Journal of Pharmaceutical Investigation DOI 10.1007/s40005-016-0281-9

Online ISSN 2093-6214 Print ISSN 2093-5552

REVIEW

Drug delivery techniques for buccal route: formulation strategies and recent advances in dosage form design Sonia Barua1 • Hyeongmin Kim1 • Kanghee Jo1 • Chang Won Seo1 • Tae Jun Park1 • Kyung Bin Lee1 • Gyiae Yun2 • Kyungsoo Oh1 • Jaehwi Lee1

Received: 18 August 2016 / Accepted: 4 October 2016  The Korean Society of Pharmaceutical Sciences and Technology 2016

Abstract The buccal mucosa has been investigated for the local drug therapy and the systemic delivery of potent peptides, proteins, and other small drug molecules that are subjected to hepatic metabolism and enzymatic degradation in the gastrointestinal tract. Being non-invasive, this route is more feasible for the delivery of therapeutic entities than that of invasive or parenteral drug administration. However, the mucosa of oral cavity represents a major barrier to drug penetration. In addition, the presence of several enzymes in saliva, salivary flow, discomfort feelings after administration of dosage forms, and bitter taste of the drugs have limited the drug delivery via the buccal cavity. Thus, extensive studies have been conducted to develop novel pharmaceutical formulations for effective buccal drug delivery. Various buccal dosage forms such as tablets, gels, and patches/films are now commercially available and have demonstrated high patient compliance. Recently, several manufacturing companies have launched new buccal drug delivery systems such as aerosol, sprays, and particulate systems and they have actively been investigated by numerous pharmaceutical scientists. If the successful development of such systems could be achieved, buccal drug delivery systems would be one of the most promising technology in the near future. In this review, we described the recent development of buccal dosage forms, anatomy of buccal mucosa, drug transport mechanisms,

& Jaehwi Lee [email protected] 1

College of Pharmacy, Chung-Ang University, 84 Heuksukro, Dongjak-gu, Seoul 06974, Republic of Korea

2

Department of Food Science and Technology, Chung-Ang University, Anseong 17546, Republic of Korea

and formulation strategies to enhance the drug permeation through the buccal mucosa. Keywords Buccal delivery  Penetration enhancers  Bioahesive polymers  Enzyme inhibitors  Innovative delivery systems

Introduction The oral cavity is mostly preferred for drug delivery due to ease of administration and avoidance of possible drug degradation in the gastrointestinal tract (GI) and hepatic first pass metabolism (Perioli and Pagano 2013). Drugs are administered via buccal route immediately drained into the internal jugular vein, which is gateway to direct access into the systemic circulation, thereby overcoming the disadvantages associated with oral drug delivery systems (Holm et al. 2013; Pather et al. 2008). There are four potential regions for drug delivery in the oral cavity, namely buccal, sublingual, palatal, and gingival (Birudaraj et al. 2005). Among those various oral routes, buccal mucosa specifically refers to the delivery of drugs for obtaining both local and/or systemic pharmacological actions (Hao and Heng 2003; Schwarz et al. 2013). This route seems promising, especially for the delivery of hydrophilic macromolecules such as peptide and protein drugs in order to avoid the rapid enzymatic degradation in the GI tract and the liver. In addition, other small therapeutic agents can also effectively deliver via buccal route (Puratchikody et al. 2011; Schwarz et al. 2013). Other benefits include low enzymatic activity, painless administration, easy to remove the dosage forms in case of mucosal irritation, high patient compliance, versatility in designing as multidirectional or unidirectional release systems for local or systemic actions, making this

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route more suitable and acceptable for drug delivery (Gilhotra et al. 2014; Kulkarni et al. 2010; Rossi et al. 2005). Different types of buccal delivery systems are being investigated and have been used for drug absorption via the oral mucosa. These include aqueous solutions (e.g. mouthwash, a dose of 25 ml), conventional buccal and sublingual tablets, liquid-filled capsules, adhesive tablets, adhesive gels, adhesive patches, flexible films, wafers, chewing gums, metered-dose aerosols and devices attached to the teeth or implanted in the tooth enamel (Kianfar et al. 2012; Jiao et al. 2016; Sharma et al. 2012). Figure 1 represents the various types of buccal dosage forms. However, the relatively short residence time, small surface area, significant loss of drug due to uncontrollable swallowing, salivary scavenging and barrier properties of the mucosa are the main limitations of drug absorption by

Fig. 1 Various types of buccal dosage forms

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this route (Li and Robinson 2005; S¸ enel and Hincal 2001). Various strategies have been implemented to overcome such obstacles and to improve the bioavailability of the drugs. Among them, absorption enhancers (such as surfactants, bile salts, chelators or fatty acids), enzyme inhibitors, vehicles (with or without adjuvants) alone or in combination with protease inhibitors (aprotinin and sodium glycocholate), drug-polymer conjugation and bioadhesive materials have been employed (Caon et al. 2014; Bonferoni et al. 2009; Hassan et al. 2010). Very recently, various innovative drug delivery systems, such as lipophilic gels, buccal spray, and phospholipid vesicles have been proposed to deliver a variety of compounds, particularly peptide and protein drugs that currently require parenteral administration. If the successful development of these novel approaches could be achieved, then the drawbacks

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

associated with parenteral dosage forms such as poor patient compliance because of frequent dosing (required for the short half-lives of such drugs) and high manufacturing costs, (Rossi et al. 2005) will be minimized. Various marketed formulations of buccal dosage forms are enlisted in Table 1. This review aims to describe the recent development of buccal dosage forms. After a brief description of the anatomical structure of buccal mucosa and drug penetration pathway, strategies adopted to improve the buccal absorption of drugs will be discussed.

Structure of buccal mucosa and routes of permeation The buccal mucosa represents one-third of the total oral mucosa surface and covers the lining of the cheek and the upper and lower lips (Rossi et al. 2005). The thickness of the buccal mucosa is 500–800 lm and is potential sites for retentive delivery systems due to its rough texture. The turnover time for epithelial cells is reported to be 3–8 days and 14–24 days while that of skin is demonstrated as approximately 30 days (Smart Smart and Keegan 2010).

Table 1 Commercially available various buccal dosage forms. Reproduced from Hearnden et al. (2012) and updated Dosage forms

Generic name

Trade name

Company

Tablets/ Lozenges

Triamcinolone acetonide

Aphtach

Teijin Ltd, Japan

Prochlorperazine controlled release

Buccastem buccal Reckitt, UK

Oral transmucosal fentanyl citrate lozenge Actiq

Teva Pharmaceuticals, Sellersville,PA, USA

Fentanyl buccal tablet

FentoraTM

Cephalon, Inc., Frazer, PA, USA

Miconazole lauriad mucoadhesive tablet

Oravig

Strativa Pharmaceuticals Inc., Woodcliff Lake, NJ, USA

Loramyc

Wafers/films

Gels

Sprays



Therabel Lucien Pharma Laboratories, Levallois-Perret, France

Nitroglycerin transmucosal

Nitrogard

Testosterone sustained release buccal system (mucoadhesive tablet)

StriantTM

Columbia Laboratories, Inc., Livingston, NJ, USA

Prochlorperazine

Tementil

Rhone-Poulenc Rorer



Forest Pharmaceuticals, St. Louis, MO, USA

Fentanyl citrate

Onsolis

Buprenorphine/Naloxone

Suboxone

Rizatriptan

Maxalt Wafers

Merck & Co. Inc., Whitehouse Station, NJ, USA

Chlorhexidin digluconate

Carsodyl gel

GlaxoSmithcline

Dry mouth relief gel

OralBalance

GlaxoSmithKlein, plc, Bentford, Middlesex, UK



Meda Pharmaceuticals Inc., Somerset, NJ, USA Reckitt Benckiser Pharmaceuticals Inc., Richmond, VA, USA

