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Oromucosal drug delivery, both local and transmucosal (buccal), is an effective alternative to traditional oral and parenteral dosage forms because it increases drug bioavailability and reduces systemic drug toxicity. The oral mucosa has a good blood supply, which ensures that drug molecules enter the systemic circulation directly, avoiding drug metabolism during the first passage through the liver. At the same time, the mucosa has a number of barriers, including mucus, epithelium, enzymes, and immunocompetent cells, that are designed to prevent the entry of foreign substances into the body, which also complicates the absorption of drugs. The development of oromucosal drug delivery systems based on mucoadhesive biopolymers and their derivatives (especially thiolated and catecholated derivatives) is a promising strategy for the pharmaceutical development of safe and effective dosage forms. Solid, semi-solid and liquid pharmaceutical formulations based on biopolymers have several advantageous properties, such as prolonged residence time on the mucosa due to high mucoadhesion, unidirectional and modified drug release capabilities, and enhanced drug permeability. Biopolymers are non-toxic, biocompatible, biodegradable and may possess intrinsic bioactivity. A rational approach to the design of oromucosal delivery systems requires an understanding of both the anatomy/physiology of the oral mucosa and the physicochemical and biopharmaceutical properties of the drug molecule/biopolymer, as presented in this review. This review summarizes the advances in the pharmaceutical development of mucoadhesive oromucosal dosage forms (e.g., patches, buccal tablets, and hydrogel systems), including nanotechnology-based biopolymer nanoparticle delivery systems (e.g., solid lipid particles, liposomes, biopolymer polyelectrolyte particles, hybrid nanoparticles, etc.). [ABSTRACT FROM AUTHOR]

Oral candidiasis (OC) is an opportunistic fungal infection, common amongst the elderly and the immunocompromised. Unfortunately, the therapeutic efficacy of common antifungals is imperiled by the rise of antifungal drug resistance. An alternative promising therapeutic option possibly contributing to antifungal therapy is drug repurposing. Herein, we aimed to employ novel pharmaceutical drug delivery for enhancing the emerging antifungal potential of the hypocholesterolemic drug atorvastatin (ATV). ATV-propylene-glycol-liposomes (ATV/PG-Lip) were prepared then integrated in 3D-printed (3DP) mucoadhesive films comprising chitosan, polyvinyl-alcohol and hydroxypropyl methylcellulose, as an innovative blend, for the management of OC. ATV/PG-Lip demonstrated good colloidal properties of particle size (223.3 ± 2.1 nm), PDI (0.12 ± 0.001) and zeta potential (-18.2 ± 0.3 mV) with high entrapment efficiency (81.15 ± 1.88%) and sustained drug release. Also, ATV/PG-Lip showed acceptable three-month colloidal stability and in vitro cytocompatibility on human gingival fibroblasts. The developed 3DP-films exhibited controlled ATV release (79.4 ± 1.4% over 24 h), reasonable swelling and mucoadhesion (2388.4 ± 18.4 dyne/cm2). In vitro antifungal activity of ATV/PG-Lip was confirmed against fluconazole-resistant Candida albicans via minimum inhibitory concentration determination, time-dependent antifungal activity, agar diffusion and scanning electron microscopy. Further, ATV/PG-Lip@3DP-film exceeded ATV@3DP-film in amelioration of infection and associated inflammation in an in vivo oral candidiasis rabbit model. Accordingly, the results confirm the superiority of the fabricated ATV/PG-Lip@3DP-film for the management of oral candidiasis and tackling antifungal resistance. [ABSTRACT FROM AUTHOR]

The interest in buccal drug delivery is under consideration due to some distinct properties compared to the traditional pharmaceutical formulations for oral administration: significantly higher bioavailability, a faster absorption rate of the drug, and substantial compliance for special needs patients. Oral films are obtained through various technologies, from conventional tools to 3D and 4D printing approaches. This minireview aims to describe the current additive manufacturing technologies in oral film fabrication, display their advantages and limitations, and discuss various formulation strategies. It also provides advanced data regarding synthetic and natural polymers used in 3D printing technologies for oral films. Moreover, it shows the most recent studies with 3D-printed orodispersible films and mucoadhesive buccal films manufactured through previously analyzed methods. Finally, conclusions and future perspectives are also briefly summarized. [ABSTRACT FROM AUTHOR]

Buccal drug-delivery systems present a promising approach for the drug delivery to the buccal mucosa, addressing oral cavity-specific problems, enabling systemic delivery and minimizing adverse effects on biological systems. Numerous strategies have been proposed to load drug-containing nanoparticles (NPs) to the buccal mucosa for local and systemic applications. There has been considerable interest in the development of mucoadhesive buccal formulations, particularly hydrogel composites utilizing mucoadhesive films incorporating NPs. Drug permeability and controlled drug release through buccal drug delivery continues to pose a challenge despite the availability of various remedies. This review highlights the need for, mechanisms and latest advances in NP-based transbuccal drug delivery with a focus on various pathological disorders and examples and limitations of the different methods. [ABSTRACT FROM AUTHOR]

Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. The objective of this article is to review buccal drug delivery by discussing the structure and environment of the oral mucosa and highlighting the mechanisms of drug permeation and methodology in evaluating buccal formulations. This review also highlights a brief description of advantages, limitations of buccal drug delivery and theories involved in mucoadhesion along with method of preparation mucoadhesive system, mucoadhesive polymer, and classification of buccal system. [ABSTRACT FROM AUTHOR]

