Overview and Future Potential of Buccal Mucoadhesive Films as Drug Delivery Systems for Biologics

The main route of administration for drug products is the oral route, yet biologics are initially developed as injectables due to their limited stability through the gastrointestinal tract and solubility issues. In order to avoid injections, a myriad of investigations on alternative administration routes that can bypass enzymatic degradation and the first-pass effect are found in the literature. As an alternative site for biologics absorption, the buccal route presents with a number of advantages. The buccal mucosa is a barrier, providing protection to underlying tissue, but is more permeable than other alternative routes such as the skin. Buccal films are polymeric matrices designed to be mucoadhesive properties and usually formulated with permeability enhancers to improve bioavailability. Conventionally, buccal films for biologics are manufactured by solvent casting, yet recent developments have shown the potential of hot melt extrusion, and most recently ink jet printing as promising strategies. This review aims at depicting the field of biologics-loaded mucoadhesive films as buccal drug delivery systems. In light of the literature available, the buccal epithelium is a promising route for biologics administration, which is reflected in clinical trials currently in progress, looking forward to register and commercialize the first biologic product formulated as a buccal film.     

Buccal Drug Delivery of Pravastatin Sodium

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal tablets of pravastatin sodium using carrageenan gum as the base matrix. The tablets were prepared by direct compression method. Polyvinyl pyrrolidone (PVP) K 30, Pluronic® F 127, and magnesium oxide were used to improve tablet properties. Magnesium stearate, talc, and lactose were used to aid the compression of tablets. The tablets were found to have good appearance, uniform thickness, diameter, weight, pH, and drug content. A 2³ full factorial design was employed to study the effect of independent variables viz. levels of carrageenan gum, Pluronic F 127 and PVP K30, which significantly influenced characteristics like in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time. The tablet was coated with an impermeable backing layer of ethyl cellulose to ensure unidirectional drug release. Different penetration enhancers were tried to improve the permeation of pravastatin sodium through buccal mucosa. Formulation containing 1% sodium lauryl sulfate showed good permeation of pravastatin sodium through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for the administration of pravastatin sodium.     

Design and <Emphasis Type="Italic">In Vitro/In Vivo</Emphasis> Evaluation of Ultra-Thin Mucoadhesive Buccal Film Containing Fluticasone Propionate

Fluticasone propionate is a synthetic corticosteroid drug distinguished by its potent anti-inflammatory action with low systemic side effects in comparison to other corticosteroids making it a potential drug for local buccal delivery. The aim of the present study was to design mucoadhesive buccal film containing fluticasone that is aesthetically acceptable and could maintain local drug release for a sustained period to manage the sign and symptoms of severe erosive mouth lesions. Solvent casting technique was used in film preparation. Different polymeric blends were used either alone or in combination with mucoadhesive polymers, sodium carboxymethyl cellulose (SCMC), or Carbopol 971P at different concentrations. The physicochemical properties, in vitro mucoadhesion time as well as the drug release properties for all prepared formulations were determined. Selected formulations with adequate properties were further examined by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) and subjected to in vivo evaluation. Films containing hydroxypropyl methylcellulose (HPMC)/ethyl cellulose (EC) showed acceptable physicochemical properties, homogenous drug distribution, convenient mucoadhesion time, moderate swelling as well as sustained drug release up to 12 h. The biological performance of these formulations was assessed on healthy human volunteers and compared with a prepared mouthwash which showed enhanced pharmacokinetic parameters for the selected films in comparison to the mouthwash. The results revealed that the optimized formulation containing HPMC/EC and 10% SCMC could successfully achieve sustained drug release for 10 h which is considered promising for local treatment of severe mouth lesions.     