Bioadherent oral gel

Gelclair

Cannabinnoids

Sativex

GW Pharmaceuticals, PLC Expert, UK

Vitamins

Vitamins Trans Buccal Spray

Regency Medical research Ltd, USA

Insulin

ORALGEN (US)

Generex Biotechnology Corporation

EKR Therapeutics, Inc., Bedminster, NJ, USA

ORALGEN (Canada) Periogard Peridex

Procter and Gamble, Cincinatti, OH, USA and ColgatePalmolive Company, New York, NY, USA

Antiseptic essential oil mouthrinse

Listerine

McNeill-PPC, Inc. Skillman, NJ, USA

Dexamethazone elixir Aminocaproic acid syrup

Decadron Amicar

G&W Laboratories, Inc., South Plainfield, NJ, USA VersaPharm Inc., Marietta, GA

Amlexanox oral paste

Aphthasol

Discus Dental, Inc., Culver City, CA, USA

Triamcinalone acetonide dental paste

Kenalog in Orabase

Bristol-Myers Squibb Co., Princeton, NJ, USA

Oralone

Taro Pharmaceuticals, Hawthorne, NY, USA

Mouthwashes Chlorhexidine gluconate mouthrinse

Pastes

Patches

Lidocain extended release

Dentipatch

Noven pharmaceutical Inc, USA

Oromucosal pellets

Hydrocortisone

Corlan pellets

Celltech Pharmaceuticals Inc., USA

Chewing gum

Nicotine

Nicorette

Leo Pharmaceuticals

Glyceryl trinitrate

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The buccal epithelium is non-keratinized and composed of multiple layers of cells, which exhibit different patterns of maturation between the basal layers and the superficial layers (Hearnden et al. 2012; Johnston 2015). The permeability barrier of buccal mucosa is composed of intercellular lipids, which are originated from the membranecoating granules. These granules are known as small lipid organelles that are located in prickle cell layer. Although the relationship between the membrane-coating granules and epithelial barrier formation is poorly understood, it is assumed that the intercellular lipids are responsible for the barrier formation in the upper epithelium (Marxen et al. 2016). This penetration barrier exists in the outermost quarter to one-third of the epithelium (Hao and Heng 2003). The structure of mucosal barrier is associated with loosely packed intercellular lipids and the presence of large amounts of phospholipids in nonkeratinized or keratinized mucosa. The buccal epithelia is mostly non-keratinized and contains small amounts of ceramides and neutral, but polar lipids mainly cholesterol sulfate and glucosyl ceramides. In comparison to keratinized mucosa, non-keratinized mucosa is highly permeable, (Bhati and Nagrajan 2012; Consuelo et al. 2005; Marxen et al. 2016) thus, forming the major administration site in the oral cavity. Basement membrane, lamina propria followed by the submucosa are located below this layer (Patel et al. 2012). In lamina propria region, the presence of blood vessels and capillaries that open to the internal jugular vein bypass the first-pass clearance of buccal-delivered drugs providing direct entrance to the circulatory system (Shojaei 2011). The buccal mucosa also contains minor salivary glands. Saliva, which secrets by these glands, contains many organic components or enzymes such as amylase, lipase, mucin, proline-rich proteins (PRP), tyrosine-rich proteins, histidine-rich proteins, peroxidase, lysozyme, secretory immunoglobulin (IgA), and protease inhibitors (Sudhakar et al. 2006). The functions of these components include digestion of complex food substances (through enzymatic activity), lubrication to permit swallowing, and the protection of dental tissues from bacterial decay. Mucin is one of the major component of the saliva, which binds to the surface of oral mucosa and participates in the barrier function (Smart and Keegan 2010). Mechanism of drug penetration Similar to the other epithelia in the body, the buccal route also follows some mechanisms for drug absorption. Exogenous substances traverse across the buccal epithelial mucosa by means of simple or passive diffusion (Pather et al. 2008; Shojaei and Li 1997), carrier mediated diffusion (Hearnden et al. 2012; Kurosaki et al. 1998) and other specialized mechanisms such as endocytosis or active

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transport systems. Most of the drug substances are mainly transported via paracellular and transcellular routes (Hearnden et al. 2012; Nicolazzo and Finnin 2008). The permeation of polar molecules such as peptide-based therapeutic agents often occurs by the paracellular route. Since the paracellular pathway is situated at the aqueous extracellular region, some structural features such as molecular size, charge and hydrophilicity are involved in the absorption process as well as the area of the intercellular spaces and its tortuosity. The transcellular pathway, in contrast, drugs permeate across the cell membrane and then hydrophilic interior of the cell before passing through two cell membranes and then to the next cell until entering to the systemic circulation (Pather et al. 2008; Sudhakar et al. 2006). Therefore, lipophilic drugs must have some hydrophilicity if uptake of the drug into the circulatory system is required (Mahalingam et al. 2007; Pather et al. 2008). The steady-state flux (JP) model for hydrophilic drugs through the paracellular route is given below. JP ¼

DP  e  CD hP

where e is the area fraction of the paracellular route, hp is the length of the paracellular pathway, Dp is the diffusion coefficient in the intercellular spaces and CD is the concentration of drug in the donor chamber. (Shojaei and Li 1997; Sudhakar et al. 2006). In contrast, lipophilic compounds are transported across lipophilic biological membranes (transcellular) and the steady-state flux (JT) is given below. JT ¼

ð1  eÞ  DT  KP  CD hT

where, Kp is the partition coefficient between the lipophilic phase (cell membrane) and the hydrophilic donor phase, hT is the length of the transcellular route and DT is the diffusion coefficient in the lipophilic phase (Shojaei and Li 1997; Sudhakar et al. 2006). In very few cases, absorption of drugs, particularly small molecules such as monosaccharides and amino acids, via carrier-mediated systems have been reported (Utoguchi et al. 1997, 1999; S¸ enel and Hincal 2001). Nevertheless, the permeation mechanism in terms of location, transport capacity or specificity in the buccal mucosa needs further clarification. The absorption of D- and L- forms of amino acids and glucose through the buccal mucosa indicated that the existence of carrier-mediated transport in buccal cavity (Patel et al. 2011; Veuillez et al. 2001). The apparent saturation kinetics, mutual inhibition, and partial sodium dependency sometimes observe for certain components if absorption takes place via carrier transport systems (Kimura et al. 2002; Oyama et al. 1999).

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

Barrier to drug penetration across buccal mucosa The absorption barrier found in the oral mucosa can be divided into a metabolic and a physical barrier. The physical barrier includes the epithelium cell structure, membrane-coating granules, cell periphery and salivary mucin while the metabolic barrier function comprises proteolytic enzyme-related inactivation (Sudhakar et al. 2006). Due to the complex structure of buccal epithelium, it can serve as a barrier to the absorption of various hydrophilic molecules into the tissues (Salamat-Miller et al. 2005; Smart 2005). The thickness of this barrier is measured to be 16 lm. The composition of oral epithelium lipids varies depending on the species and the region of the oral cavity and various animal models have been employed to demonstrate the molecular structure of buccal epithelium (Amores et al. 2014; Patel et al. 2012). For example, porcine oral epithelia (non-keratinised) contains typically phospholipids, glycosylceramides, ceramides, cholesterol, cholesterol sulphate, fatty acids, triglycerides, and cholesteryl esters. Among these, phospholipids are major components in all regions of the oral cavity and mainly consist of sphingomyelin, phosphatidylcholine, and phosphatidylethanolamine. The porcine buccal mucosa is considered to be the most acceptable model for drug penetration studies due to its close resemblance with human tissue (Montenegro-Nicolini and Morales 2016; Consuelo et al. 2005). Apart from lipid compositions, the extent of keratinization also provides barrier limiting factors to drug penetration via the oral mucosa (Sudhakar et al. 2006). The buccal tissues of human, monkey, porcine and rabbit are non-keratinised while for rodents such as rat, guinea pig, and hamster, are keratinized (Consuelo et al. 2005; ). The surface area of the buccal epithelium is covered with a thin layer of high molecular weight salivary mucoproteins and mucopolysaccharides. This layer also represents the physical barrier function known as the mucus barrier (Jankowska et al. 2007). Enzyme-related metabolism in the oral mucosal membrane as well as in the saliva is regarded as one of the most hostile barriers to be overcome, especially for peptide and protein drugs. Saliva contains various carbohydrases and phosphatases acting in the pH range of 5.8–7.2. To reach the systemic circulation, drugs have to overcome these enzymatic barriers that exist on the mucosal surface and in the mucosa (Caon et al. 2014; Walker 2002). However, due to lack of peptide hydrolysis enzymes such as pepsin, trypsin, and chymotrypsin, the enzymatic activity of buccal mucosa is less effective than that of the GI tract (Caon et al. 2014). On the other hand, the presence of other proteolytic enzymes such as aminopeptidases, endopeptidases, carboxypeptidases, esterases, and phosphatases in the buccal