Buccal film formulations, including antifungal nystatin, anti-inflammatory agent hydrocortisone acetate, and local anesthetic lidocaine hydrochloride for pain relief, were developed. Bioadhesive films were fabricated with hydrophilic polymers, hydroxyethyl cellulose (HEC), and xanthan gum (XG) and dried in the incubator. Textural, swelling, and bioadhesive properties, physicochemical and in vitro release characteristics, and antifungal activities of bioadhesive films were evaluated. Bioadhesive films significantly extended nystatin release by prolonging retention time of the target area formulation while rapidly releasing hydrocortisone acetate and lidocaine HCl, reducing drug administration. The polymer type affected bioadhesion strength and erosion ratio, and XG formulations had more polymer suitability. Consequently, XT-O2 formulation that was prepared with xanthan gum and tween 80, was best for its highest antifungal film activity (20.00 ± 0.07 mm), released nystatin (44.296% ± 1.695), and lowest erosion matrix (36.719% ± 0.249). The selected formulation can be used for compatibility, stability and in vivo studies targeted oral candidiasis infections. [ABSTRACT FROM AUTHOR]

The potential of the mucoadhesive film technology is hard to ignore, owing to perceived superior patient acceptability versus buccal tablets, and significant therapeutic opportunities compared to conventional oral drug delivery systems, especially for those who suffer from dysphagia. In spite of this, current translation from published literature into the commercial marketplace is virtually non-existent, with no authorised mucoadhesive buccal films available in the UK and very few available in the USA. This review seeks to provide an overview of the mucoadhesive buccal film technology and identify key areas upon which to focus scientific efforts to facilitate the wider adoption of this patient-centric dosage form. Several indications and opportunities for development were identified, while discussing the patient-related factors influencing the use of these dosage forms. In addition, an overview of the technologies behind the manufacturing of these films was provided, highlighting manufacturing methods like solvent casting, hot melt extrusion, inkjet printing and three-dimensional printing. Over thirty mucoadhesive polymers were identified as being used in film formulations, with details surrounding their mucoadhesive capabilities as well as their inclusion alongside other key formulation constituents provided. Lastly, the importance of physiologically relevant in vitro evaluation methodologies was emphasised, which seek to improve in vivo correlations, potentially leading to better translation of mucoadhesive buccal films from the literature into the commercial marketplac. [Display omitted] [ABSTRACT FROM AUTHOR]

Taekwang Keum,1,2,* Gyubin Noh,1,2,* Jo-Eun Seo,1 Santosh Bashyal,1,2 Dong Hwan Sohn,1 Sangkil Lee1,2 1College of Pharmacy, Keimyung University, Daegu, Republic of Korea; 2Center for Forensic Pharmaceutical Science, Daegu, Republic of Korea*These authors contributed equally to this workCorrespondence: Sangkil Lee, College of Pharmacy, Keimyung University, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 42601, Republic of Korea, Tel +82-53-580-6655, Fax +82-53-580-5164, Email skdavid@kmu.ac.krIntroduction: The buccal route has been considered an attractive alternative delivery route for injectable formulations. Cell-penetrating peptides (CPPs) are gaining increased attention for their cellular uptake and tissue permeation effects. This study was aimed to evaluate the in vitro and ex vivo permeation-enhancing effect of penetratin-conjugated liposomes for salmon calcitonin (sCT) in TR146 human buccal cells and porcine buccal tissues.Methods: Penetratin was conjugated to phospholipids through a maleimide-thiol reaction. Liposomes were prepared and sCT was encapsulated using a thin-film hydration method. Physical properties such as particle size, zeta potential, encapsulation efficiency, and morphological images via transmission electron microscopy were obtained. Cellular uptake studies were conducted using flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). A cell permeation study was performed using a Transwell® assay, and permeation through porcine buccal tissue was evaluated. The amount of sCT permeated was quantified using an ELISA kit and was optically observed using CLSM.Results: The particle size of penetratin-conjugated liposomes was approximately 123.0 nm, their zeta potential was +29.6 mV, and their calcitonin encapsulation efficiency was 18.0%. In the cellular uptake study using FACS and CLSM, stronger fluorescence was observed in penetratin-conjugated liposomes compared with the solution containing free sCT and control liposomes. Likewise, the amount of sCT permeated from penetratin-conjugated liposomes was higher than that from the free sCT solution and control liposomes by 5.8-fold across TR146 cells and 91.5-fold across porcine buccal tissues.Conclusion: Penetratin-conjugated liposomes are considered a good drug delivery strategy for sCT via the buccal route.Keywords: buccal drug delivery, peptide delivery, penetratin, liposomes, TR146 cells, porcine buccal tissues

