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Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 ISSN 2231-2935 Review Article www.ijrls.pharmascope.org A systematic review on: Buccoadhesive drug delivery systems 1 2 Ravi Kumar Reddy J* , Indira Muzib Y 1 Jawaharlal Nehru Technological University, Kakinada, Andhra Pradesh, India 2 Sri Padmavati Mahila Visvavidyalayam, Tirupati, Andhra Pradesh, India ABSTRACT Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. Buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms delivery. Buccal delivery offers a safer mode of drug utilization, since drug absorption can be promptly terminated in cases of toxicity by removing the dosage form from the buccal cavity. Since the above reasons, delivery of the desired drug as buccoadhesive drug delivery systems has been subject of interest since last 3 decades. However, the need for safe and effective buccal permeation, absorption enhancers is a crucial component for a prospective future in the area of buccal drug. Transmucosal is relatively new drug delivery strategy; in this traditional polymers are replaced by novel bioadhesive polymers such as thiomers (e.g.chitosan) and lectins etc to overcome limitations of traditional polymers. Some of the buccoadhesive products like Nitrostat , Buccastem, Striant, Suscard are commercially available in the market to play a vital role in the treatment of various diseases. The buccoadhesive products are increasing day by day in the market, so they have steady growth rate of above 10 % in the world market. This article describes physiological barriers for the oral mucosa, Theories of mucoadhesion, components of drug permeation, general considerations in dosage form design, recent developments in the buccal drug delivery systems, which will be useful to circumvent the difficulties associated with the formulation design for further research in buccal drug delivery. Keywords Adhesive polymers; buccal drug delivery; mucoadhesion; thiomers; transmucosal. INTRODUCTION Buccal, sublingual, palatal and gingival (Amir H S et al., 2001) regions shows effective drug delivery in oral cavity. Buccal and sublingual route of drug delivery are most widely in which local and systemic effects are treated. The permeability of oral mucosa denotes the physical nature of the tissues. The permeable part is sublingual mucosa and buccal mucosa is thinner part and in which there is a high blood flow and surface area; it is a feasible site when a rapid onset of action is desired. For the treatment of acute disorders sublingual route is a preferred one; however its surface washed with saliva which makes formulations in the oral cavity hard in nature (Satheesh M N V et al., 2009; Yajaman S et al., 2006). Various newer researches are carried out their research work recent days in the buccal delivery, like antihypertensive, anti-anginal, analgesic, antiinflammatory, anti-asthmatic, anti-infective, anti* Corresponding Author Email: [email protected] Contact +91-8565-249309 Received on: 19-07-2012 Revised on: 28-11-2012 Accepted on: 05-12-2012 neoplastic, hormonal and ophthalmic drugs. In this article various developments in formulations of buccal dosage forms, physiological barriers for permeation, theories of mucoadhesion in consolidate, future trends were described. Even many reviews are available in this area of work, but this article gives a comprehensive data on buccal drug delivery from the year 1990 to 2012. Literature review is collected from publications of various online sources includes Science direct, Pub med, Med know, Google Scholars etc. Overview of the oral mucosa 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. 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 lining of the oral cavity is referred to as the oral mucosa, and includes the buccal, sublingual, gingival, palatal and labial mu- ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences 143 Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 cosa. The buccal, sublingual and the mucosal tissues at the ventral surface of the tongue accounts for about 60% of the oral mucosal surface area. The top quarter to one-third of the oral mucosa is made up of closely compacted epithelial cells. The primary function of the oral epithelium is to protect the underlying tissue against potential harmful agents in the oral environment and from fluid loss. Beneath the epithelium are the basement membrane, lamina propia and submucosa. The oral mucosa also contains many sensory receptors including the taste receptors of the tongue (Gandhi R.E and Robinson J.R, 1988; Harris D and Robinson J R, 1992; Amir H S et al., 1998). The oral mucosae in general is a somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. As indicative by the wide range in this reported value, there are considerable differences in permeability between different regions