<Emphasis Type="Italic">In Vitro</Emphasis> Characterization of Chitosan Gels for Buccal Delivery of Celecoxib: Influence of a Penetration Enhancer

Celecoxib (Cx) shows high efficacy in the treatment of osteoarthritis and rheumatoid arthritis as a result of its high specificity for COX-2, without gastrolesivity or interference with platelet function at therapeutic concentrations. Besides of anti-inflammatory effects, Cx also has a potential role for oral cancer chemoprevention. For these conditions, oral administration in long-term treatment is a concern due to its systemic side effects. However, local application at the site of injury (e.g., buccal inflammation conditions or chemoprevention of oral cancer) is a promising way to reduce its toxicity. In this study, the in vitro characterization of mucoadhesive chitosan (CHT) gels associated to Azone® was assessed to explore the potential buccal mucosal administration of Cx in this tissue. Rheological properties of gels were analyzed by a rheometer with cone-plate geometry. In vitro Cx release and permeability studies used artificial membranes and pig cheek mucosa, respectively. Mucoadhesion were measured with a universal test machine. CHT gels (3.0%) containing 2.0% or 3.0% Az showed more appropriate characteristics compared to the others: pH values, rheology, higher amount of Cx retained in the mucosa, and minimal permeation through mucosa, besides the highest mucoadhesion values, ideal for buccal application. Moreover, the flux (J) and amounts of drug released decreased with increased CHT and Az concentrations. CHT gels (3.0%) associated with 2.0% or 3.0% Az may be considered potential delivery systems for buccal administration of Cx.     

3D-Printed Network Structures as Controlled-Release Drug Delivery Systems: Dose Adjustment,API Release Analysis and Prediction

3D printing evolved as a promising technique to improve individualization of drug therapy. In particular, when printing sustained release solid dosage forms, as for instance implants, inserts, and also tablets, estimation of the drug release profile in vivo is necessary. In most cases, corresponding analyses cannot be performed at hospital or community pharmacies. Therefore, the present study aimed to develop a sustained release drug delivery system produced via 3D printing, which allows dose adaption and estimation of drug release at the same time. Filaments as feedstock for the printer were produced via hot-melt extrusion and consisted of Eudragit® RL as sustained release polymer, 30% theophylline as model active pharmaceutical ingredient, and stearic acid as solid plasticizer. Assuming that the surface/mass ratio was constant, network structures of different densities were printed as novel solid dosage form. Their weight (263 to 668 mg), thereby their dose, and surface area, determined using X-ray microcomputed tomography, showed a linear correlation with the fill density. The specific surface area of the network hardly varied with changing fill density. Dissolution studies showed a slower drug release for dosage forms with a denser network. Higuchi’s model was used for prediction of drug release and showed limited applicability due to different release kinetics for different fill densities. However, using linear interpolation for the prediction resulted in good RMSEP values between 1.4 and 3.7%. These findings might be useful to enable customized production of sustained release solid dosage forms via 3D printing in hospital and community pharmacies in the future.     

Formulation and <Emphasis Type="Italic">In Vitro</Emphasis> Characterization of Thiolated Buccoadhesive Film of Fluconazole

The present work is focused on the development of thiolated film for fluconazole buccal delivery. To this end, unmodified polymers chitosan and sodium carboxymethylcellulose (NaCMC) backbone was covalently modified by thioglycolic acid (TGA) and cysteine, respectively. The thiolated buccoadhesive film was evaluated in terms of thickness, weight uniformity, water-uptake capacity, drug content, and release patterns. Moreover, mucoadhesion profile was investigated on buccal mucosa. The resulting chitosan–TGA and NaCMC–cysteine conjugates displayed 171?±?13 and 380?±?19 μmol thiol groups per gram of polymer (mean?±?SD; n?=?3), respectively. The water binding capacity of the thiolated film was significantly ～2-fold higher (p?<?0.05) as compared to unmodified film. The obtained thiolated film displayed 5.8-fold higher mucoadhesive properties compared with corresponding film. Controlled release of drugs from film was observed over 8 h. The transport of fluconazole across excised buccal mucosa was enhanced up to 17-fold in comparison with fluconazole applied in buffer. Based on these findings, thiolated film seems to be promising for fluconazole buccal delivery.     

Fabrication,Physicochemical Characterization,and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.     

Chitosan-Based Mucoadhesive Systems for the Inclusion of the Echinochrome Active Substance

Polyelectrolyte complexes (PECs) of chitosan (CH) with kappa/beta carrageenan (κ/β-K), a polysaccharide of red algae, were obtained in a soluble form and as films. Using porcine intestinal mucosa as a model, it was shown that single-layer films obtained from polysaccharides and a three-layer film containing their polyelectrolyte complex exhibited mucoadhesive properties. The mucoadhesive ability of the films depended on the polysaccharide type and changed after PEC formation. Comparative analysis of the ζ-potential values determined for the soluble form of polyelectrolyte complexes in an aqueous solution and in a mucin-containing solution confirmed the mucoadhesive properties of the PECs. It was found that the complexes retained their mucoadhesive properties upon the inclusion of echinochrome A in their soluble form. This made it possible to consider them noninvasive forms of drug delivery.     