mucosa of human, pig, monkey, rat, rabbit and cultured hamster buccal cells has been demonstrated (Caon et al. 2014; Kragelund et al. 2008). These enzymes are responsible for the main barrier of saliva or proteolytic degradation of most peptide or protein drugs in buccal mucosa. The use of mucoadhesive polymers as enzyme inhibitors is a new approach to overcome this hostile environment for the efficient and safe delivery of peptide and protein drugs (Park et al. 2011).

Strategies to enhance drug absorption through buccal mucosa Penetration enhancers The upper layer of the buccal epithelium limits the passage of most of the drug molecules. Substances that promote the flux/absorption of drugs through buccal mucosa are referred as penetration enhancers (Aungst 2012). To improve efficacy and to reduce toxic effects of the formulations, it is essential to understand the molecular interaction between the enhancers and the epithelial membranes and obviously their transport mechanisms. A number of factors need to be considered during the selection of enhancers including physicochemical properties of the drugs and the enhancers and compositions of the vehicles (Mao et al. 2009). Mechanisms by which penetration enhancers are thought to be improved the mucosal absorption are as follows: (i) changing mucus rheology, (ii) increasing the fluidity of epithelial lipid bilayers, (iii) affecting the components involved in the formation of intercellular junctions and (iv) increasing the thermodynamic activity of a drug in the vehicles (Sudhakar et al. 2006). Various classes of permeants such as bile salts, surfactants, fatty acids, chitosans have been investigated to promote the drug absorption through buccal mucosa (Table 2) (Salamat-Miller et al. 2005; Smart 2005). Although permeation enhancers exhibit beneficial effects in mucosal absorption, their adverse effects in terms of enzyme inactivation, swelling of tissues, extraction of lipid components, long term toxicity and enhanced permeability of pathogenic microorganisms must be carefully considered. These negative effects have limited the clinical usefulness of many potential permeability promoters (Hearnden et al. 2012). Sodium lauryl sulphate is extensively used in the pharmaceutical dosage forms due to its ability to disorganize the membrane structure and thereby, expand the intercellular spaces facilitating the permeation of drugs within tissue. However, this potential promoters may cause mucosal irritation by extracting the membrane lipids (intercellular or cellular) (Hao and Heng 2003; Morales and McConville 2014). On the other hand,

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Enzyme inhibitors

Penetration enhancers

Hydrogels

Adhesive polymers

Investigated drugs

Portero et al. (2002)

Fluorescentlabeled dextrans

Bird et al. (2001) Marschu¨tz and BernkopSchnu¨rch (2000)

Cid et al. (2012)

Celecoxib Mannitol

Sodium glycocholate, camostate mesilate, bacitracin Altering the confirmation of peptides or protein Endomorphine-1 soyabean, trypsin inhibitor, carboxymethyl celluloseand protecting the drug against enzymatic Insulin elastinal, carbomers, polycarbophil, bestatin, degradation aprotinin, and streptozocin

Increase retention time of drug in contact with mucosa and disruption of intercellular lipid organization

Chitosan

Jug et al. (2009)

Tsutsumi et al. (2002)

Morishita et al. (2001)

Nicolazzo et al. (2004) Insulin

Xiang et al. (2002)

Oh et al. (2011)

Colonna et al. (2006)

Rai et al. (2011)

Naz et al. (2016)

Estradio

Atenolol

Increase drug solubility Enhances drug permeation and absorption

Inclusion complexes

Cyclodextrins

Dyawanapelly et al. (2016) Sogias et al. (2012)

Caffeine l

Ergotaminetartarate

Increase fluidity of intercellular lipids

Sodium deoxyglycocholate, sodium glycocholate, sodium taurocholate, sodium taurodihydrofusidate, sodium glycodihydrofusidate Fatty acids and derivatives

Salmon calcitonin20 30 dideoxycytidine

Myoglobin

Naltrexone

Oleic acid, caprylic acid, capric acid, acylcarnitines, Acylcholines, cord liver oil

Lipid extraction from the mucosa

Ionic interaction with negative charge on the mucosal surface

Lipid extraction from the mucosa

Bile salts and derivatives

Cationic compounds Chitosan, trimethyl chitosan, poly-L-arginine, L-lysine

Positively charged polymers

Sodium lauryl sulphate, polyoxyethylene-9-lauryl ether, polyoxyethylene- 20-cetyl ether,tween 80, brij 58

Surfactants

Sodium carboxy methyl cellulose, chitosan, pectin

Fluconazol

Form covalent mucus bridging leading to improve mucoadhesion

Thiolated polymers

Bovine serum albumin

Geresh et al. (2004)

Theophylline

Shojaei and Li (1997) Ameye et al. (2002)

Acyclovir Testosterone

Ibuprofen

Enhance membrane permeation

Increase drug residence time

Varshosaz and Dehghan (2002) Munasur et al. (2006)

Nifedipine

Boyapally et al. (2010)

Cilurzo et al. (2010)

References

Propranolol

Drug release takes place either by diffusion or by Clobetasol polymer degradation or combination of both Theophylline

Mechanism of action

Polyacrylates, polycarbophil, chitosan

Multifunctional polymers

Acrylic acid and polyethylene glycol monomethylethermonomethacrylate, starch– poly(acrylic acid) grafted copolymers

Copolymers

Polyacrylates, ethylene vinyl alcohol, polyethylene oxide, poly vinyl alcohol, guar gum, xantham gum, methyl cellulose, hydroxypropyl cellulose

Examples

Approaches

Table 2 Various approaches for improving drug absorption

S. Barua et al.

bile salts are widely used as penetration enhancers because they are able to solubilize the epithelial lipids, possibly by micellization without causing major mucosal damages and this lead to the main driving force of the permeants to diffuse through the mucosal membranes (Mao et al. 2009; Palermo et al. 2011). However, until now, the majority of research focus on transdermal enhancement and much less information is available on buccal absorption enhancement. Further clarification is required to understand the molecular interactions, safety and enhancement effect of the permeants on mucosal absoprtion. Very few successful buccal formulations with penetration enhancers have been established, (Hearnden et al. 2012) and most of the marketed buccal formulations does not contain absorption promoters due to unsatisfactory profiles of laboratory based trials with respect to irritation and enhancement efficacy (Hao and Heng 2003). Protect the drugs against enzymatic degradation

Han et al. (1999)

Cui et al. (2008) Insulin

Increase pharmacological activity of parent drug Nalbuphine hydrochloride

Enhanced drug permeation and bioavailability Buccal spray

Nalbuphine enanthate Prodrugs

Yang et al. (2002) Insulin Transfersomes

Soybean phosphatidylcholine (SPC), cholesterol and sodium deoxy cholate

Enhance buccal epithelial permeation

Venugopalan et al. (2001) Improve drug bioavailability Polyacrylamide nanoparticles