of the oral cavity because of the diverse structures and functions of the different oral mucosa. In general, the permeabilities of the oral mucosae decrease in the order of sublingual greater than buccal, and buccal greater than palatal.This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and nonkeratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized (Sevda S and Atilla H A, 2001; Squier C A et al., 1997; Haas J and Lehr C.M, 2002). Physiological barriers for oral transmucosal drug delivery The environment of the oral cavity presents some significant challenges for systemic drug delivery. The drug needs to be released from the formulation to the delivery site (e.g. buccal or sublingual area) and pass through the mucosal layers to enter the systemic circulation. Certain physiological aspects of the oral cavity play significant roles in this process, including pH, fluid volume, enzyme activity and the permeability of oral mucosa. For drug delivery systems designed for extended release in the oral cavity (e.g. mucodhesive systems), the structure and turnover of the mucosal surface is also a determinant of performance. The principle physiological environment of the oral cavity, in terms of pH, fluid volume and composition, is shaped by the secretion of saliva. Saliva provides a water rich environment of the oral cavity which can be favorable for drug release from delivery systems especially those based on hydrophilic polymers. However, saliva flow decides the time span of the released drug at the delivery site. This flow can lead to premature swallowing of the drug before effective absorption occurs through the oral mucosa and is a well accepted concept as “saliva wash out”. However, there is little research on to what extent this phenomenon affects the efficiency of oral transmucosal delivery from different drug delivery 144 systems and thus further research needs to be conducted to better understand this effect (Herrera J.L et al., 1988; Slomiany B.L et al., 1996). Drug permeability through the oral (e.g. buccal/sublingual) mucosa represents another major physiological barrier for oral transmucosal drug delivery. The oral mucosal thickness varies depending on the site as does the composition of the epithelium. The relative impermeability of the oral mucosa is predominantly due to intercellular materials derived from the so-called membrane coating granules Q (MCGs). MCGs are spherical or oval organelles that are 100 - 300 nm in diameter and found in both keratinized and nonkeratinized epithelia. They are found near the upper, distal, or superficial border of the cells, although a few occur near the opposite border (Gilles P et al., 1996). Another factor of the buccal epithelium that can affect mucoadhesion of drug delivery systems is the turnover time. The turnover time for the buccal epithelium has been estimated 3-8 days compared to about 30 days for the skin which may change permeability characteristics frequently (Gandhi R.B et al., 1994). Theories of mucoadhesion The most widely investigated group of mucoadhesives used in buccal drug delivery systems are hydrophilic macromolecules containing numerous hydrogen bondforming groups. The presence of hydroxyl, carboxyl or amine groups on the molecules favors adhesion. They are called "wet" adhesives as they are activated by moistening and will adhere nonspecifically to many surfaces. Unless water uptake is restricted, they may over hydrate to form slippery mucilage. For dry or partially hydrated dosage forms two basic steps in mucoadhesion have been identified. Step one is the "contact stage" where intimate contact is formed between the mucoadhesive and mucous membrane. Within the buccal cavity the formulation can usually be readily placed into contact with the required mucosa and held in place to allow adhesion to occur. Step two is the "consolidation" stage where various physicochemical interactions occur to consolidate and strengthen the adhesive joint, leading to prolonged adhesion (Lee J W et al., 2000; Smart J.D, 2005). Mucoadhesion is a complex process and numerous theories have been presented to explain the mechanisms involved. These theories include mechanicalinterlocking, electrostatic, diffusion-interpenetration, adsorption and fracture processes, whilst undoubtedly the most widely accepted theories are founded upon surface energy thermodynamics and interpenetration/diffusion. The wettability theory is mainly applicable to liquid or low viscosity mucoadhesive systems and is essentially a measure of the spreadability of the drug delivery system across the biological substrate. The electronic theory describes adhesion occurs by means of electron transfer between the mucus and the mucoadhesive system arising through differences in ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 their electronic structures. The electron transfer between