]

Lele et al, investigated novel polymers of PAA complexed with PEGylated drug conjugate.[39] A new class of hydrophilic pressure sensitive adhesives(PSA) have been developed by corium technologies. Corplex have been prepared by non covalent hydrogen bonding crosslinking of a film forming hydrphillic polymer with a short chain plasticizer having reactive OH groups at chain ends. Bogataj et. Al prepared and studied Mucoadhesive microspheres for application in urinary bladder[40] Langath N et.al. investigated the benefit of thiolated polymers for the development of buccal drug delivery systems.[41] Alur H.H. et.al., studied the transmucosal sustained delivery of chlorphenazine maleate in rabbits using a novel natural mucoadhesive gum from hakea as an excipient in buccal tablets. The gum provided sustained releawse and sufficient mucoadhesion.[42]

7. METHODS OF EVALUATION Mucoadhesive polymers can be evaluated by testing their adhesion strength by both in vitro and in vivo tests. 7.1 In vitro tests / exvivo The importance is layed on the elucidation of the exact mechanisms of bioadhesion. These methods are,[43] - 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

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electrical conductance swelling properties in vitro drug release studies mucoretentability studies

7.2 in vivo methods[44] use of radioisotopes use of gamma scintigraphy use of pharmacoscintigraphy use of electron paramagnetic resonance(EPR) oximetry X ray studies Isolated loop technique ORAL

Buccal mucoadhesive dosage forms may be classified into three types, - a single layer device with multidirectional drug release. - An dosage form with impermeable backing layer which is superimposed on top of an drug loaded bioadhesive layer, creating a double layered device and preventing loss from the top surface of the dosage form into the oral cavity. - Unidirectional release device, the drug is releasesd only from the side adjacent to the buccal mucosa. The following drugs have been formulated as oral mucoadhesive drug delivery devices in the form of tablets, films, patches etc.(table no. 1). 9. CONCLUSIONS: The phenomenon of mucoadhesion can be used as a model for the controlled drug delivery approaches for a number of drug candidates. The various advantages of the oral mucoadhesive drug delivery systems like prolongation of the residence time of the drug which in turn increases the absorption of the drug are important factors in the oral bioavailability of many drugs. The factors which are determinant in the overall success of the mucoadhesive drug delivery are the polymer physicochemical properties and the in-vivo factors such as the mucin turn over rate, mucin flow. A number of both in-vitro and in-vivo techniques have been developed for the evaluation of the mucoadhesive drug delivery systems. Mucoadhesive dosage forms extend from the simple oral mucosal delivery to the nasal, vaginal, ocular and rectal drug delivery systems. The most widely studied and accepted polymers for mucoadhesion have been the hydrophilic, high molecular weight, anionic molecules like carbomers. Recently the focus has been on the novel second generation

8. RECENT APPLICATIONS IN MUCOADHESIVE DRUG DELIVERY

Oral mucoadhesive drug delivery has widespread applications for many drugs which on oral administration result in poor bioavailability and are rapidly degraded by the oral mucoadhesive drug delivery provides advantages of high accessibility and low enzymatic activity.[2] Earlier the hydrophilic polymers like SCMC, HPC and polycarbophil were used for the treatment of periodontal diseases, but now the trend is shifting towards the effective utilization of these systems to the delivery of peptides, proteins and polysaccharides.[2,45] The buccal cavity has additional advantages of high patient compliance. Orabase, a first generation mucoadhesive paste has been used as barrier system for mouth ulcers. Semisolids offer more ease in administration, but tablets have also been formulated. Tablet include matrix devices or multilayered systems containing a mucoadhesive agent. the tablet is kept under the upper lip to avoid clearance mechanism of the salivary gland. Buccostem, an adhesive antiemetic tablet containing prochlorperazine is usually administered in this manner.[46,47]