Insulin Increase adherence in buccal mucosa Pelleted nanoparticles

Lankkalapalli and Tenneti (2015) Rifampicin Enhance drug permeation Liposomes

References Investigated drugs Mechanism of action Examples Approaches

Table 2 continued

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

Buccal adhesive polymers The interaction between the polymer candidates and epithelial membrane occurs through a series of events. Although several theories have been proposed to explain this phenomenon, it is preferable to divide this process into two main steps (Andrews et al. 2009). In the first step, formation of a double layer due to swelling of the polymers into the mucus network. Followed by, various physicochemical interactions, i.e., covalent and ionic bonds, hydrogen bonds, electrostatic interactions, and van der Waals forces occur between the two substrates. These interactions are essential to prolong the contact period and strengthen the mucoadhesion of the dosage forms at targeted sites. The types of bonding forces are dependent on the chemical structure of the polymers (Russo et al. 2016). The functional groups responsible for the bioadhesion properties of polymers include hydroxyls, carboxyls, amines, and amides. On the basis of their functional groups bioadhersive polymers can be grouped into (1) water-soluble polymers, which are typically linear or random (e.g., polyacrylic acid) and (2) water-insoluble polymers, which are commonly a swellable network formed by covalent or ionic bonds via a crosslinking agent (e.g., polycarbophil). The dissolution rate of the polymer is a suitable method to evaluate the duration of residence time of water soluble polymers in the mucosal surface. On the other hand, due to poor solubility of the cross-link polymers in common solvents, the duration of bioadhesion with oral mucosa depends on the rate of mucus/tissue turnover (Caon et al. 2014; Smart 2005). The degree of bioadhesion and the contact period of the buccal dosage forms relies on a number of factors such as polymer-related factors (e.g. average molecular weight, chain flexibility, hydration, hydrogen bonding capacity and charge)

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and buccal environmental factors (e.g. pH, ionic strength and mucins) (Laffleur et al. 2016; Ludwig 2005). In order to develop a successful buccal delivery system by the addition of mucoadhesive polymers, these factors have to be considered. Table 2 enlisted the various classes of mucoadhesive polymers are used in the buccal dosage forms. Drug and polymer conjugations The conjugation of drug molecules with mucoadhesive polymers is a novel invention to minimize the instability and degradation of drugs, especially protein and peptide drugs, in the oral mucosa resulted in enhanced diffusion and absorption of drugs via buccal route. Covalent conjugation of peptide and protein drugs to polymers can increase the stability, solubility and plasma half-life of the drugs after administration through the buccal mucosa. Conjugation of lipophilic polymers such as polystyrenemaleic acid/anhydride with hydrophilic peptide drugs have been investigated to enhance the lipophilicity of drug molecules and thereby promote the drug permeation through endothelial and epithelial barriers (Veuillez et al. 2001). The addition of thiolated polymers such as thiolated polycarbophil also has been shown to enhance the mucoadhesion time and the stability of peptides against enzymatic degradation and considered to be one of the useful tools for buccal delivery of peptides (Langoth et al. 2005). Various macromolecules such as polyethylene glycol (PEG), poly (styrene maleic acid) copolymer (SM), albumin and dextrans have been reported to modify the structural properties of the peptides (Veuillez et al. 2001). These polymers should possess some characteristic features such as soluble in water, biocompatible, biodegradable and non-immunogenic. Although such approaches are considered to be promising in literature reports, very few studies are conducted on buccal mucosa. Enzyme inhibitors The coadministration of a drug with enzyme inhibitors is another strategy for improving the buccal absorption, particularly peptide and protein drugs. Enzyme inhibitors such as aprotinin, bestatin, puromycin, and bile salts have been shown to stabilize the protein drugs against enzymatic degradation by affecting the activity of proteolytic enzymes, altering the conformation of the peptide drugs or forming micelles (Morales and McConville 2014). The stability of peptides or formation of micelles or direct enzyme inactivation is depending on the types of inhibitors that are used in the formulations. It has been reported that glutathione, which acts as both enzyme inhibitor and permeation enhancer, showed excellent stabilization of

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peptides against enzymatic degradation as well as improved permeation of peptides in excised porcine buccal mucosa (Langoth et al. 2006). Similar results also observed when aprotinin (enzyme inhibitor and permeation enhancer) was added in the insulin containing lyophilized thiolated chitosan and showed improved in vitro and ex vivo TM permeation of insulin through Epioral and sheep buccal membrane respectively. However, the addition of glutathione was not able to enhance the permeation effect of xerogel (Baoteng et al. 2014). The anionic mucoadhesive polymers such as polycarbophil and carbomer (Carbopol 934P) also have been shown to inhibited the activity of enzymes a chymotrypsin and carboxypeptidase-A by binding with enzyme cofactors calcium ion and zinc ion leading to alteration or partial denaturation of the enzyme structure (Morales and McConville 2014; Rossi et al. 2005). Likewise, derivatization of polymers with thiol groups on polyacrylates or structural modification of polymers with enzyme inhibitors have been proved to improve the enzyme inhibitory effects of polymers in the buccal mucosa (Morales and McConville 2014; BernkopSchnu¨rch et al. 2004). Examples of common use enzyme inhibitors are given in Table 2.

Dosage forms designed for buccal administration Solid buccal dosage forms Buccoadhesive tablets Tablets have been the most commonly investigated dosage forms for buccal drug delivery. Conventional and adhesive tablets have been used for buccal or sublingual administration as they can easily be prepared, are easy to handle and to remove from the site of administration. These tablets are generally manufactured by directly compressing the active ingredients and suitable pharmaceutical excipients or a granulated mixture of actives and inert components (Bayrak et al. 2011; Mansuri et al. 2016; Semalty et al. 2010; Smart and Keegan 2010). Sufficient pressure is required to keep the hardness of the tablets so that after administration into the buccal pouch it dissolves or erodes slowly (Salamat-Miller et al. 2005). The employment of direct compression is more feasible in case of peptide or protein drugs because it does not essentially require the addition of water or organic solvent and heat (i.e. no granulation and drying process), which might convert the peptide or protein drugs into inactive forms. Conventional tablets are mainly chosen in case of emergency treatment such as nitroglycerin for the instance relieve of chest pain. On the other hand, the adhesive tablets have been used in order to achieve prolonged contact period with slow drug

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

release, prevent the loss of a drug fraction due to continuous dilution by salivary flow and allow drinking and speaking (Boyapally et al. 2010; Keegan et al. 2012; Salamat-Miller et al. 2005). An important feature of buccal tablets is that it should maintain the drug release in a unidirectional way towards the mucosa for the purpose of avoiding the drug loss due to salivary wash-out and promoting the drug absorption. Therefore, an impermeable backing layer has been designed in buccal tablet formulations to improve the drug residency in buccal mucosa. Using this technology, various scientists have prepared bilayer and multi-layer tablets (Emami et al. 2013; Mylangam et al. 2016; Perioli and Pagano 2013). Patel et al. (2007) has developed bilayered and multi-layered buccal adhesive tablets of propranolol hydrochloride in which sodium carboxymethyl cellulose and carbopol 934 have used as bioadhesive polymers to impart bioadhesion and ethyl cellulose (EC) to act as an impermeable backing layer. Ex vivo studies, improved bioadhesive strength as well as bioadhesion time with slow drug release were obtained by multi-layered tablets as compared to bilayered tablets. Both buccal devices elicited the drug release in non-Fickian diffusion mechanism. The efficiency of adhesive tablets also can be enhanced by formulating the drugs in certain physical states such as microspheres or microparticles, before direct compression to produce final tablet forms (Jelvehgari et al. 2014; Yedurkar et al. 2012). Very recently, propranolol hydrochloride containing chitosan/gelatin microparticle based buccal tablet has been prepared and in vitro studies such system exhibited excellent mucoadhesive properties, allowing permeation of the greatest amount of drug (Abruzzo et al. 2015). Another study, matrix tablets containing polycarbophil and ethylcellulose were prepared by thermal treatment on direct compression tablets so as to get a swellable and unerodable matrix for a controlled release of actives over an extended period. This novel approach would be advantageous in the formulation of sustained release dosage forms (Caviglioli et al. 2013). A schematic representation of several kinds of matrix tablets is given in Fig. 2. The simplest version of buccal tablets is monolithic tablets which exhibit bidirectional release and consist of a mixture of drug with a swelling bioadhesive/sustained release polymer (Fig. 2a). They can be coated on the outer or on all sides but one face with water impermeable hydrophobic substances to allow unidirectional drug release for systemic delivery (Fig. 2b, c). In two layered tablets, for local effects, the inner layer comprises with bioadhesive polymers and the outer nonbioadhesive layer contains the actives in order to get bidirectional release (Fig. 2d) while in case of systemic actions, drugs are loaded in the inner layer and the outer layer serves as a protective layer (Fig. 2e). In an alternative way, bioadhesive layer employs to control the drug release