Commitment to the 3Rs principle (Replacement, Reduction, and Refinement) led to the development of a cell-based system to measure buccal bioadhesion in vitro and replace the use of porcine buccal and esophageal tissues (PBT and PET, respectively). Additionally, the aim is to bridge the gap in knowledge regarding the bioadhesion properties of PBT and PET. The in vitro models are based on the human buccal epithelial cell line-TR146 without ("Model I") or with ("Model II") 5% (w/v) mucous layer. The in vitro setup also provides a method to evaluate the bioadhesion between two soft materials. Standard bioadhesive hydrogels (alginate, chitosan, and gelatin) are used to test and compare the results from the in vitro models to the ex vivo tissues. The ex vivo and in vitro models show increased bioadhesion as the applied force and contact time increases. Furthermore, Model I exhibits bioadhesion values-of alginate, chitosan, and gelatin-comparable to those obtained with PBT. It is also found that contact time and applied force similarly affect PBT and PET bioadhesion, while PET exhibits greater values. In conclusion, Model I can replace PBT for measuring bioadhesion and be incorporated into the experimental design of bioadhesive DDS, thus minimizing animal tissue usage., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Santosh Bashyal,1 Jo-Eun Seo,1 Taekwang Keum,1,2 Gyubin Noh,1,2 Shrawani Lamichhane,1,2 Jeong Hwan Kim,1,2 Chang Hyun Kim,3 Young Wook Choi,3 Sangkil Lee1,2 1College of Pharmacy, Keimyung University, Daegu, Republic of Korea; 2Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, Republic of Korea; 3College of Pharmacy, Chung-Ang University, Seoul, Republic of KoreaCorrespondence: Sangkil LeeCollege of Pharmacy, Keimyung University, 1095 Dalgubeol-Daero, Dalseo-Gu, Daegu, 42601, Republic of KoreaTel +82 53 580 6655Fax +82 53 580 5164Email skdavid@kmu.ac.krBackground: The clinical use of therapeutic peptides has been limited because of their inefficient delivery approaches and, therefore, inadequate delivery to target sites. Buccal administration of therapeutic peptides offers patients a potential alternative to the current invasive routes of administration.Purpose: The aim of the study was to fabricate hydrophobic ion-pairing (HIP)-nanocomplexes (C1 and C2) utilizing anionic bile salts and cationic peptides, and to assess their permeability across TR146 buccal cell layers and porcine buccal tissue.Methods: C1 and C2-nanocomplexes were fabricated using the HIP approach. In addition, their physiochemical and morphological attributes, in vitro and ex vivo permeability properties, and qualitative and quantitative cellular uptake were evaluated and compared. The localization of C1 and C2-nanocomplexes in porcine buccal tissue was determined using confocal laser scanning microscopy.Results: The C1-nanocomplex was the superior nanocarrier and significantly enhanced the transport of insulin across TR146 cell layers and porcine buccal tissue, exhibiting a 3.00- and 51.76-fold increase in permeability coefficient, respectively, when compared with insulin solution (p < 0.01). C1-nanocomplex was more efficient than C2-nanocomplex at facilitating insulin permeability, with a 2.18- and 27.64-fold increase across TR146 cell layers and porcine buccal tissue, respectively. The C1-nanocomplex demonstrated immense uptake and localization of insulin in TR146 cells and porcine buccal tissue, as evidenced by a highly intense fluorescence in TR146 cells, and a great shift of fluorescence intensity towards the inner region of buccal tissue over time. The increase in fluorescence intensity was observed in the order of C1 > C2 > insulin solution.Conclusion: In this study, we highlighted the efficacy of potential nanocarriers in addressing the daunting issues associated with the invasive administration of insulin and indicated a promising strategy for the buccal administration and delivery of this life-saving peptide hormone.Keywords: hydrophobic ion-pairing, bile salts, peptide delivery, buccal drug delivery, buccal absorption, TR146 cells, porcine buccal tissue

In this study, modified kappa‐carrageenan/pectin hydrogel patches were fabricated for treatment of buccal fungal infections. For this purpose, kappa‐carrageenan‐g‐acrylic acid was modified with different thiolated agents (L‐cysteine and 3‐mercaptopropionic acid), and the thiol content of the resulting modified kappa‐carrageenan was confirmed by elemental analyzer. Then, the hydrogel patches were fabricated, and characterized by Fourier‐transform infrared spectroscopy, thermogravimetric analysis, ex vivo mucoadhesion test, and swelling behavior. Triamcinolone acetonide was added either directly or by encapsulating within the poly(lactic‐co‐glycolic acid) nanoparticles. The release amount of the drug from the directly loaded patch was 7.81 mg/g polymer, while it was 3.28 mg/g polymer for the encapsulated patch with the same content at 7 hr. The hydrogel patches had no cytotoxicity by cell culture studies. Finally, the drug loaded hydrogel patches were demonstrated antifungal activity against Aspergillus fumigatus and Aspergillus flavus. These results provide that the novel modified kappa‐carrageenan and pectin based buccal delivery system has promising antifungal property, and could have advantages compared to conventional buccal delivery systems. [ABSTRACT FROM AUTHOR]

Transmucosal drug delivery represents a promising noninvasive option when drugs are employed which have a low oral bioavailability like CBD. However, this concept can only be successful as long as the formulation provides sufficient buccal retention and mucosal penetration. In this study, mucoadhesive carrier systems were evaluated consisting of CBD-loaded silica (Aeroperl 300) carriers, mucoadhesive polymers (Hypromellose (HPMC), chitosan and carbomer) and propylene glycol as a penetration enhancer. Mucoadhesive effect, drug release and penetration ability were evaluated for each carrier system. The results show that the addition of HPMC and carbomer substantially improve mucoadhesion compared to pure CBD, with an increase of 16-fold and 20-fold, respectively. However, due to their strong swelling, HPMC and carbomer hinder the penetration of CBD and rely on co-administration of propylene glycol as an enhancer to achieve sufficient mucosal absorption. Chitosan, on the other hand, achieves an 8-fold increase in mucoadhesion and enhances the amount of CBD absorbed by three times compared to pure CBD. Thus, chitosan represents a promising polymer to combine both effects. Considering the results, the development of silica-based buccal drug delivery systems is a promising approach for the effective delivery of CBD. [ABSTRACT FROM AUTHOR]