the mucus and the mucoadhesive results in the formation of a double layer of electrical charges at the mucus and mucoadhesive interface. The net result of such a process is the formation of attractive forces within this double layer. According to fracture theory, the adhesive bond between systems is related to the force required to separate both surfaces from one another. This "fracture theory" relates the force for polymer detachment from the mucus to the strength of their adhesive bond. The work of fracture has been found to be greater when the polymer network strands are longer or if the degree of cross-linking within such as system is reduced (Andrews G.P et al., 2009; Madsen F et al., 1998). According to adhesion theory, adhesion is defined as being the result of various surface interactions (primary and secondary bonding) between the adhesive polymer and mucus substrate. Primary bonds due to chemisorption result in adhesion due to ionic, covalent and metallic bonding, which is generally undesirable due to their permanency. The diffusioninterlocking theory proposes the time-dependent diffusion of mucoadhesive polymer chains into the glycoprotein chain network of the mucus layer. This is a twoway diffusion process with penetration rate being dependent upon the diffusion coefficients of both interacting polymers (Ugwoke M.I et al., 2005; Dodou D et al., 2005; Ahagon A et al., 1975). Components of drug permeation In order for a drug to be absorbed across mucosal epithelia it must first diffuse across a layer of mucus, and any associated unstirred water layer. A number of drugs, such as testosterone and the tetracycline antibiotics have been shown to be highly bound to mucus and to exhibit significantly increased diffusion coefficients and lag times in mucus compared to those which are not bound. It is not known how many drugs are similarly affected, although determining the potential role of mucus in limiting absorption is likely to become of increasing importance as the requirement to deliver therapeutics peptides and proteins via mucosal surfaces becomes of greater significance. Selected components of the absorption process are being investigated in isolation to determine the role of mucus. Diffusion of model compounds through native and partially purified mucus collected from different regions are being examined in vitro in the presence and absence of compounds known to reduce or promote structure in the mucus gel. The epithelium of the small intestine regulates some very diverse absorptive and secretory processes. Many of the secretions delivered into the intestinal lumen are synthesized and assembled within the intestinal epithelial cells. These secretions include mucus, which is provided by the goblet cells. In order for a drug (or nutrient) molecule to be absorbed it must diffuse across this layer. Factors that affect the turnover of mucus within the gastrointestinal tract and other mucosal surfaces have not been extensively investigated, although it has recently been shown that amino acids exert differential activity in promoting mucus output. The physiological mechanisms which control this junction are at present unknown, although initial studies suggest the involvement of chloride channels. It is the purpose of work in this area to establish whether amino acids promote mucus secretion at a number of different mucosal epithelia and to examine the effects on mucus output of putative antagonists to amino acids. Implications of these findings for drug delivery will be determined (Sze P. W. C. and Lee S. Y, 1995; Hassan EE and Gallo JM, 1990). Some permeation enhancers and their mechanisms which are commonly using in the buccal drug delivery system given in Table 1 Formulation design for buccal delivery For mucosal and transmucosal administration, conventional dosage forms are not able to assure therapeutic Table 1: Penetration enhancers and their mechanism of action (Chinna Reddy P et al., 2011) Category Surfactants Bile salts Fatty acids Cyclodextrins Chelators Positively charged Polymers Cationic Compounds Examples Anionic: Sodium lauryl sulfate Cationic: Cetyl pyridinium chloride Nonionic: Poloxamer, Brij, Span, Myrj, Tween Sodium glycol deoxycholate, Sodium glycocholate, Sodium tauro deoxycholate, Sodium tauro cholate Oleic acid, Caprylic acid, Lauric acid, Lyso phosphatidyl choline, Phosphatidyl choline α, β, γ, Cyclodextrin, methylated β –cyclodextrins EDTA, Citric acid, Sodium salicylate, Methoxy salicylates Chitosan, Trimethyl chitosan Poly-L-arginine, L-lysine ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences Mechanism of action Perturbation of intercellular Lipids and protein domain integrity Perturbation of intercellular Lipids and protein domain integrity Increase fluidity of phospholipid domains Inclusion of membrane Compounds Interfere with Ca+ Ionic interaction with negative