from the non-bioadhesive layer, whereas the water impermeable layer provides the monodirectional release of drugs (Fig. 2f) (Rossi et al. 2005). Although buccoadhesive tablets offer numerous advantages over conventional oral dosage forms, they constantly subject to salivary flow in oral mucosa which may interfere the absorption of drugs at the targeted site. In addition, bitter taste of the actives is another hurdle of this dosage form. Patients are reluctant to administer the adhesive tablets unless bitterness of the drug is masked by sweetening and flavoring agents. Bioadhesive particulate systems Bioadhesive micro/nano particles offer the same advantages as tablets but their smaller particle size facilitates the intimate contact of the dosage forms onto larger mucosal surface area and this lead to high absorption of drugs across buccal mucosa (Russo et al. 2016). The small size of microparticles as compared to tablets causes less mucosal irritation at the site of adhesion and also reduces the discomfort feelings in the administration sites (Sudhakar et al. 2006). These can be delivered to the buccal mucosa in the form of aqueous suspensions or aerosols or are incorporated into a paste or an ointment. In comparative studies, bioadhesive polymeric microparticles prepared from polyacrylic acid exhibited greater mucoadhesive strength when compared to microparticles prepared with chitosan or gantrez during tensile strength tests. Conversely, in elution studies, particles of chitosan or gantrez showed a prolonged residence time on porcine mucosal tissue than those assembled from polyacrylic acid (Kockisch et al. 2003, 2004). Chitosan micropaticles loaded with chlorhexidine produced prolonged therapeutic concentration in vitro within the oral cavity, in comparison to chlorhexidine diacetate powder. The microparticles were prepared by spray drying method and two different weight ratios of chlorhexidine and chitosan i.e., 1:2 and 1:4 respectively were used in order to obtain small particle sizes. To prepare the tablet forms, particles were compressed with sodium alginate, mannitol, and saccharin and then performed in vivo, where chlorhexidine was detected in the saliva for more than 3 h, longer than that of chlorhexidine mouthwash (2 h) (Giunchedi et al. 2002). Atenolol loaded microsphere was prepared by solvent free spray congealing method and poloxamer 407 was added so as to get the enhanced drug permeation through buccal mucosa. After sublingual administration in rabbits, microsphere formulations showed higher absolute bioavailability as compared to the reference tablet in spite of a lower drug dose (Monti et al. 2010) indicating the adjuvant poloxamer 407 might be increased permeation and controlled release of atenolol from the microspheres.

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S. Barua et al. Fig. 2 Schematic presentation of different matrix tablets for buccal delivery. Arrows indicate the direction of drug release. Adapted from Rossi et al. (2005)

The advantages of using nanoparticles (NPs) to buccal drug delivery was demonstrated by Holpuch et al. (2010) and found that the NPs-delivered fluorescence probe was promptly uptake by human oral explants than that of free fluorescence probe. Furthermore, the penetration and subsequent internalization of NPs through the epithelium and basement membrane into the underlying connective tissue indicated that the potential use of oral transmucosal NPs delivery for systemic therapeutics. Another study, insulin loaded with NPs significantly decreased the glucose level in alloxan-induced diabetic rats after buccal administration and suggested to be one of the promising approach to stabilize and deliver the therapeutic macromolecules for local or systemic effects (Mundargi et al. in 2011a, b). In a recent work, curcumin loaded solid lipid nanoparticles (SLNs) was incorporated into a lyophilized mucoadhesive sponge and in vivo and in vitro investigation in buccal mucosa this system provides a sustained release of

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curcumin over 14–15 h and therefore, minimizes the frequent dose interval of curcumin when administered via conventional dosage forms (Hazzah et al. 2015). Among the various thiomers, thiolated chitosan containing NPs have been suggested to be a potential delivery of a variety of active moieties via mucosal routes due to their high physical stability and twice or more mucoadhesive strength than unmodified chitosan NPs (Bernkop-Schnu¨rch et al. 2006). Liposomal carriers are another alternative approach to improve the buccal drug absorption, especially for poorly soluble drugs. For example, silymarin, a poorly water soluble drug, containing liposomal carriers exhibited steady state permeation through a chicken buccal pouch for 6 h than that of free drug powder (El-Samaligy et al. 2006). However, the drawbacks of this carrier associated with the poor loading efficiency, therefore, difficult to control the release profile of encapsulated drugs and limit the

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

permeation of hydrophilic drugs because they are mostly prepared from naturally occurring phospholipids (Discher et al. 2007). Porous-adhesive wafers This novel periodontal drug delivery system (DDS) is basically intended for the treatment of microbial infections associated with peridonities. Unlike conventional gel formulations, wafers can maintain their swollen gel structure for a longer period and provide prolonged in situ residence time after application and are able to deliver drugs more effective and reproducible way (Boateng et al. 2008). Moreover, porous structure and wide surface area of wafers facilitate the higher absorption rate with improved drug loading capacity as compared to the thin and denser solvent cast films (Boateng et al. 2010). The internal structure of wafers can be explained by a surface layer possessing adhesive properties and a bulk layer containing antimicrobial agents, biodegradable polymers and matrix polymers (Sudhakar et al. 2006). Bromberg et al. developed a wafer formulation in which the bulk layer consisted of biodegradable polymer poly(lactic-co-glycolic acid) and ethyl cellulose applied as a matrix and in vitro release studies the zero-order release of antimicrobial agents such as silver nitrate, benzylpenicillin, and tetracycline was achieved, for over 4 weeks. Now a days, researchers also are giving effort to deliver therapeutics macromolecules (peptides or proteins) for systemic therapy by incorporating into adhesive wafers. Recently, in vitro studies of lyophilized thiolated-chitosan wafers exhibited sufficient mucoadhesive strength and controlled release of bovine serum albumin (BSA) without affecting the conformational stability of the protein suggesting a potential device for buccal delivery of protein based drugs. However, ex vivo and in vivo studies of this delivery system remain to be established (Ayensu et al. 2012). Another study, Kianfar et al. (2012) developed and optimized lyophilised wafers by combining two polymers carrageenan (CAR 911) and pluronic acid (F127) for buccal drug delivery of soluble and insoluble drugs. The texture analysis of lyophilised wafers showed desirable mucoadhesive properties and in vitro analysis displayed ideal release patterns in conditions simulating those of saliva depicting the promising technology for buccal drug delivery (Kianfar et al. 2012). Laminated wafers with highly porous structure for the buccal delivery of proteins was prepared by using thiolated chitosan containing 10 % glutathione as an enzyme inhibitor. Good mucoadhesive properties were observed by these wafers because of the strong covalent bond between the thiol ligands and the cysteine-rich residues on the glycoproteins of mucin (Boateng and Ayensu 2014). Finally, in a recent work, a combined mixture of chitosan

and sodium alginate was added to prepare a wafer for the delivery of bovine serum albumin (BSA) used as a model drug in order to evaluate the effect of complex mixtures of polymers in protein delivery. The results obtained from the drug dissolution studies showed a sustained release pattern of BSA which remained amorphous in the final wafer and this effect might attribute to the rate of hydration, swelling and subsequently erosion of polymer mixtures. (Boateng and Areago 2014).