Buccal administration of different active ingredients as an alternative to oral or dermal routes has been widely studied. The films are one of the most investigated dosage forms regarding the buccal formulations developed using bioadhesive polymers. Having thin and flexible structures, the films remain in the mouth for their duration of action without causing any discomfort. There are many studies conducted to develop buccal films for local treatment of oral fungal infections. In this research, buccal films were prepared using terbinafine hydrochloride, which is frequently used orally and systemically in the treatment of fungal infections and has low water solubility. The films were prepared by solvent casting method using hydroxypropyl methyl cellulose (HPMC) and polyvinyl pyrrolidone K30 (PVP) as the bioadhesive polymers and glycerin (2-3%) as the plasticizer. Characterization properties including thickness, weight uniformity, flexibility, tensile strength, swelling capacity were examined and the bioadhesive characteristics were determined by Texture Analyzer device using bovine buccal tissue. According to the findings of bioadhesion studies, the highest bioadhesive properties were detected in F1 and F7 formulations, which contained 5% HPMC. In vitro release studies exhibited that F1 and F7 film formulations with 5% HPMC represented slower and more controlled release compared to F2 and F8 film formulations having 4% HPMC + 1% PVP. The results revealed that the developed buccal formulations loaded with terbinafine hydrochloride might be convenient for the local treatment of oral fungal infections. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to optimize unidirectional buccal patches loaded with metoprolol (MT-MBPs) to provide adequate mucoadhesive and water uptake properties as well as controlled drug release for the effective treatment of different cardiovascular diseases. Methods: The patches were prepared layer-by-layer using the solvent casting method. A central composite design was employed to statistically optimize the formulation variables. Chitosan and Pluronic® F-127 (poloxamer 407) concentrations were chosen as the independent variables, while ex vivo mucoadhesive force, ex vivo residence time, in vitro water uptake (%), and in vitro drug release (%) were to be considered the dependent variables. The optimized formulation was also characterized and evaluated in terms of morphology, thermal behavior, tensile strength, elongation at break, and ex vivo drug permeation. Results: The optimized MT-MBPs were successful in terms of mucoadhesive force (3.58 ± 0.62 N), residence time (342.67 ± 17.21 min), and water uptake at 1 h (24.53 ± 3.62%). A controlled drug release was obtained for 8 h. Thermal and morphologic analyses demonstrated that metoprolol was homogeneously distributed throughout the microporous chitosan-based polymer matrix. Furthermore, the MT-MBPs exhibited a tensile strength of 3.76 ± 0.55 N/mm2 and an elongation at break of 36.52 ± 13.88%. The results of ex vivo permeation through pig buccal mucosa indicated that therapeutic metoprolol concentrations can be reached by using a patch of 5.62 cm2. Conclusions: Optimal composition of the MT-MBPs included 2.9% (w/v) and 2.6% (w/v) of chitosan and Pluronic® F-127, respectively, which constitutes the most suitable makeup for metoprolol buccal delivery. [ABSTRACT FROM AUTHOR]

Abstract In the present work, commercial arrowroot starch (AR starch) has been successfully used as a base material with sodium salt of carboxy methyl cellulose (CMC) for buccal drug delivery system. Different ratio of CMC and AR starch has been prepared with constant ratio of drug. In our study, glipizide has been used as the drug for controlled drug delivery through buccal mucosa. Films were cast by solution casting method with glycerol as plasticizer. All the films were characterized for thickness, swelling index, moisture content, relative pH, drug content uniformity, compatibility of polymer and drug, surface morphology of films, muco adhesive property and in-vitro drug release study. Formulation F3 shows a residence time of 140 minutes with good mucoadhesive property, compatibility within polymers, drug content uniformity of 100 ± 6.0% and a controlled drug release among all the ratios.

The aims of this study were to prepare and characterize hydroxypropyl methylcellulose (HPMC)/polycarbophil (PC) mucoadhesive blend films saturated with propranolol hydrochloride (PNL)-loaded nanoparticles to improve permeability of drugs that undergo first-pass metabolism. An ionic cross-linking method and film casting technique was used to prepare nanoparticles and mucoadhesive blend films, respectively. Increasing concentrations of PNL (70, 80, 90 mg/film) in HPMC/PC blend films containing PNL-loaded nanoparticles (PN-films) and HPMC/PC blend films containing PNL (80 mg/film) without nanoparticles (PP-films) were prepared to test swelling, mucoadhesiveness, release, permeation and physicochemical properties. Scanning electron microscope (SEM) images showed a partially smooth surface with a wrinkled occurrence and spherically shaped, well-dispersed nanoparticles on the surface of PN-films containing PNL 80 mg/film (PN-films-80). The size of the nanoparticles on the surface of PN-films-80 was around 100 nm, which was similar to the nanoparticle size observed using light scattering technique. The swelling index (SI) of all PN-films and PP-films increased greatly in the first period time (10–20 min) and reached swelling equilibrium at 20 min and 30 min, respectively. For the PN-films, the concentration of PNL influenced the mucoadhesive properties and tended to be higher when the amount of PNL increased. Immediate release of all blend film formulations was found in early time points (10–30 min). After 120 min, the release of PN-films-70 was lower than the other PN-films. Permeation studies using porcine buccal mucosa showed that inclusion of nanoparticles in the films increased the permeability of PNL compared to PP-films. Therefore, buccal administration of mucoadhesive blend films containing PNL-loaded nanoparticles could be a promising approach for drugs that undergo first-pass metabolism.

The main objective of the present study was to formulate and evaluate mucoadhesive in situ buccal gels of dexamethasone based on gellan gum-poloxamer 407. Formulations were characterized for gelling capacity, drug content, pH, viscosity, rheological studies, mechanical studies and in vitro drug release. The drug content, clarity and pH of the formulations were found to be satisfactory. Mucoadhesive in situ gels showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 30-37°C. Formulations exhibited pseudoplastic flow and typical gel-type mechanical spectra (G' > G?) at different frequecy values and 37°C. Prepared gels resulted in preparations with desirable rheological features as well as texture (appropriate hardness, compressibility, adhesiveness, cohesiveness and elasticity) properties, which could benefit the therapeutic efficacy, by increasing the residence time and easiness for local application on the buccal mucosa. Additionally, the developed preparations exhibited sustained drug release up to 72 h as intended for these systems. Optimized formulation containing 14% w/v poloxamer 407 and 0.4% w/v gellan gum exhibited desired characteristics (mechanical and rheological properties) for developing buccal drug delivery systems. Thus, buccal dexamethasone loaded mucoadhesive in situ gel was found to be a promising formulation. [ABSTRACT FROM AUTHOR]