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polymers like the thiolated polymers, lectins and lecithins. Despite the huge amount of work been done on this drug dekivery platform, the focus has been primarily on the formulation of gastroretentive dosage forms, hence, work must be done to exploit this drug delivery system for various other approaches like drug targeting and site specific drug delivery systems. 10. REFERENCES 1. S. Ganga, mucosal drug delivery a review, Vol. 5 issue 6, 2007. http// www.pharmainfo.net. Accessed on 08/07/2010. 2. G.P. Andrews et al., Mucoadhesive polymeric platforms for controlled drug delivery, Eur. J. Pharm. Biopharm,71,2009,505-518. 3. Chowdary K.P.R., Srinivas L., Mucoadhesive drug delivery systems: A review of current status, Indian Drugs, 2000,37(9), 400-406. 4. Gandhi R.B., Robinson J.R., Bioadhesion in drug delivery. Ind. J. Pharm. Sci., 1988,50(3), 145-152. 5. Yang X, Robinson JR. In : Okano T, ed. Biorelated functional polymers and gels : controlled release and applications in biomedical engineering, San Diego: Academic Press, 1998, 135. 6. Chen J.L., Cyr. G.N., Composition producing adhesion through hydration., In mainly R.S., ed., Adhesion in biological system. New York; Academic Press, 163-181. 7. Chng H.S., Park H., Kelly P., Robinson J.R., Bioadhesive polymers as platform for oral controlled drug delivery., II: Synthesis and evaluation of some swelling water insoluble bioadhesive polymers. ,J. Pharm. Sci,1985,74, 399-405.

8. G.S. Asane, mucoadhesive gastro intestinal drug delivery system : an overview,vol. 5 issue 6,(2007). http// www.pharmainfo.net. Accessed on 06/07/2010. 9. Squier, C.A.and Wertz, P.W., Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in, M.J. Rathbone, Eds; Oral Mucosal Drug Delivery, (1996),Marcel Dekker, Inc., New York,1-26. 10. Gandhi, R.E. and Robinson, J.R., Bioadhesion in drug delivery, Ind. J. Pharm. Sci., 50, 1988, 145-152. 11. Harris, D. and Robinson, J.R., Drug delivery via the mucous membranes of the oral cavity, J. Pharm. Sci., 81, 1992, 1-10. (1992). 12. Wertz, P.W. and Squier, C.A., Cellular and molecular basis of barrier function in oral epithelium, Crit. Rev. Ther. Drug Carr. Sys, 8, 1991, 237-269. 13. Squier, C.A., Cox, P., and Wertz, P.W., Lipid content and water permeability of skin and oral mucosa, The J. Invest. Dermat, 96, 1991, 123-126. 14. Zhang, J., Niu, S., Ebert, C., and Stanley, T.H., An in vivo dog model for studying recovery kinetics of the buccal mucosa permeation barrier after exposure to permeation enhancers: apparent evidence of effective enhancement without tissue damage, Int. J. Pharm.,101, 1994, 15-22. 15.Squier, C.A.and Wertz, P.W., Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in, M.J. Rathbone, Eds; Oral Mucosal Drug Delivery, (1996), Marcel Dekker, Inc., New York,1-26.

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16.Harris, D. and Robinson, J.R., Drug Delivery via the Mucous Membranes of The Oral Cavity, J. Pharm. Sci., 81, 1992, 1-10. 17.Khar, R.K., Ahuja, A. and Ali, J., In; Jain, N.K., Eds , Controlled and Novel Drug Delivery, CBS Publishers & Distributors, New Delhi, 2002, 353-55. 18.Gandhi, R.B. and Robinson, J.R., Oral cavity as a Site for Bioadhesive Drug Delivery, Adv. Drug Del. Rev., 13, 1994, 43-74. 19.Allur, H.H., Johnston, T.P. and Mitra, A.K., In; Swarbrick,J. and Boylan, J.C., Eds., Encyclopedia of Pharmaceutical Technology, Vol.20(3), (1990), Marcel Dekker, New York, 193-218. 20 Y. Huang, W. Leobandung, A. Foss, N.A. Peppas, molecular aspects of mucoadhesion and bioadhesion: tethered structures and site specific surfaces, J. Control. Release 65, 2000, 63-71. 21 Y. Sudhakar, K. Kuotsu, A.K. Bandyopadhyay, buccal bioadhesive drug delivery a promising option for orally less efficient drugs, J. Control. Release 114, 2006, 15-40. 22. M.E. Imam, M. Hornof, C. Valenta, G. Reznicek, A. Bernkop- Schnurch, evidence for the interpretation of mucoadhesive polymers into the mucus gel layer, STP Pharma. Sci. 13, 2003, 171-176 23. M.I. Ugwoke, R.U. Agu, N. Verbeke, R. Kinget, nasal mucoadhesive drug delivery: background, applications, trends and future perspectives, Adv. Drug delivery. Rev. 57, 2005,1640-1665. 24. A. Bernkop-Schnurch, J.Freudl, comparative in vitro study of different chitosan-complrxing

agent conjugates, Pharmazie 54, 1999, 369371.