Thin erodable disks Disks are characterized by a high diameter-thickness ratio, can be prepared by compression or solvent evaporation method (Mansuri et al. 2016). Although disks are similar to tablets, they are thinner and flat in shapes and are able to formulate into different sizes and shapes, thereby more suitable to be placed into the buccal cavity. An in vivo evaluation of a buccal disk of cetylpyridinium chloride revealed the high patient compliance in terms of comfort feelings, taste, non-irritancy and no symptoms of severe dry mouth/severe salivation or heaviness at the place of attachment was observed. A good correlation was found between the drug concentration in situ and concentration of drug in saliva collected from healthy human volunteers (Ali et al. 2002; Patel et al. 2011). An in vivo release studies of thiocolchicoside containing buccal disks showed prolonged drug absorption than that of fast dissolving sublingual form which possessed quick uptake of drug within 15 min (Artusi et al. 2003). Recently, Jaipal et al. (2013) formulated xanthan gum based buccal disks of buspirone by direct compression method. The author suggested that by changing of calcium sulfate concentration in xanthan gum matrix can alter the drug release behaviors and mucoadhesion properties of buccal disks (Jaipal et al. 2013) and considered to be one of the promising strategy to modulate the drug release from erodible disks. In subsequent studies, the effect of various bioadhesive polymers on mechanical strength and drug release properties of buccal disks was demonstrated by the same authors (Jaipal et al. 2015). The increased levels of hydroxypropyl methyl cellulose (HPMC) in buccal disks retarded the drug release with improved mucoadhesion in comparison to mannitol which showed faster drug release when added more amount due to the formation of pores in the matrix. In pharmacokinetics studies, HPMC containing buccal disks exhibited considerable absolute bioavailability when administered to rabbits (Jaipal et al. 2015). Tenoxicam loaded in hydrophilic, mucoadhesive carriers (alginate, chitosan, guar gum and Carbopol) was prepared by solvent evaporation method and in vivo investigation in six healthy volunteers, this novel buccal disk exhibited a rapid onset of

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action and improved bioavailability of tenoxicam when compared to conventional oral tablets (Makky et al. 2012). Buccal adhesive patches and thin-films The marketed buccal formulations of these systems have been considerably increased owing to their soft and flexible properties that reduce the discomfort feelings of patients after administration as compared to buccal tablets (Morrow et al. 2010; Pendekal and Tegginamat 2012). In addition, similar to buccal tablets, multidirectional and unidirectional drug release also can be occurred from buccal patches and/or films. The films are thinner, therefore, they are more susceptible to over hydration and loss of the mucoadhesive properties (Patel et al. 2011; Squier and Kremer 2001). The internal structure of patches can be described by an impermeable backing layer, a reservoir layer from which Fig. 3 Schematic presentation of possible unidirectional (a, b) and multidirectional (c– e) release from the buccal adhesive patches. Arrows indicate the direction of drug release

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slow release of drug occurs, and a bioadhesive surface to contact with the mucosal surface. Buccal patches are identical to the transdermal drug delivery systems (TDDS) (Mansuri et al. 2016). The drug release profiles and direction from the patches depend on the absence and the presence of an impermeable backing layer or the amount and kind of polymers are added to produce mucoadhesion and slow or sustained drug release (Adhikari et al. 2010; Nafee et al. 2003). The presence of an impermeable layer surrounding a patch, except for one surface area (Fig. 3a) and patches containing core-type drug reservoir (Fig. 3b) make the drug release unidirectional. The model patches are shown in Fig. 3c, d will be suitable for the treatment of intraoral disease while the patches like Fig. 3e will deliver drugs transmucosally and/or orally (DeGrande et al. 1996). Adhesive patches are prepared by two methods: (a) solvent casting method and (b) direct milling method. In the solvent casting method, the intermediate sheet is prepared by

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

casting the solution of drug-polymer mixtures onto a backing layer sheet, and later on allowing the solvent to evaporate (Semalty et al. 2010) and then patches are punched out. In the direct milling method, ingredients are homogeneously mixed and compressed to the desired thickness, and after getting the predetermined size and shape of patches that are cut or punched out (Mansuri et al. 2016; Boddupalli et al. 2010). An impermeable backing layer can also be formulated to modulate the direction of drug release, impede the drug loss, and to reduce the deformation and the disintegration of the device during administration (Laffleur et al. 2016) (Fig. 3). Chlorhexidine containing mucoadhesive patches were prepared by using a gel-forming polysaccharide psyllium. Ex vivo and in vitro evaluation of psyllium containing adhesive patches displayed prolonged zero-order release due to the slower swelling rate of the system and this effect might attribute to the highly branched chains of psyllium form a thick gel and its anionic properties exhibited strong affinity towards the cationic drugs (such CHX) (Cavallari et al. 2015). Bioadhesive patches containing interpolymer complexes of chitosan (CH) and pectin (PE) showed higher bioavailability of carvedilol in vitro and in vivo when compared with carvedilol oral solution suggesting that using of interpolymer complex would be one of promising approach to formulate effective buccal patches (Kaur and Kaur 2012). An ideal film should be flexible, elastic, soft and strong enough to resist breakage due to the stress from mouth movements. It must also show strong bioadhesion in order to be retained in the mouth over an extended period (Nappinnai et al. 2008). Similar to laminated patch manufacturing process, films are mainly prepared by solvent casting method (Kumria et al. 2013; Muzib et al. Muzib and Kumari 2011). The selection of appropriate polymers is one of the most important factors during formulating bioadhesive films. The main use of mucoadhesive polymers is to maintain an intimate and prolonged contact of the formulations with the oral mucosa allowing high drug influx rate (Sudhakar et al. 2006). The bioadhesive properties of an SCMC (sodium carboxymethyl cellulose/ polyethylene glycol 400/carbopol 934P) and an HPMC (hydroxypropyl methyl cellulose/polyethylene glycol 400/carbopol 934P) films was reported by Peh and Wong (1999) and the obtained in vivo results showed the greater bioadhesion was obtained by HPMC and it is preferred over SCMC films due to the former exhibited more elastic, bioadhesive and swelling properties in the oral cavity than the latter. Very recently, nanofibre-based mucoadhesive films were invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines (Bhardwaj and Kundu 2010; Lu et al. 2009; Malinova et al. Malinova´ et al. 2013). This mucoadhesive film consists of