Transmucosal drug delivery represents a promising noninvasive option when drugs are employed which have a low oral bioavailability like CBD. However, this concept can only be successful as long as the formulation provides sufficient buccal retention and mucosal penetration. In this study, mucoadhesive carrier systems were evaluated consisting of CBD-loaded silica (Aeroperl 300) carriers, mucoadhesive polymers (Hypromellose (HPMC), chitosan and carbomer) and propylene glycol as a penetration enhancer. Mucoadhesive effect, drug release and penetration ability were evaluated for each carrier system. The results show that the addition of HPMC and carbomer substantially improve mucoadhesion compared to pure CBD, with an increase of 16-fold and 20-fold, respectively. However, due to their strong swelling, HPMC and carbomer hinder the penetration of CBD and rely on co-administration of propylene glycol as an enhancer to achieve sufficient mucosal absorption. Chitosan, on the other hand, achieves an 8-fold increase in mucoadhesion and enhances the amount of CBD absorbed by three times compared to pure CBD. Thus, chitosan represents a promising polymer to combine both effects. Considering the results, the development of silica-based buccal drug delivery systems is a promising approach for the effective delivery of CBD.

The buccal cavity, also known as the oral cavity, is a complex anatomical structure that plays a crucial role in various physiological processes. It serves as a gateway to the digestive system and facilitates the initial stages of food digestion and absorption. However, its significance extends beyond mere digestion as it presents a promising route for drug delivery, particularly to the brain. Transferosomes are lipid-based vesicles that have gained significant attention in the field of drug delivery due to their unique structure and properties. These vesicles are composed of phospholipids that form bilayer structures capable of encapsulating both hydrophilic and lipophilic drugs. Strategies for the development of buccal transferosomes for brain delivery have emerged as promising avenues for pharmaceutical research. This review aims to explore the various approaches and challenges associated with harnessing the potential of buccal transferosomes as a means of enhancing drug delivery to the brain. By understanding the structure and function of both buccal tissue and transferosomes, researchers can develop effective formulation methods and characterization techniques to optimize drug delivery. Furthermore, strategic approaches and success stories in buccal transferosome development are highlighted, showcasing inspiring examples that demonstrate their potential to revolutionize brain delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Bilayered oromucosal film preparations (buccal films) offer a promising way to enable drug administration via the oral cavity. Polymeric film formulations containing chitosan, sodium alginate or carbopol were evaluated to select a formulation for the development of buccal drug delivery systems. Quality by Design (QbD) is increasingly becoming an important and widely used approach in the pharmaceutical industry. QbD requires producing an understanding of the critical variables affecting the attribues of products. In this study, the principles of QbD have been uniquely applied to 54 different kinds of film formulation contain different excipients as Chitosan, Carbopol, Sodium Alginate, Glycerine, PEG 400, Propylene Glycol to obtain appropriate buccal formulations. Each of the prepared formulations contains different ingredients combination and ingredients' ratio (% w/v), which appear changes. For this aim, to evaluate the effects of variables to the film formulations, they were characterized as thickness, weight uniformity, swelling and moisture loss. [ABSTRACT FROM AUTHOR]

Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive presystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parentral route of administration is the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the right dosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and permeation. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug and excipients. Advances in experimental and computationa l methodologies will be helpful in shortening the processing time from formulation design to clinical use. This paper aims to review the developments in the buccal adhesive drug delivery systems to provide basic principles to the young scientists, which will be useful to circumvent the difficulties associated with the formulation design. [ABSTRACT FROM AUTHOR]

Bilayer films were fabricated based on natural-based and biocompatible polymers such as esterified cellulose nanocrystals (ECNCs) and shellac, aiming for use in buccal drug delivery. Baicalin was used as the model drug. The swelling properties, drug loading and mechanical properties of films were evaluated and further characterized for mucoadhesion and in vitro drug release properties. The film (F2) containing ECNCs 45%, shellac 25% and polyethylene glycol 30% shows the best properties for the development of the film formulation. The swelling capacity of films was in the range of 36.5 ± 4.1-279.2 ± 14.1%. In vitro drug release shows that anomalous transport behavior indicates that transport includes drug diffusion and polymer relaxation. For film F2, the tensile strength and adhesion strength reaches to the maximum value of 21.57 ± 0.83 MPa and 0.073 ± 0.004 N, respectively. The interfacial interactions between drug and film components were confirmed by FTIR and XRD. [ABSTRACT FROM AUTHOR]

Buccal tissues are considered one of the potential alternative delivery route because of fast drug absorption and onset of action due to high vascularization and a non-keratinized epithelial membrane. In this study, the effect of Penetratin on the permeation of salmon calcitonin (sCT), a model macromolecular peptide drug, through TR146 buccal cells and porcine buccal tissues has been evaluated. To observe permeation profile of sCT, TR146 buccal cells were treated with Alexa 647 conjugated sCT (Alexa 647-sCT) with different concentrations of fluorescein isothiocyanate -labeled Penetratin (FITC-Penetratin) ranging from 0 to 40 μM, and analyzed using flow cytometry and confocal laser scanning microscopy. Intracellular penetration of FITC-Penetratin rapidly increased at low concentrations from 0 to 15 μM and it gradually increased at concentrations above 15 μM. Intracellular penetration of Alexa 647-sCT enhanced with the increase of FITC-Penetratin concentration. When TR146 cell layers and buccal tissues were co-treated with sCT and Penetratin as permeation enhancer, the flux of sCT increased as per Penetratin concentration. Compared to the control, 12.2 μM of Penetratin enhanced the flux of sCT in TR146 cell layers and buccal tissues by 5.5-fold and 93.7-fold, respectively. These results strongly suggest that Penetratin may successfully act as a non-invasive permeation enhancer for macromolecular peptide drug delivery through buccal routes.