25.H. Hagerstrom, M. Paulsson, K.Edsman, evaluation of mucoadhesion for two polyethylene gels in simulated physiological conditions using a rheological method, Eur. J. Pharm. Sci 9, 2000, 301-309 26. H. Sigurdsson, T. Loftsson, C. Lehr, assessment of mucoadhesion by a resonant mirror biosensor, Int. J. Pharm. 325, 2006, 7581. 27. S.A. Mortazavi, J.Smart, an investigation into the role of water movement and mucus gel dehydration in mucoadhesion, J.Control. Release 25, 1993, 197-203 28. J.W.Lee, J.H. Park, J.R. Robinmson, bioadhesive based dosage forms: the next generation, J Pharm. Sci 89, 2000, 850-866. 29. N.Peppas. Y. Huang, nanoscale technology of mucoadhesive interactions, Adv. Drug Deliv. Rev. 56, 2004, 1675-1687. 30. A. Shojaei, X. Li, Mechanisms of buccal mucoadhesion of novel copolymers of acrylic acid and polyethylene glycol monomethylether monomethacrylate, J.Control, Release 47, 1997, 151-161. 31. K. Park, J. R. Robinson, bioadhesive polymers as platforms for oral controlleds drug delivery: method 32. ,Jian-Hwa Guo, PhD ,Carbopol polymers for pharmaceutical drug delivery applications. Excipient Updates. Drug Delivery Technology. http://www.drugdeliverytech.com/cgibin/articles.cpi?idArticle=159

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33. P.He, S.Davis, L Illum, in vitro evaluation of the mucoadhesive properties of chitosan microspheres, Int.J.Pharm. 166,1998, 75-88. 34. H.Onishi, Y.Machida, biodegradation and distribution of water soluble chitosan in mice, biomaterials 20, 1999, 175-182. 35. M.A. Clark, B.Hirst, M. Jepson, lectin mediated mucosal delivery bof drugs and microparticles, Adv. Drug Deliv. Rev. 43, 2000, 207-223. 36. C.Lehr, lectin mediated drug delivery: the second generation of bioadhesives, J.Control. Release 65, 2000, 135-143.

gum as an Excipient in Buccal Tablets, Int. J. Pharm.,88(1),1999, 1-10. 42.Langoth, N., Kalbe, J. and BernkopSchnurch, A., Developmen6t of Buccal Drug Delivery Systems Based on a Thiolated Polymer, Int. J. Pharm., 252,2003, 141-48. 43.Botagataj, M., Mrhar, A. and Korosec, L., Influence of Physicochemical and Biological Parameters on Drug Release from Microspheres Adhered on Vesicular and Intesitnal Mucosa, Int. J. Pharm., 177, 1999, 211-20. 44. Sam AP, Van Dan Heuij JT, Tukker J. Mucoadhesion of both film- forming and nonfilm forming polymeric materials as evaluated with the Wilhelmy plate method. Int J Pharm, 53, 1989, 97-105. 45. DavisSS, Hardy JG, Taylor MJ, Stockwell A, Whalley DR, Wilson CG. The in vivo evaluation of an osmotic device (osmet) Using gamma scintography. J Pharm Pharmacol, 36, 1984, 740-742. 46. V.M. Patel, B.G. Prajapati, M.M. Patel, formulation, evaluation and comparision of bilayered and multilayered mucoadhesive buccal devices of propranolol hydrochloride. AAPS PharmSciTech. 8, 2007, 22-28. 47. N.Nafee, F. Ismail, N.Boraie, L. Mortada, Mucoadhesive buccal patches of miconazole nitrare : in vitro/in vivo performance and effect of ageing, Int.J.Pharm. 264, 2003, 1-14. 48. I. Bravo- Osuna, C. Vauthier, A. Fartabollini, G. Palmieri, G. Ponchel, mucoadhesion mechjanism of chitosan and thiolated chitosan poly(isobutylcyanoacrylate) core- shell nanoparticles, biomaterials 28 ,2007, 2233-2243.