an electrospun nanofibrous reservoir layer, a mucoadhesive film layer, and a protective backing layer. It was assumed that nanofibrous reservoir layers are intended to promote the prolonged release of nanoparticles with sufficient mucoadhesion into the submucosal tissue, after application. To prove this hypothesis, trans-/intramucosal and lymphnode delivery of poly (D,L-lactide-co-glycolide)-block-poly (ethylene glycol) (PLGA–PEG) nanoparticles was evaluated in a porcine model and suggested that various types of polymeric materials and NPs could be combined with nanofibrous materials to develop appropriate products for non-invasive mucosal application. The industrial production of this newly developed mucoadhesive films is now in progress (Masek et al. 2016). Insulin loaded NPs made of poly (ethylene glycol) methyl ether-block-polylactide (PEG-b-PLA) exhibited good physicochemical properties and in vitro sustained release of insulin over 5 weeks, proposing as a promising platform for the delivery of proteins through buccal mucosa. The ex vivo effect of this NPs is now under progress (Giovino et al. 2013). Azim et al. (2015) formulated liposomal carriers containing mucoadhesive films for the efficient delivery and permeation of water soluble vitamins. The obtained results showed that the incorporation of Vitamin B6 (VB6) loaded liposomes into buccal mucoadhesive film ensured slower drug release with improved permeability across chicken pouch membrane as compared to film containing free VB6 (Azim et al. 2015). Vaccination via non-invasive route is one of the most challenging and attractive technology to the researchers and pharmaceutical industries. (Cui and Mumper 2002) formulated a bilayer film containing plasmid DNA consisting of an impermeable backing layer and a drug containing layer face towards the mucosa. After administration, all rabbits immunized with plasmid DNA via the buccal route but none by the subcutaneous route with protein antigen, demonstrated splenocyte proliferative immune responses. The authors concluded that the vaccination with non-invasive devices would provide a beneficial effect in terms of both safety and costs over conventional injectable vaccination (Cui and Mumper 2002). Semi-solid dosage forms Bioadhesive gels Bio adhesive polymers are basically used to formulate the buccal gels because they provide strong adherence to the mucosal tissue leading to a controlled release of drugs over an extended period. Gels are capable of enhancing the residence time in buccal mucosa when compared to solutions and this leads to increased drug influx rate (Khan et al. 2012; Pathak et al. 2013). Various mucoadhesive

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polymers are extensively used in buccal gel formulations, which are biodegradable and have strong mucoadhesive properties with swelling in aqueous solvents and are able to entrap drug molecules for subsequent controlled release by diffusion or erosion (Lefnaoui and Moulai-Mostefa 2011; Rai et al. 2014). Cellulosic mucoadhesive polymers are considered to be a smart strategy to extend the contact period and to enhance the absorption of localization of drug on several membranes (Pathak et al. 2013). The reason behind this, the abundance of hydrogen bond forming groups is able to hydrate and to swell these macromolecules in aqueous solvents and thereby, they exhibit excellent mucoadhesive properties (Lefnaoui and MoulaiMostefa 2011). A ternary mixture of cellulosic polymers containing mucoadhesive gel has been shown to increase residence time and improve the distribution of antifungal agents in buccal mucosa of goat ex vivo (Rai et al. 2014). The effect various polymers on buccal drug absorption was evaluated by formulating mucoadhesive gels containing piroxicam (PC), as a model drug, with sodium alginate, HPMC (hydroxymethyl cellulose), methylcellulose, HEC (hydroxyethyl cellulose), sodium CMC (carboxymethyl cellulose), carbopol 934 P and the highest drug influx rate were obtained by PC loaded with sodium alginate and HPMC across rabbit buccal mucosa. By changing the concentration of polymers and drug in the gel and/or the addition of enhancers may also be controlled the drug permeation rate through buccal mucosa. In clinical studies, PC loaded sodium alginate showed the efficient delivery of drug through buccal route for the management of postoperative dental pain and edema following maxillofacial operations and prevention of the serious adverse effects of the conventional oral formulations (Attai et al. 2004). Very recently, the mucoadhesive chitosan gels were formulated for the delivery of toluidine blue O (TBO) for the buccal cancer treatment. Both in vivo and in vitro investigation showed enhanced release and retention of TBO with strong mucoadhesion properties and in vivo the mucoadhesive gels containing TBO were able to induce the cell apoptosis after administration into the anesthetized mice. The effects of this delivery system in tumor cell will be investigated in the near future. (Graciano et al. 2015). However, the bioadhesive gels are incapable of delivering the accurate amount of drugs at the targeted sites and therefore, their use is limited for the drugs with narrow therapeutic window (Sudhakar et al. 2006; Patel et al. 2011). Bioadhesive ointments As compared to tablets and patches, bioadhesive ointments have not been extensively described in the literature. The transport mechanism and long term effect of hyperemic drug benzyl nicotine (BN) were demonstrated after

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incorporation in three different adhesive ointments: orabase, carbopol 934P and polymethylacrylate. The obtained results showed that the highest efficiency of drug action was observed with 2 % BN in polymethylacrylate and suggested to be effective for buccal drug delivery (Petelin et al. 2004). In another study, liposome containing polymethyl methacrylate based mucoadhesive formulation showed an efficient delivery of liposomes for local application in the buccal cavity and suggested to be one of promising vehicle for the treatment of periodontal disease (Petelin et al. 1998). Liquid dosage forms Various types of liquid based marketed buccal formulations such as antibacterial mouthwashes and mouth-fresheners are available to exert local action for the treatment of infectious disease in the oral cavity. These types of dosage forms include solutions or suspensions prepared by solubilizing the drugs or suspended into suitable aqueous vehicles. However, the disadvantages associated with liquid dosage forms are that they are not able to retain or target to buccal mucosa and deliver relatively uncontrolled amounts of drug throughout the oral cavity. However, this drawback could be overcome by the incorporation of mucoadhesive polymers such as chitosan, methylcellulose, gelatin, carbopol and polycarbophil which may able to retain the liquid dosage forms for an extended period, thus enhance the drug influx rate across buccal mucosa. (Patel et al. 2011). An in vitro studies, in hamster cheek pouch, mucoadhesive mouthwash formulations containing the corticosteroid triamcinolone acetonide, and carbopol 934 exhibited increased drug absorption and did not accumulate on the mucosal surface (Ungphaiboon and Maitani 2001). Lectins are proteins or glycoproteins that bind to specific sugar residues and therefore, it can interact with the glycoconjugates including those present on cell surfaces or the mucins in the salivary pellicle. Lectins originates from Triticum vulgaris have been shown to strongly bind to the buccal mucosal cells in vitro and was still detected at similar levels after 2 h (Smart et al. 2002). Another approach to improve the buccal permeation of liquid dosage forms by incorporating iontophoretic techniques, which are prominent for the delivery of drugs through skin, but have also been investigated for drug delivery across the buccal mucosa. Campisi et al. (2010) demonstrated that the delivery of naltrexone via iontophoresis showed higher plasma levels even after 6 h of administration as compared to intravenous administration of naltrexone. The author concluded that the presence of a drug reservoir within the buccal mucosa after iontophoresis from which naltrexone released gradually and was systemically available (Campisi et al. 2010). The intravenous preparation of midazolam

Drug delivery techniques for buccal route: formulation strategies and recent advances in…

hydrochloride is another alternative tool for improving the drug absorption via buccal cavity. In comparison to diazepam suppositories, it exhibited more rapid and effective action of midazolam in preventing seizures after administration into the buccal cavity between the gum and cheeks. However, the author concluded that drug absorption may occur from a variety of sites due to the fact that the solution will spread throughout the oral cavity after administration and may indeed be swallowed (McIntyre et al. 2005). This treatment option is now advocated by the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN). Nevertheless, the possibility of dose confusion has raised a few years ago as it is twice the strength of the injection that was initially used for this purpose (Pather et al. 2008). Innovative drug delivery systems Innovative drug delivery systems, such as lipophylic gels, buccal sprays and phospholipid vesicles have been recently proposed to deliver peptides or other therapeutic moieties via the buccal route. Liquid crystal phase The liquid crystalline phases have been used in various fields of the pharmaceutical dosage forms due to their unique microstructures and the presence of both hydrophobic and hydrophilic domains, demonstrating a great flexibility (Guo et al. 2010; Shah et al. 2001). The release behavior is dependent on various factors, including the drug properties, initial water content, types of mesophases, swelling capacity, drug loading, and electrostatic interaction between the drugs and lipid bilayers (Phan et al. 2011). Among the different mesophase structures, the cubic and hexagonal mesophases of lamellar liquid crystals such as glyceryl monooleate (GMO), polyethylene glycol 200 and progesterone are considered to be promising for successful buccal delivery of peptide drugs. This is due to the fact that they contain less than two hydroxyl groups which facilitate the formation of a strong hydrogen bond between the liquid crystal phase and the mucous membrane (Lee and Kellaway 2000; Swarnakar et al. 2007). It has been suggested that GMO in the cubic and lamellar mesophases could be eroded without the action of an enzyme and then penetrate across the excised porcine buccal mucosa. Moreover, the flux of a [DAla2, D-Leu5] enkephalin incorporated from the cubic and lamellar mesophases was significantly increased compared with PBS solution during the initial 3 h (Lee et al. 2000). However, no in vivo investigation was reported (Lee et al. 2000). Very recently, Souza et al. (2014) demonstrated that the strong mucoadhesion properties of poly (hexamethylene biguanide) hydrochloride (PHMB) containing GMO mainly