The work was aimed at developing an in vitro method able to provide rapid and reliable evaluation of drug absorption through buccal mucosa. Absorption simulator apparatus endowed with an artificial membrane was purposely developed by experimental design. The apparent permeation coefficient (P app ) through excised porcine buccal mucosa of naproxen, selected as model drug, was the target value to obtain with the artificial membrane. The multivariate approach enabled systematic evaluation of the effect on the response (P app ) of simultaneous variations of the variables (kind of lipid components for support impregnation and relative amounts). A screening phase followed by a response-surface study allowed optimization of the lipid-mixture composition to obtain the desired P app value, and definition of a design space where all mixture components combinations fulfilled the desired target at a fixed probability level. The method offers a useful tool for a quick screening in the early stages of drug discovery and/or in preformulation studies, improving efficiency and chance of success in the development of buccal delivery systems. Further studies with other model drugs are planned to confirm the buccal absorption predictive capacity of the developed membrane. [ABSTRACT FROM AUTHOR]

A series of mucoadhesive nanocomposites with self disinfection properties composed of acrylic acid, polyethylene glycol and ZnO nanoparticles (AAc/PEG)-ZnO were developed for localized buccal Propranolol HCl delivery. γ-irradiation as a clean tool for graft copolymerization process was used for the preparation of (AAc/PEG) hydrogels. In suite precipitation technique was used for ZnO nanoparticles immobilization within (AAc/PEG) hydrogels. The developed (AAc/PEG)-ZnO nanocomposites were characterized by X-ray diffraction (XRD), UV–Vis spectrophotometer, energy dispersive X-ray spectroscopy (EDX) and scanning electron microscopy (SEM) to confirm the success of ZnO nanoparticles formation within the (AAc/PEG) matrices. The presence of ZnO nanoparticles improves the thermal stability as indicated using thermogravimetric analysis (TGA). The mucoadhesion characteristics such as hydration degree, surface pH, and mucoadhesive strength were evaluated in artificial saliva solution. The self disinfection property of the developed (AAc/PEG)-ZnO nanocomposites was investigated by examining their resistance to pathogenic microorganisms such as Staphylococcus aureus , Bacillus subtilis , and Escherichia coli using disc diffusion method. The release of Propranolol -HCl drug in artificial saliva was found to obey a non-Fickian diffusion mechanism. The obtained results suggests that (AAc/PEG)-ZnO nanocomposites could be used as mucoadhesive carrier for buccal drug delivery with efficient antibacterial properties. [ABSTRACT FROM AUTHOR]

The aims of this study were to prepare and characterize hydroxypropyl methylcellulose (HPMC)/polycarbophil (PC) mucoadhesive blend films saturated with propranolol hydrochloride (PNL)-loaded nanoparticles to improve permeability of drugs that undergo firstpass metabolism. An ionic cross-linking method and film casting technique was used to prepare nanoparticles and mucoadhesive blend films, respectively. Increasing concentrations of PNL (70, 80, 90 mg/film) in HPMC/PC blend films containing PNL-loaded nanoparticles (PN-films) and HPMC/PC blend films containing PNL (80 mg/film) without nanoparticles (PPfilms) were prepared to test swelling, mucoadhesiveness, release, permeation and physicochemical properties. Scanning electron microscope (SEM) images showed a partially smooth surface with a wrinkled occurrence and spherically shaped, well-dispersed nanoparticles on the surface of PN-films containing PNL 80 mg/film (PN-films-80). The size of the nanoparticles on the surface of PN-films-80 was around 100 nm, which was similar to the nanoparticle size observed using light scattering technique. The swelling index (SI) of all PN-films and PP-films increased greatly in the first period time (10-20 min) and reached swelling equilibrium at 20 min and 30 min, respectively. For the PN-films, the concentration of PNL influenced themucoadhesive properties and tended to be higher when the amount of PNL increased. Immediate release of all blend film formulations was found in early time points (10-30 min). After 120 min, the release of PN-films-70 was lower than the other PNfilms. Permeation studies using porcine buccalmucosa showed that inclusion of nanoparticles in the films increased the permeability of PNL compared to PP-films. Therefore, buccal administration of mucoadhesive blend films containing PNL-loaded nanoparticles could be a promising approach for drugs that undergo first-pass metabolism. [ABSTRACT FROM AUTHOR]

Buccal delivery is considered to be a major alternative to the peroral route and the unique environment of the oral cavity offers its potential as a site of drug delivery. Buccal drug delivery has lately become an important route of drug administration. The rich in vascularization of oral mucosa and its permeability too many drugs make this route an attractive alternative to the oral and parenteral routes for systemic drug delivery. Absorption through the buccal mucosa overcomes premature drug degradation due to the enzyme activity and pH of gastrointestinal tract, avoids active drug loss due to pre-systemic metabolism (First-pass hepatic metabolism), acid hydrolysis and therapeutic plasma concentration of the drug can de rapidly achieved. There is always increase in demand for the patient convenience and compliance related research and novel methods are the development of mucoadhesive buccal formulations which results the greater bioavailability with reducing dose frequency to mouth plasma peak levels, which in turn minimize adverse/side effects and also make it cost effective. Moreover, rapid onset of action can be achieved.it is also possible to administer the drug to patients who are unconscious and less co-operative. In the present review, recent advancements and literature regarding mucoadhesive buccal patches is compiled and it suggests that this delivery system can be adopted by various pharmaceutical companies in the future at the large scale because it is the novel frontier in drug delivery technology that provides a very convenient means of taking medication. This review also highlight a brief description of advantages, disadvantages, limitation and theories involved in mucoadhesive, and classification of buccal system. [ABSTRACT FROM AUTHOR]