Mucoadhesive Bilayered Patches for Administration of Sumatriptan Succinate

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal patches of sumatriptan succinate using chitosan as the base matrix. The patches were prepared by the solvent casting method. Gelatin and polyvinyl pyrrolidone (PVP) K30 were incorporated into the patches, to improve the film properties of the patches. The patches were found to be smooth in appearance, uniform in thickness, weight, and drug content; showed good mucoadhesive strength; and good folding endurance. A 3² full factorial design was employed to study the effect of independent variables viz. levels of chitosan and PVP K30, which significantly influenced characteristics like swelling index, in-vitro mucoadhesive strength, in vitro drug release, and in-vitro residence time. Different penetration enhancers were tried to improve the permeation of sumatriptan succinate through buccal mucosa. Formulation containing 3% dimethyl sulfoxide showed good permeation of sumatriptan succinate through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for administration of sumatriptan succinate.     

The Influence of Recrystallized Caffeine on Water-Swellable Polymethacrylate Mucoadhesive Buccal Films

The aim of this work was to investigate the influence of particles on the properties of polymethacrylate films intended for buccal delivery. A solvent casting method was used with Eudragit RS and RL (ERS and ERL, respectively) as film-forming rate-controlling polymers, with caffeine as a water-soluble model drug. The physicochemical properties of the model films for a series of formulations with increasing concentrations of caffeine were determined in terms of morphology, mechanical and mucoadhesive properties, drug content uniformity, and drug release and associated kinetics. Typically regarded as non-mucoadhesive polymers, ERS and mainly ERL, were found to be good mucoadhesives, with ERL01 exhibiting a work of mucoadhesion (WoA) of 118.9 μJ, which was about five to six times higher than that observed for commonly used mucoadhesives such as Carbopol^® 974P (C974P, 23.9 μJ) and polycarbophil (PCP, 17.4 μJ). The mucoadhesive force for ERL01 was found to be significantly lower yet comparable to C974P and PCP films (211.1 vs. 329.7 and 301.1 mN, respectively). Inspection of cross-sections of the films indicated that increasing the concentration of caffeine was correlated with the appearance of recrystallized agglomerates. In conclusion, caffeine agglomerates had detrimental effects in terms of mucoadhesion, mechanical properties, uniformity, and drug release at large particle sizes. ERL series of films exhibited very rapid release of caffeine while ERS series showed controlled release. Analysis of release profiles revealed that kinetics changed from a diffusion controlled to a first-order release mechanism.     

Mucoadhesive bilayered tablets for buccal sustained release of flurbiprofen

The aim of this work was the design of sustained-release mucoadhesive bilayered tablets, using mixtures of mucoadhesive polymers and an inorganic matrix (hydrotalcite), for the topical administration of flurbiprofen in the oral cavity. The first layer, responsible for the tablet retention on the mucosa, was prepared by compression of a cellulose derivative and polyacrylic derivative blend. The second layer, responsible for buccal drug delivery, was obtained by compression of a mixture of the same (first layer) mucoadhesive polymers and hydrotalcite containing flurbiprofen. Nonmedicated tablets were evaluated in terms of swelling, mucosal adhesion, and organoleptic characteristics; in vitro and in vivo release studies of flurbiprofen-loaded tablets were performed as well. The best results were obtained from the tablets containing 20 mg of flurbiprofen, which allowed a good anti-inflammatory sustained release in the buccal cavity for 12 hours, ensuring efficacious salivary concentrations, and led to no irritation. This mucoadhesive formulation offers many advantages over buccal lozenges because it allows for reduction in daily administrations and daily drug dosage and is suitable for the treatment of irritation, pain, and discomfort associated with gingivitis, sore throats, laryngopharyngitis, cold, and periodontal surgery. Moreover, it adheres well to the gum and is simple to apply, which means that patient compliance is improved. Published: July 13, 2007     

Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride

The aim of this work was to develop and characterize chitosan/gelatin films as innovative mucoadhesive system for buccal delivery of propranolol hydrochloride. FT-IR and TGA analysis confirmed the interaction between chitosan and gelatin. The presence of higher chitosan amounts in chitosan/gelatin films allowed the lowest percent water-uptake ability (235.1 ± 5.3%) and the highest in vivo residence time in the buccal cavity (240 ± 13 min). Moreover, the presence of mannitol in the formulation allowed 80% drug permeation through porcine buccal mucosa in 5 h. This behaviour suggests that the application of four and two films containing 5 mg of propranolol hydrochloride could be suitable for achieving the proposed daily dose for hypertension and atrial fibrillation treatment, respectively. Another interesting aspect of chitosan/gelatin films was their compatibility with buccal microflora in the absence of drug and their ability to determine growth inhibition for pathogen bacteria, but not for probiotic species, when loaded with drug.     

Controlled Release of 5-Fluorouracil from Alginate Beads Encapsulated in 3D Printed pH-Responsive Solid Dosage Forms

Three-dimensional printing is being steadily deployed as manufacturing technology for the development of personalized pharmaceutical dosage forms. In the present study, we developed a hollow pH-responsive 3D printed tablet encapsulating drug loaded non-coated and chitosan-coated alginate beads for the targeted colonic delivery of 5-fluorouracil (5-FU). A mixture of Eudragit® L100-55 and Eudragit® S100 was fabricated by means of hot-melt extrusion (HME) and the produced filaments were printed utilizing a fused deposition modeling (FDM) 3D printer to form the pH-responsive layer of the tablet with the rest comprising of a water-insoluble poly-lactic acid (PLA) layer. The filaments and alginate particles were characterized for their physicochemical properties (thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction), their surface topography was visualized by scanning electron microscopy and the filaments’ mechanical properties were assessed by instrumented indentation testing and tensile testing. The optimized filament formulation was 3D printed and the structural integrity of the hollow tablet in increasing pH media (pH 1.2 to pH 7.4) was assessed by means of time-lapsed microfocus computed tomography (μCT). In vitro release studies demonstrated controlled release of 5-FU from the alginate beads encapsulated within the hollow pH-sensitive tablet matrix at pH values corresponding to the colonic environment (pH 7.4). The present study highlights the potential of additive manufacturing in fabricating controlled-release dosage forms rendering them pertinent formulations for further in vivo evaluation.     

<Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">Ex Vivo</Emphasis> Evaluation of Novel Curcumin-Loaded Excipient for Buccal Delivery

This study aimed to develop a mucoadhesive polymeric excipient comprising curcumin for buccal delivery. Curcumin encompasses broad range of benefits such as antioxidant, anti-inflammatory, and chemotherapeutic activity. Hyaluronic acid (HA) as polymeric excipient was modified by immobilization of thiol bearing ligands. L-Cysteine (SH) ethyl ester was covalently attached via amide bond formation between cysteine and the carboxylic moiety of hyaluronic acid. Succeeded synthesis was proved by H-NMR and IR spectra. The obtained thiolated polymer hyaluronic acid ethyl ester (HA-SH) was evaluated in terms of stability, safety, mucoadhesiveness, drug release, and permeation-enhancing properties. HA-SH showed 2.75-fold higher swelling capacity over time in comparison to unmodified polymer. Furthermore, mucoadhesion increased 3.4-fold in case of HA-SH and drug release was increased 1.6-fold versus HA control, respectively. Curcumin-loaded HA-SH exhibits a 4.4-fold higher permeation compared with respective HA. Taking these outcomes in consideration, novel curcumin-loaded excipient, namely thiolated hyaluronic acid ethyl ester appears as promising tool for pharyngeal diseases.     