due to their ability to absorb water from the surrounding aqueous environment such as mucus gel or mucosal surface, hence slow release and improved antimicrobial activity of PHMB could be achieved by such system (Souza et al. 2014). Not only the bulk mesophases but also their dispersions can be employed for mucosal drug delivery. Swarnakar et al. (2007) reported that improved transmucosal flux of progesterone loaded hexosomes was observed after administration on the albino rabbit mucosa for 12 h and that was fivefold higher than that of progesterone loaded gel and approximately fourfold higher than plain progesterone suspension. In addition, confocal and FT-IR studies showed that the presence of pores in the epithelium of mucosa, indicating a possible intercellular ‘virtual channel’ for hexosomes diffusing. Very recently, a novel mucoadhesive formulation based on liquid crystalline nanoparticles was designed. In situ transition of nanoparticles to the hexasomes by inducing pH exhibited enhanced adsorption onto the mucosal surface (Du et al. 2014). The author suggested that this novel approach is a favorable tool for overcoming the limited bioavailability of drug through buccal route (Du et al. 2014). Although the liquid crystal phases suggested a promising carrier system for buccal delivery, more investigation is required regarding the safety issues, especially effect of surfactants on mucosal irritation. Aerosols/spray An aerosol dosage form is preferred as the most efficient and safe alternative device for drug delivery against conventional dosage forms. As the spray directly delivers the drugs in the form of fine particles or droplets onto the mucosal surface reducing the lag time for a drug to appear at the site of absorption and thereby it promotes the absorption of drugs for the systemic or local effects (Patel et al. 2011). After buccal administration of insulin spray in patients with Type I diabetes showed no significant difference in glucose, insulin and C-peptide plasma level in comparison to insulin administered subcutaneously (Pozzilli et al. 2005) indicating the rapid absorption of insulin when delivered via spray to buccal mucosa. Xu et al. (2002) investigated that the addition of absorption promoters such as soybean lecithin and propanediol enhanced the absorption of insulin when administered with buccal spray on diabetic rats and rabbits. The obtained results indicated that insulin administered via the buccal spray is an efficient therapeutic alternative to that of injectable insulin formulation for treating diabetes (Xu et al. 2002). In 2002, Generix Biotechnology Corporation has developed a novel liquid aerosol formulation Oralin for the management of patients with Type 1 and Type 2 diabetes (Modi et al. 2002). This Rapidmist device delivers insulin via a metered-dose spray in the form of fine aerosolized

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droplets directed into the mouth. After administration the amounts of drug in the mouth drastically increased as compared to conventional dosage forms. This oral aerosol formulation is rapidly absorbed through the buccal route, and reduces the plasma glucose levels in diabetic patients (Heinemann and Jacques 2009; Lassmann-Vague and Raccah 2006; Palermo et al. 2011; Yaturu 2013). This novel non-invasive technology has a number of advantage, including rapid absorption, easy to administer, precise dosing control (comparable to injection within one unit) and bolus delivery of drug (Rossi et al. 2005). Recently, this company incorporated several other drugs such as fentanyl citrate, morphine and low molecular weight heparin in RapidMistTM technology, which are in clinical trials (Patel et al. 2011). In August 2007, Health Canada approved a cannabis-derived pharmaceutical buccal spray, Sativex (GW Pharmaceuticals; marketed by Bayer, a subsidiary of Bayer AG) which spray has been designed to relieve pain in advanced cancer patients suffering from multiple sclerosis (Pather et al. 2008). Sativex has now been launched in 15 countries (including the UK, Spain, Italy, and Germany) and in the USA it is undergoing Phase III trials. Transfersomes Phospholipid deformable vesicles have been recently designed for the delivery of insulin in the buccal cavity (Yang et al. 2002). They are morphologically similar to liposomes but are able to respond the external stresses by rapid shape deformation requiring low energy. This characteristic feature allows them to deliver drugs through epithelial barriers (Shuwaili et al. 2016; Lei et al. 2013). To prepare these vesicles, surfactants, such as sodium cholate or sodium deoxycholate are incorporated into the vesicular membrane. Although insulin administration via traditional liposomes was able to control the blood glucose levels in rabbits compared with injectable administration of insulin solution, the bioavailability of insulin was significantly greater when delivered by deformable vesicles than that of the classical vesicles. It is necessary to note that most of the data have been generated by testing in animal models that possess different anatomical features of buccal mucosa than that of human. Therefore, it is better to perform an experiment on other animal models that better simulate human (Rossi et al. 2005). Proniosomes Proniosomes are a dry, free-flowing, granular product of nonionic surfactant prepared by dissolving the surfactant in a organic solvent and in a minimal amount of water (Yuksel et al. 2016). This dry product can be hydrated

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immediately before by sonicating for a few minutes in a hot aqueous media in order to get aqueous noisome dispersions (Ammara et al. 2011). Although the final niosomal dispersions are similar to conventional niosomes, those originate from proniosomes are superior in terms of physical stability, transportation, precise dosing and more uniform in size. Thus, this novel carrier system is more efficient to deliver a wide range of active components (Abd-Elbary et al. 2008). In a recent work, benzocaine (BZC) containing proniosomal gel by using Span 60, Span 80 or Span 85 and their mixtures have shown the improved local anesthetic activity of BZC in buccal cavity. The in vitro release and ex vivo permeation studies of proniosomal BZC showed an initial burst release followed by a sustained release profile of BZC for a prolonged effect of BZC, which would be advantageous for the treatment of mucosal pain (El-Alim et al. 2014). However, in vivo investigation of this vehicle system needs to be evaluated.

Conclusion Buccal adhesive systems offer a feasible and attractive alternative to oral drug delivery and other non-oral routes of drug delivery. The buccal mucosa provides a variety of advantages such as avoiding hepatic first-pass metabolism and extensive drug degradation in the GI tract. The area is well suited for the retentive devices and shows high patients compliance Adhesion of these drug delivery devices to the mucosal surface causes an increased drug concentration gradient at the absorption site and thereby improves the bioavailability of drugs in the circulatory system. Accordingly, scientists are investigating to develop more innovative buccal adhesive systems through various approaches such as an inclusion of pH modifiers, enzyme inhibitors, and permeation enhancers. Currently, solid dosage forms, liquids, and gels applied to oral cavity are commercially successful. Particulate bioadhesive systems are particularly interesting as they offer better protection to active ingredients as well as the controlled drug release than that of conventional buccal adhesive tablets. Very recently, aerosol or spray technology has been drawn a great interest to the researchers and the manufacturing industries for the effective delivery of potent drugs, especially peptides and proteins. However, until now many issues related to the buccal delivery of novel devices are unresolved and are still in clinical development. Successful development of these novel formulations requires more extensive studies in order to achieve a safe and efficacious delivery system for buccal delivery. Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2015R1A5A1008958). This work was also

Drug delivery techniques for buccal route: formulation strategies and recent advances in… supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2015R1D1A1A02062278). This article does not contain any studies with human and animal subjects performed by any of the authors. Complaince with ethical standards Conflict of interest The authors S. Barua, H. Kim, K. Jo, C.W. Seo, T.J. Park, K.B. Lee, G. Yun, K. Oh, and J. Lee declare that they have no conflict of interest.

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