Buccal administration route is a promising way for a large number of drugs exhibiting a low oral bioavailability. The present work describes the formulation and evaluation of a mucoadhesive and thermosensitive in situ gelling delivery system based on poloxamer 407, poloxamer 188 and xanthan gum for buccal drug delivery. First, the mucoadhesion properties were evaluated using a tensile test. The effect of xanthan gum on the mucoadhesion force was demonstrated. Then, to assess the buccal residence time which reflects the mucoadhesion properties, the validation of a fluorescence probe for in vivo optical imaging experiment was conducted. Methyl-Cyanine 5 derivative (Me-Cy5) was used to label the hydrogels, dissolution tests and permeation studies through buccal epithelium cells showed that Me-Cy5 release from hydrogels was mainly due to an erosion mechanism and presented a limited penetration across epithelium cells. These results suggest that, Me-Cy5 is a suitable marker for thermosensitive in situ gelling delivery systems as the probe mostly stays entrapped in the hydrogel and do not cross the epithelial barrier. Buccal residence performance of the hydrogel was evaluated for the first time by non-invasive optical imaging after administration to mice. This technique is an interesting alternative compared to visual observations and sacrifice involved experiments, which could also be exploited to various administration routes. [ABSTRACT FROM AUTHOR]

The mucus layer is believed to play a part in drug permeation across the oral mucosa. Human freeze-dried saliva (HFDS) and porcine gastric mucin (PGM) was evaluated as model for mucus layer per se or in conjunction with in vitro and ex vivo buccal permeability models. Four small molecules (nicotine, mannitol, propranolol, caffeine) showed decreased permeability across mucin dispersions, compared to controls, and a greater effect was seen with HFDS than with PGM. Permeability of propranolol and caffeine across filter-grown TR146 cells was decreased by the presence of mucin, whereas no effect was found on nicotine and mannitol. Incubation of porcine buccal mucosa with mucin dispersions for 24 h compromised the integrity of the tissue, whereas 30 min incubation did not affect tissue integrity. Tissue incubation with mucin dispersions did not decrease nicotine permeability. For the studied model drugs, it is concluded that mucin dispersions constitute a minor barrier for drug diffusion compared to the epithelium. [ABSTRACT FROM AUTHOR]

Buccal delivery may be clinically beneficial for compounds with a high gastrointestinal and hepatic first pass metabolism or in situations where a fast systemic absorption is desired. The delivery of a crystalline low soluble compounds, e.g. diazepam, may be limited due to the low volume of saliva available to facilitate solvation in order to drive the permeation of drug through the buccal mucosa. Therefore, the present study investigated the potential benefits of administering diazepam either as an amorphous or as a crystalline form in mucoadhesive tablets to conscious Göttingen mini-pigs. Presentation of the compound in the amorphous form lead to a very fast absorption, however, the obtained bioavailability was at the same level observed following buccal administration of a commercially immediate release tablet. Addition of chitosan, as a mucoadhesive excipient, resulted in a higher absolute bioavailability compared to tablets without chitosan. The absorption rate for the chitosan-based tablets was significant slower, probably due to the slower diffusion of the compound out of the tablet. In vitro release data was able to predict the variations in t max , but otherwise no correlation could be found between in vitro and in vivo data. [ABSTRACT FROM AUTHOR]

The aim of this present work was to prepare triamcinolone acetonide (TA)-loaded nanostructured lipid carriers (TA-loaded NLCs) for buccal drug delivery systems using the Box-Behnken design. A hot homogenization method was used to prepare the TA-loaded NLCs. Spermaceti (X1), soybean oil (X2), and Tween 80 (X3) were used as solid lipid, liquid lipid, and stabilizer, respectively. The particle size of TA-loaded NLCs was lower than 200 nm and the zeta potential displayed the negative charge in all formulations. The percentage encapsulation efficiency (%EE) of the TA-loaded NLCs showed that it was higher than 80% for all formulations. Field emission scanning electron microscope (FESEM) confirmed that the size of TA-loaded NLCs was approximately 100 nm and energy-dispersive X-ray spectroscopy (EDS) confirmed that the TA could be incorporated in the NLC system. The Higuchi model gave the highest value of the R2, indicating that this model was a fit for the TA release profiles of TA-loaded NLCs. Confocal laser scanning microscopy (CLSM) was used to observe the drug penetration within the porcine buccal mucosa and Nile red-loaded NLCs showed significantly higher penetration depth at 8 h than at 2 h. Therefore, TA-loaded NLCs could be an efficient carrier for drug delivery through the buccal mucosa.

Dimenhydrinate (DMH)-loaded buccal bioadhesive films for the prevention and treatment of motion sickness were prepared and optimized. This study examines the rate of drug release from the films for prolonged periods of time to reduce or limit the frequency of DMH administration. Based on preliminary studies using various polymers and concentrations, hydroxyethylcellulose (2.5, 3.0, and 3.2%), and xanthan gum (2.8%) were chosen as matrix polymers. The films were analyzed with respect to their mechanical, physicochemical, bioadhesive, swelling, andin-vitrorelease properties. Inin-vivopharmacokinetic studies, xanthan gum-based DMH buccal film was associated with significantly increased DMH plasma levels between 1 h and 5 h after DMH dosing when compared with an oral drug solution. The area under the curve AUC0–7 hvalue of the mucoadhesive buccal film was two-fold higher than the oral DMH solution. Histological analysis revealed that DMH films cause mild morphological and inflammatory changes in rabbit buccal mucosa. The DMH buccal film is effective for approximately 7 h, thus representing an option for single-dose antiemetic therapy. This dosage regimen could be particularly beneficial for chain travelers who travel for long periods of time. [ABSTRACT FROM PUBLISHER]