Preparation and Characterization of Nicotine–Magnesium Aluminum Silicate Complex-Loaded Sodium Alginate Matrix Tablets for Buccal Delivery

Nicotine (NCT) buccal tablets consisting of sodium alginate (SA) and nicotine–magnesium aluminum silicate (NCT–MAS) complexes acting as drug carriers were prepared using the direct compression method. The effects of the preparation pH levels of the NCT–MAS complexes and the complex/SA ratios on NCT release, permeation across mucosa, and mucoadhesive properties of the tablets were investigated. The NCT–MAS complex-loaded SA tablets had good physical properties and zero-order release kinetics of NCT, which indicate a swelling/erosion-controlled release mechanism. Measurement of unidirectional NCT release and permeation across porcine esophageal mucosa using a modified USP dissolution apparatus 2 showed that NCT delivery was controlled by the swollen gel matrix of the tablets. This matrix, which controlled drug diffusion, resulted from the molecular interactions of SA and MAS. Tablets containing the NCT–MAS complexes prepared at pH 9 showed remarkably higher NCT permeation rates than those containing the complexes prepared at acidic and neutral pH levels. Larger amounts of SA in the tablets decreased NCT release and permeation rates. Additionally, the presence of SA could enhance the mucoadhesive properties of the tablets. These findings suggest that SA plays the important role not only in controlling release and permeation of NCT but also for enhancing the mucoadhesive properties of the NCT–MAS complex-loaded SA tablets, and these tablets demonstrate a promising buccal delivery system for NCT.     

Preparation and Evaluation of Buccal Bioadhesive Films Containing Clotrimazole

Buccal bioadhesive films, releasing topical drugs in the oral cavity at a slow and predetermined rate, provide distinct advantages over traditional dosage forms. The aim of present study was to prepare and evaluate buccal bioadhesive films of clotrimazole for oral candidiasis. The film was designed to release the drug at a concentration above the minimum inhibitory concentration for a prolonged period of time so as to reduce the frequency of administration of the available conventional dosage forms. The different proportions of sodium carboxymethylcellulose and carbopol 974P (CP 974P) were used for the preparation of films. Carbopol was used to incorporate the desired bioadhesiveness in the films. The films were prepared by solvent casting method and evaluated for bioadhesion, in vitro drug release and effectiveness against Candida albicans. In vitro drug release from the film was determined using a modified Franz diffusion cell while bioadhesiveness was evaluated with a modified two-arm balance using rabbit intestinal mucosa as a model tissue. Films containing 5% CP 974P of the total polymer were found to be the best with moderate swelling along with favorable bioadhesion force, residence time and in vitro drug release. The microbiological studies revealed that drug released from the film could inhibit the growth of C. albicans for 6 h. The drug release mechanism was found to follow non-Fickian diffusion.     

Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa

Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of β-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of β-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility.     

Buccal Dosage Forms: General Considerations for Pediatric Patients

The development of an appropriate dosage form for pediatric patients needs to take into account several aspects, since adult drug biodistribution differs from that of pediatrics. In recent years, buccal administration has become an attractive route, having different dosage forms under development including tablets, lozenges, films, and solutions among others. Furthermore, the buccal epithelium can allow quick access to systemic circulation, which could be used for a rapid onset of action. For pediatric patients, dosage forms to be placed in the oral cavity have higher requirements for palatability to increase acceptance and therapy compliance. Therefore, an understanding of the excipients required and their functions and properties needs to be particularly addressed. This review is focused on the differences and requirements relevant to buccal administration for pediatric patients (compared to adults) and how novel dosage forms can be less invasive and more acceptable alternatives.     

Development and Evaluation of Buccal Films Based on Chitosan for the Potential Treatment of Oral Candidiasis

In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.     

Formulation, evaluation, and comparison of bilayered and multilayered mucoadhesive buccal devices of propranolol hydrochloride

The purpose of this research work was to establish mucoadhesive buccal devices of propranolol hydrochloride (PRH) in the forms of bilayered and multilayered tablets. The tablets were prepared using sodium carboxymethylcellulose (SCMC) and Carbopol-934 (CP) as bioadhesive polymers to impart mucoadhesion and ethyl cellulose (EC) to act as an impermeable backing layer. Buccal devices were evaluated by different parameters such as weight uniformity, content uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in vitro drug release, and in vitro drug permeation. As compared with bilayered tablets, multilayered tablets showed slow release rate of drug with improved ex vivo bioadhesive strength and enhanced ex vivo mucoadhesion time. The mechanism of drug release was found to be non-Fickian diffusion (value of n between 0.5 and 1.0) for both the buccal devices. The stability of drug in both the optimized buccal devices was tested for 6 hours in natural human saliva; both the buccal devices were found to be stable in natural human saliva. The present study concludes that mucoadhesive buccal devices of PRH can be a good way to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of PRH. Published: March 16, 2007