charge on the mucosal surface Ionic interaction with negative charge on the mucosal surface 145 Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 drug levels in the mucosa and circulation because of the physiological removal of the oral cavity (washing effect of saliva and mechanical stress), which take the formulation away from the mucosa, resulting in a very short exposure time and unpredictable distribution of the drug on the site of action/absorption. To obtain the therapeutic action, it is therefore necessary to prolong and improve the contact between the active substance and the mucosa. To fulfill the therapeutic requirements, formulations for buccal administration should contain: mucoadhesive agents, to maintain an intimate and prolonged contact of the formulation with the absorption site; penetration enhancers, to improve drug permeation across mucosa (transmucosal delivery) or into deepest layers of the epithelium (mucosal delivery), enzyme inhibitors, to protect the drug from the degradation by means of mucosal enzymes and solubility modifiers to enhance solubility of poorly soluble drugs (Clark MA et al., 2000; Miller N. S et al., 2005). General considerations in dosage form design: Physiological aspects Constant flow of saliva and mobility of the involved tissues challenge drug delivery to the oral cavity. The residence time of drugs delivered to the oral cavity is typically short; in the range of <5–10 min. Buccal mucoadhesive formulations are expected to overcome this problem. Bioadhesive polymers offer a means by which a delivery system is attached to the buccal mucosa, and hence, provide substantially longer retention times at the absorption site. They also provide a means to confine and maintain high local concentrations of the drug and/or excipient(s) to a defined, relatively small region of the mucosa in order to minimize loss to other regions and limit potential side effects. The buccal mucosa is a very suitable region for bioadhesive system application because of its smooth and relatively immobile surface, as well as direct accessibility. However, there are some inherent limitations associated with buccal drug delivery, including short residence time, small absorption area, and barrier properties of the buccal mucosa. The size of a buccal dosage form is restricted by the very limited area available for application of the delivery system. This size restriction, in turn, limits the amount of drug that can be incorporated in the dosage forms. In general, a buccal delivery device that is 1–3 cm in size and a drug with a daily dose requirement of 25 mg or less would be preferred. In addition, an ellipsoid shape appears to be most acceptable, and the thickness of buccal delivery devices is usually limited to a few millimeters (Rathbone M. J et al., 1994; Anders R et al., 1989). Pathological aspects Many diseases can affect the thickness of the epithelium, resulting in alteration of the barrier property of the mucosa. Some diseases or treatments may also influence the secretion and properties of the mucus, as 146 well as the saliva. Changes at the mucosal surface due to these pathological conditions may complicate the application and retention of a bioadhesive delivery device. Therefore, understanding the nature of the mucosa under relevant disease conditions is necessary for designing an effective buccal delivery system. In addition, drugs with the potential of changing the physiological conditions of the oral cavity may not be suitable for buccal delivery (Khanvilkar K et al., 2001). Pharmacological aspects A buccal dosage form may be designed to deliver a drug to the systemic circulation, or merely indicated for local therapy of the oral mucosa. Selection of dosage forms is affected by the intended application, target site of action, drug characteristics, and the site to be treated (periodontal pockets, gingival, teeth, buccal mucosa, or systemic) (Ch’ng H. S et al., 1985). Pharmaceutical aspects Regardless of dosage form types, the drug must be released from the delivery system and subsequently taken up by the oral mucosa. Poor drug solubility in saliva could significantly retard drug release from the dosage form. Cyclodextrin has been used to solubilize and increase the absorption of poorly water-soluble drugs delivered via the buccal mucosa. Other factors affecting both drug release and penetration through buccal mucosa must also be considered in the formulation design. In addition to the physicochemical characteristics required for desirable drug release and absorption, organoleptic properties of the drug or the delivery device should also be considered, since the buccal delivery systems are to be exposed to a highly developed sensory organ (Park H et al., 1985; Andrews G.P et al., 2009). Some commercially available bioadhesive buccal formulations are listed in Table 2 Table 2: Dosage forms developed for the buccal mucosal drug delivery systems Dosage forms developed Solutions, Tablets, Lyophilized tablets, Chewing gum, Bioadhesive tablets, Solutions spray, Laminated systems and patches, Hydrogels, Adhesive films, Hollow fibres, Microspheres, Liposomes Commercially available bioadhesive buccal delivery systems Bioadhesive tablets Sublingual mucosal delivery of nitroglycerine: Susadrin® Buccal mucosal delivery of Prochloroperazine: Buccastem® Chewing gum Bucccal mucosal delivery of nicotine: Nicorette ® ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 Recent developments in buccal drug delivery systems Since few decades lot of developments were taken place in the pharmaceutical field towards delivery of drugs. In this developments buccal drug delivery also made a significant mark, here listed some of the advances which recently focused by researchers. Commercial formulations or under clinical trials formulation intended for buccal delivery are represented in Table 3 Micro/nano-particulates These are typically delivered as an aqueous suspension but can also be applied by aerosol or incorporated into a paste or ointment. Particulates have the advantage of being relatively small and, therefore, more likely to be acceptable to the patient. However, the dose of drug retained on the buccal mucosa and, therefore, delivered may not be consistent relative to a singleunit dosage form such as a patch or buccal tablet. Polymeric microparticles (23-38 μm) of Carbopol®, polycarbophil, chitosan or Gantrez® were found to be capable of adhering to porcine oesophageal mucosa, with particles prepared from the polyacrylic acids exhibiting greater mucoadhesive strength during tensile testing studies whereas, in "elution" studies, particles of chitosan or Gantrez were seen to persist on mucosal tissue for longer periods of time (Kockisch S et al., 2003; Kockisch S et al., 2004). Holpuch and co-workers (Holpuch A.S et al., 2010) explored the use of nanoparticles for local delivery to the oral mucosa. Two types of nanoparticles were studied in a proof of concept study which were solid lipid nanoparticles incorporating either idarubicin or BODIPY® FL C12 as model fluorescent probes and polystyrene nanoparticles (FluoSpheres®) in monolayer-cultured human oral squamous cell carcinoma (OSCC) cell lines and normal human oral mucosal explants. The results demonstrated that OSCC cells internalized solid lipid nanoparticles. The observed penetration of nanoparticles through the epithelium and basement membrane into the underlying connective tissue suggested the possibility of oral transmucosal nanoparticle delivery for systemic therapy. Monti and co-workers (Monti D et al., 2010) produced an atenolol containing microsphere using Poloxamer 407 and evaluated the formulation in vivo in rabbits against marketed tablet formulation as a reference. After administration of the microsphere formulations, the atenolol concentration remained higher than the reference tablet during the entire elimination phase showing a sustained release profile from the microspheres; the concentrations at 24 h were 0.75 ± 0.1 μg /ml vs 0.2 ± 0.1 μg /ml for the microspheres and marketed tablet, respectively. Moreover, the absolute bioavailability of microsphere formulations was higher than that of reference tablets in spite of a lower drug dose in the former, suggesting a possible dose reduction by atenolol microparticles via orotransmucosal administration (Laitinen R et al., 2009; Turunen E et al., 2010). Delivery of proteins and peptides The buccal mucosa represents a potentially important site for controlled delivery of macromolecular therapeutic agents, such as peptides and proteins. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. A variety of proteins/peptides with or without penetration enhancer were studied by different scientists using different animal models like dogs, rabbits, rats, pigs and humans. Some of those examples are given in Table 4. Alginate Raft System The effects of alginate molecular structure and formulation variables on the physical characteristics of alginate raft systems. Bacterial Cellulose The effects of pH, salt, heating and freezing on the physical properties of bacterial cellulose. Bioadhesive Films Mechanical characterization of Tetracaine containing bioadhesive films for percutaneous local anesthesia. Biogels Characterization of binary drug delivery platforms. Blood Plasma Gels Functional properties of heat induced gels form liquid and spray dried porcine blood plasma as influenced by pH. Bones Increase in bone calcification in young rats fed bread highly fortified with calcium. Stylianopoulous, Effects of fortification and enrichment of maize tortillas on growth and brain development of rat throughout two generations. Bones Substitute A new inject able bone substitute combining poly (Ecaprolactone) microparticles with biphasic calcium phosphate granules. Injectable bone substitute using a hydrophilic polymer. Carbopol Organogels Controlled release of Tetracycline from Carbopol organogels. Cellulose Films ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences 147 Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 Table 3: Commercial formulations or under clinical trials formulation intended for buccal delivery (Chinna Reddy P et al., 2011; Alagusundaram M et al., 2011) Manufacturer Wyeth Pharma Ceuticals Product Insulin Buccal Spray ORALGEN (US) ORALIN (Canada) Heparin Buccal Delivery System Fentanyl Buccal Delivery Systems Testosterone Buccal Tablet (Straint) Desmopressin Buccal Tablet Androdiol Buccal Tablets (Cyclo-Diol SR) Norandrodiol Buccal Tablets (Cyclo-Nordiol SR) Pilocarpine Buccal Tablet (PIOLOBUC) Prochlorperazine Buccal Tablet (Buccastem) Glyceryl Trinitrate (Suscard Buccal Tablet) Oral Transmucosal Fentanyl Citrate Solid Dosage Form (ACTIQ) Lorazepam Buccal Tablets (Temesta Expidet) Oxazepam Buccal Tablets (Seresta Expidet) IVAX Corporation Estrogen Buccal Tablet Regency Medical research Vitamins Trans Buccal Spray Nicotine Mucoadhesive Tablet (Nicorette) Nicotine Chewing Gum (Nicotinell) Triamcinolone acetonide(Aftach) Prochlorperazine Bioadhesive Buccal Tablet (Tementil) Prochlorperazine Bioadhesive Buccal controlled release Tablet (Buccastem) Buprenorphine HCl Tablets (Subutex) Generex Biotechnology Corporation Columbia Laboratories Inc. Ergo Pharm Cytokine Pharma Sciences Inc. Britannia Pharmaceuticals Ltd Pharmax Limited Cephalon, Inc. Leo Pharmaceuticals Teijin Ltd. Rhone-Poulenc Rorer Reckitt Benckiser Reckitt Benckiser Present status Commercially available Clinical Trials Completed Clinical Trials Completed Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Under Phase III clinical trials Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Commercially available Table 4: Few Buccal adhesive formulations of proteins/ peptides Protein/peptide drug Buserelin Calcitonin Glucose like peptide Gonadotropin Oxytoxin Protrelin (TRH) Dosage form Patch Tablet Tablet Tablet Patch Patch Enhancer SGDC No enhancer STC SC, SDC No enhancer Citric acid, Sodium 5Methoxy salicylate Aqueous ethyl cellulose dispersion containing plasticizers of different water solubility and hydroxypropyl methyl cellulose as coating material for diffusion pellets. Properties of sprayed films. Poly saccharides gels As a result of huge interest in the research of bucal drug delivery, currently some formulation developments are seen, such as lipophilic gel, buccal spray and phospholipid vesicles have been recently proposed to deliver peptides via the buccal route. In particular, some authors proposed the use of cubic and lamellar liquid crystalline phases of glyceryl monooleate as buccal drug carrier for peptide drugs. A novel liquid aerosol formulation (Oralin, Generex Biotechnology) has 148 Animal model Pig, rat Rabbits Human Dog Rabbit Human Rats % increase in bioavailability 12.7% 37% 4 – 23% -Slight increase Increase in plasma thyrotropin concentration been developed recently. Phospholipid deformable vesicles, transfersomes, have been recently devised for the delivery of insulin in the buccal cavity. Research carried out so far A review of literature survey has been carried out through various Indian and international journals that are view the Formulation design for buccal delivery, recent developments in buccal drug delivery and related aspects. Some of the important works are revealed here, over the last few decades pharmaceutical scientists throughout the world are trying to explore buccoadhesive and buccal drug delivery as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms Bottenburg et al., developed a bioadhesive fluoride containing slow release tablet from modified starch, polyacrylic acid, polyethylene glycol and sodium carboxymethyl cellulose (Na CMC). The fluoride release from the tablet was evaluated in healthy human volunteers and found that fluoride levels sustained significantly longer than those obtained with the administration of toothpaste having four times the fluoride content (Bottenberg P et al., 1991). Anders and Merkle, developed and evaluated laminated mucoadhesive patches of protirelin for buccal drug delivery. The patches consisted of laminates of an impermeable backing layer and a hydrocolloid polymer layer containing the drug. The duration of mucosal adhesion in vivo was found to be dependent on the type of polymer used, its viscosity grade, the polymer load per patch and drying procedure for the preparation (Anders R et al., 1989). Ali et al., prepared buccoadhesive films of triamcinolone acetonide, for the treatment of oral lesions using propylene glycol as plasticizer & different bioadhesive polymers. The films were evaluated on the basis of their physical