This study aimed to develop films for potential delivery of omeprazole (OME) via the buccal mucosa of paediatric patients. Films were prepared using hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), sodium alginate (SA), carrageenan (CA) and metolose (MET) with polyethylene glycol (PEG 400) as plasticiser, OME (model drug) and L-arg (stabiliser). Gels (1% w/w) were prepared at 40°C using water and ethanol with PEG 400 (0-1% w/w) and dried in an oven (40°C). Optimised formulations containing OME and L-arg (1:1, 1:2 and 1:3) were prepared to investigate the stabilisation of the drug. Tensile properties (Texture analysis, TA), physical form (differential scanning calorimetry, DSC; X-ray diffraction, XRD; thermogravimetric analysis, TGA) and surface topography (scanning electron microscopy, SEM) were investigated. Based on the TA results, SA and MET films were chosen for OME loading and stabilisation studies as they showed a good balance between flexibility and toughness. Plasticised MET films were uniform and smooth whilst unplasticised films demonstrated rough lumpy surfaces. SA films prepared from aqueous gels showed some lumps on the surface, whereas SA films prepared from ethanolic gels were smooth and uniform. Drug-loaded gels showed that OME was unstable and therefore required addition of L-arg. The DSC and XRD suggested molecular dispersion of drug within the polymeric matrix. Plasticised (0.5% w/w PEG 400) MET films prepared from ethanolic (20% v/v) gels and containing OME: L-arg 1:2 showed the most ideal characteristics (transparency, ease of peeling and flexibility) and was selected for further investigation. [ABSTRACT FROM AUTHOR]

Drug administration via buccal mucosa is an attractive drug delivery strategy due to good patient compliance, prolonged localized drug effect, and avoidance of gastrointestinal drug metabolism and first-pass elimination. Buccal drug delivery systems need to maintain an intimate contact with the mucosa lining in the wet conditions of the oral cavity for long enough to allow drug release and absorption. For decades, mucoadhesive polymers such as chitosan (CS) and its derivatives have been explored to achieve this. In this study, inspired by the excellent wet adhesion of marine mussel adhesive protein, we developed a buccal drug delivery system using a novel catechol-functionalized CS (Cat-CS) hydrogel. We covalently bonded catechol functional groups to the backbone of CS, and crosslinked the polymer with a non-toxic crosslinker genipin (GP). We achieved two degrees of catechol conjugation (9% and 19%), forming Cat9-CS/GP and Cat19-CS/GP hydrogels, respectively. We confirmed covalent bond formation during the catechol functionalization and GP crosslinking during the gel formation. The gelation time and the mechanical properties of Cat-CS hydrogels are similar to those of CS only hydrogels. Catechol groups significantly enhanced mucoadhesion in vitro (7 out of the 10 Cat19-CS hydrogels were still in contact with porcine mucosal membrane after 6 h, whereas all of the CS hydrogels lost contact after 1.5 h). The new hydrogel systems sustained the release of lidocaine for about 3 h. In-vivo, we compared buccal patches made of Cat19-CS/GP and CS/GP adhered to rabbit buccal mucosa. We were able to detect lidocaine in the rabbit's serum at concentration about 1 ng/ml only from the Cat19-CS patch, most likely due to the intimate contact provided by mucoadhesive Cat19-CS/GP systems. No inflammation was observed on the buccal tissue in contact with any of the patches tested. These results show that the proposed catechol-modified CS hydrogel is a promising mucoadhesive and biocompatible hydrogel system for buccal drug delivery. [ABSTRACT FROM AUTHOR]

Buccal film formulations, including antifungal nystatin, anti-inflammatory agent hydrocortisone acetate, and local anesthetic lidocaine hydrochloride for pain relief, were developed. Bioadhesive films were fabricated with hydrophilic polymers, hydroxyethyl cellulose (HEC), and xanthan gum (XG) and dried in the incubator. Textural, swelling, and bioadhesive properties, physicochemical and in vitro release characteristics, and antifungal activities of bioadhesive films were evaluated.Bioadhesive films significantly extended nystatin release by prolonging retention time of the target area formulation while rapidly releasing hydrocortisone acetate and lidocaine HCl, reducing drug administration. The polymer type affected bioadhesion strength and erosion ratio, and XG formulations had more polymer suitability. Consequently, XT-O2 formulation that was prepared with xanthan gum and tween 80, was best for its highest antifungal film activity (20.00 ± 0.07 mm), released nystatin (44.296% ± 1.695), and lowest erosion matrix (36.719% ± 0.249). The selected formulation can be used for compatibility, stability and in vivo studies targeted oral candidiasis infections., (© 2022. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Mucoadhesive films containing curcumin-loaded nanoparticles were developed, aiming to prolong the residence time of the dosage form in the oral cavity and to increase drug absorption through the buccal mucosa. Films were prepared by the casting method after incorporation of curcumin-loaded chitosan-coated polycaprolactone nanoparticles into plasticized chitosan solutions. Different molar masses of mucoadhesive polysaccharide chitosan and concentrations of plasticizer glycerol were used to optimize the preparation conditions. Films obtained using medium and high molar mass chitosan were found to be homogeneous and flexible. Curcumin-loaded nanoparticles were uniformly distributed on the film surface, as evidenced by atomic force microscopy and high-resolution field-emission gun scanning electron microscopy (FEG-SEM) images. Analyses of film cross sections using FEG-SEM demonstrate the presence of nanoparticles inside the films. In addition, films proved to have a good rate of hydration in simulated saliva solution, displaying a maximum swelling of around 80% and in vitro prolonged-controlled delivery of curcumin. These results indicate that the mucoadhesive films containing nanoparticles offer a promising approach for buccal delivery of curcumin, which may be particularly useful in the treatment of periodontal diseases that require a sustained drug delivery. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3764-3771, 2014 [ABSTRACT FROM AUTHOR]