37. P.Bottenberg et al. development and testing of bioadhesive, fluoride-containing slow release tablets for oral use, J.Pharm. Pharmacol.43,1991, 457-464. 38.Carreno-Gomez B, Woodley J.F, Florence A.T. Studies on the uptake of tomato lectin nanoparticles in everted gut sacs. Int. J. Pharm., 183,1999, 7-11. 39. Shojaei, A.M. and LI, X., Mechanism of Buccal Mucoadhesion of Novel Copolymersof Acrylic Acid and Polyethylene Glycol Monomethylether Monomethacrylate,J. Control. Release, 47, 1997, 151-61. 40.Lele, B.S. and Hoffman, A.S., Mucoadhesive Drug Carriers Based on Complexes of poly(acrylic acid) and PEGylated Drugs having Hydrolysable PEG-anhydride-drug Linkages, J. Control. Release, 69,2000, 237248. 41.Alur, H.H., Pather, S.I., Mitra, A.K. and Johnston, T.P., Transmucosal Sustained Delivery of Chlorpheniramine Maleate in Rabbits using a Novel, Natural Mucoadhesive

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49. Ramana MV, Nagda C, Himaja M. Design and evaluation of mucoadhesive buccal drug delivery systems containing metoprolol tartrate. Indian J Pharm Sci, 69, 2007, 515-8. 50. Altaf MA, S Charyulu N. Ionic gelation controlled drug delivery systems for gastricmucoadhesive microcapsules of captopril. Indian J Pharm Sci, 70, 2008, 655-8. 51. Semalty M, Semalty A, Kumar G. Formulation and characterization of mucoadhesive buccal films of glipizide. Indian J Pharm Sci ,70, 2008, 43-8. 52. Satishbabu BK, Srinivasan BP. Preparation and evaluation of buccoadhesive films of atenolol. Indian J Pharm Sci, 70, 2008, 175-9. 53. Nappinnai M, Chandanbala R, Balaijirajan R. Formulation and evaluation of nitrendipine buccal films. Indian J Pharm Sci, 70, 2008, 6315.

54. R Khanna, SP Agarwal, A Ahuja preparation and evaluation of mucoadhesive buccal films of clotrimazole for oral candida infections. Shripati Singhania R and D Centre, J.K. Pharmaceuticals, 13th mile stone, Faridabad121003, Haryana, India. 55. Shaila Lewis, G Subramanian, S Pandey, N Udupa. Design, evaluation and pharmacokinetic study of mucoadhesive buccal tablets of nicotine for smoking cessation, Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, MAHE, Manipal576104, India. 56. PD Nakhat, AA Kondawar, IB Babla, LG Rathi, PG Yeole, studies on buccoadhesive tablets of terbutaline sulphate, Department of Pharmaceutics, Institute of Pharmaceutical Education and Research, Borgaon (Meghe), Wardha- 442001, India.

11. TABLES & FIGURES Table no.1 Recent applications of mucoadhesive drug delivery[48-56] s.no 1 Description Design and evaluation of mucoadhesive buccal delivery systems containing metoprolol tartarate I onic gelation controlled drug delivery system for gastric mucoadhesive microparticles of captopril Formulation and characterization of mucoadhesive buccal films of glipizide Prepration and evaluation Polymers used Application Carbopo934, HPMC, Prolong the duration HEC, SCMC of action

Alginate, chitosan, Control the drug carbopol-934p, CAP, release for a longer HPMC vduration of time

SCMC, HPMC, films exhibited carbopol-934p, controllede releses eudragitrl-100 for more than 6 hours of Sodium alginate, Double layer

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Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-3/ISSUE-2/APRIL/018

ISSN 0974 9446

buccoadhesive films of atenolol

Formulation and evaluation nitredipine buccal films

carbopol 934p, ethyl structure design to cellulose provide drug delivery in a unidirectional manner to the mucosa of HPMC K100, HPC, Moderate drug SCMC, sodium release fir extended alginate, polyvinyl duration alcohol, carbopol 934p

Prepration and evaluation of HPC-M,carbopol mucoadhesive buccal films of 934p clotrimazole for oral candida infections

Intended for local delivery. Concentration mainiained above MIC for 4 hours

Design, evaluation and HPMC, pharmacokinetic study of alginate, mucoadhesive buccal tablets of chitosan nicotine by smoking cessation

sodium Peak plasma carbopol, concentration of 16.78+-2.27mg was obtained in 2 hours

Studies on buccoadhesive tablets Carbopol of terbutaline sulphate methocel methocel SCMC

934p, K4M. K15M,

double layered mucoadhesive HPMC, carbomer tablets by HPMC and carbomer

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