characteristics, bioadhesive performance, release characteristic, surface pH, folding endurance and stretchability. The optimized film exhibited an in vitro adhesion time of 3.24 h and drug release of 89.98% in 3.5 h (Ali J et al., 1998). Nakhat P D et al., has developed buccoadhesive bilayered tablets of terbutaline sulphate. They reported that the carbopol 934P alone has maximum strength of bioadhesion and it get decrease with the decrease in carbopol content. Results demonstrated that effective design and stability of buccoadhesive tablets was been made possible with carbopol 934P and methocel K4M in ratio of 1:1 (Nakhat P D et al., 2007). Han-Gon Choi et al., has formulated buccoadhesive tablets of omeprazole using bioadhesive polymers and alkali materials. Magnesium oxide is acts as a stabilizer among different ones because of its strong water proofing effect in omeprazole buccal adhesive tablets. Two tablets composed as tablets containing Omeprazole which are attached to the cheeks of human and using human saliva they are stabilized for 4 h period (Han-Gon C et al., 2000). M Alagusundaram, et al., has formulated novel transbuccoadhesive bilayer tablets of Famotidine an H2receptor antagonist used as an antiulcerative agent. The buccoadhesive tablets were prepared by direct compression method using bioadhesive polymers like sodium alginate, SCMC, HPMC-K100M, PVP-K30 either alone or in combinations with EC as a backing layer. The prepared formulations were evaluated for their physicochemical characteristics (Alagusundaram M et al., 2011). Bhupinder Singh et al., Atenolol mucoadhesive tablets are formulated by method using direct compression and characterized for strength of bioadhesion and release parameters. A non-fickian kinetic release is exhibited following zero order with that of compressed matrices. An excellent control release and strength of bio adhesion were made possible with this study (Bhupinder S et al., 2006). Rajeshwar Kamal Kant Arya et al., their work involving mainly on preparation and characterization on mucoadhesive microspheres using Famotidine as drug for gastric residence time. Polymers SCMC for mucoadhesion are used in case of microspheres with a release controlling polymer sodium alginate. The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. In-vitro drug release studies were performed and drug release evaluated (Rajeshwar K K et al., 2010). Future Trends The future challenge in the development of buccoadhesive dosage forms is to modify the permeability barrier of the mucosa using safe and effective penetration enhancers (Gupta S.K et al., 2011). Mucoadhesive drug delivery systems available in the market include attach tablet (Triamcinolone acetonide), suradrin tablet (Nitroglycerin), Buccostem tablet (prochlormperazine maleate). Salcoat powder sprays (Beclomethazone dipropionate. Rhinocort powder spray (Beclomethazone Dipropionate) and sucralfate (Aluminum hydroxide). Though there are only a few mucoadhesive formulations available currently, it can be concluded that drug delivery using mucoadhesive formulations offers a great potential both for systemic and local use in the near future (Gupta A et al., 1992). Various strategies are being employed to achieve oral absorption of peptides. These strategies include manipulation of the formulation (e.g. inclusion of penetration enhancers or protease inhibitors etc.), maximizing retention of the delivery system at the site of absorption, and alteration of the peptide so as to optimize affinity for endogenous transport systems, build in chemical and metabolic stability, minimize the size and optimize the balance between lipophilicity and hydrogen bonding potential (Smart JD, 1991). Conclusion Due to the ease of access and avoidance of the hepatic metabolism, oral transmucosal drug delivery offers a promising alternative to overcome the limitations of conventional oral drug delivery and parental administration. The buccal route in particular, present favourable opportunities and many formulation approaches have been explored for such an application; although the current commercially available formulations are ©JK Welfare & Pharmascope Foundation | International Journal of Review in Life Sciences 149 Ravi Kumar Reddy and Indira Muzib., Int. J. Rev. Life. Sci., 2(4), 2012, 143-151 mostly limited to tablets and films. Oral mucoadhesive dosage forms will continue be an exciting research focus for improving drug absorption especially for the new generation of the so called "biologics", although, the palatability and irritancy and formulation retention at the site of application need to be considered in the design of such medicines Chinna Reddy P, Chaitanya K.S.C., Madhusudan Rao Y. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. 2011; 19: 385-403. REFERENCES Dodou D, Breedveld P, Wieringa P. 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