Nanotechnology-based mucoadhesive and mucus-penetrating drug-delivery systems for transbuccal drug delivery.

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.

Atorvastatin liposomes in a 3D-printed polymer film: a repurposing approach for local treatment of oral candidiasis.

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.

Development and Evaluation of Combined Effect Buccal Films for Treatment of Oral Candidiasis.

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.

Buccal films: A review of therapeutic opportunities, formulations & relevant evaluation approaches.

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 marketplace.

Optimization of Multilayer Films Composed of Chitosan and Low-Methoxy Amidated Pectin as Multifunctional Biomaterials for Drug Delivery.

Polyelectrolyte multilayers (PEMs) based on polyelectrolyte complex (PEC) structures are recognized as interesting materials for manufacturing functionalized coatings or drug delivery platforms. Difficulties in homogeneous PEC system development generated the idea of chitosan (CS)/low-methoxy amidated pectin (LM PC) multilayer film optimization with regard to the selected variables: the polymer ratio, PC type, and order of polymer mixing. Films were formulated by solvent casting method and then tested to characterize CS/LM PC PECs, using thermal analysis, Fourier transform infrared spectroscopy (FTIR), turbidity, and zeta potential measurements. The internal structure of the films was visualized by using scanning electron microscopy. Analysis of the mechanical and swelling properties enabled us to select the most promising formulations with high uniformity and mechanical strength. Films with confirmed multilayer architecture were indicated as a promising material for the multifunctional systems development for buccal drug delivery. They were also characterized by improved thermal stability as compared to the single polymers and their physical mixtures, most probably as a result of the CS-LM PC interactions. This also might indicate the potential protective effect on the active substances being incorporated in the PEC-based films.

Examination of Effective Buccal Absorption of Salmon Calcitonin Using Cell-Penetrating Peptide-Conjugated Liposomal Drug Delivery System.

INTRODUCTION: 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.

Polyelectrolyte Multilayer Films as a Potential Buccal Platform for Drug Delivery.

The goal of this research was to study the potential of polyelectrolyte multilayers as buccal dosage forms for drug delivery and to investigate how the properties of the drugs impact the overall performance of the delivery system. Multilayer films based on the polyelectrolyte interaction between casein and chitosan were developed using benzydamine, tolfenamic acid and betahistine as model drugs. The samples were characterized for surface pH, moisture content and moisture absorption, swelling behavior and mucoadhesion. Additionally, surface morphology was investigated, as well as the drugs' physical state after incorporation in the multilayer films. The samples proved to be non-irritant (pH was within the physiological range), physically stable (moisture content and moisture absorption below 5%) and mucoadhesive, adsorbing from 60 to 70% mucin. The release behavior corelated to the swelling index profiles of the samples and was strongly dependent on the drug solubility. The developed multilayer films appeared to be an optimum delivery system for sparingly soluble drugs due to the high drug loading achieved.

Development of mucoadhesive modified kappa-carrageenan/pectin patches for controlled delivery of drug in the buccal cavity.

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.

Influence of additives on swelling and mucoadhesion properties of glyceryl monooleate liquid crystals

Abstract Liquid crystalline systems of glyceryl monooleate/water are used as drug delivery systems due to their complex structure that controls drug diffusion. Mucoadhesive properties of glyceryl monooleate suggest it can be used for buccal delivery. Using additives is a strategy to modify physical and chemical properties of liquid crystalline systems and optimize their performance as a drug delivery system. However, the presence of additives can significantly alter properties such as phase behavior, swelling and mucoadhesion. Our aim is to investigate the influence of additives on swelling and mucoadhesion of glyceryl monooleate-based liquid crystals, intending them to be used as buccal drug delivery systems. The systems were characterized regarding their mesophases, swelling rate, and mucoadhesion. All the systems studied were able to absorb water and presented mucoadhesion, which is interesting for the development of buccal drug delivery systems. Additives induced phase transitions and affected the swelling performance, while mucoadhesive properties were poorly affected. Propylene glycol increased water uptake, while oleic acid induced the phase transition to the hexagonal phase and reduced the swelling rate. The association of oleic acid (5%) and propylene glycol (10%) resulted in a cubic phase system with strong mucoadhesive properties that can be a potential drug carrier for buccal delivery.

High-Payload Buccal Delivery System of Amorphous Curcumin-Chitosan Nanoparticle Complex in Hydroxypropyl Methylcellulose and Starch Films.

Oral delivery of curcumin (CUR) has limited effectiveness due to CUR's poor systemic bioavailability caused by its first-pass metabolism and low solubility. Buccal delivery of CUR nanoparticles can address the poor bioavailability issue by virtue of avoidance of first-pass metabolism and solubility enhancement afforded by CUR nanoparticles. Buccal film delivery of drug nanoparticles, nevertheless, has been limited to low drug payload. Herein, we evaluated the feasibilities of three mucoadhesive polysaccharides, i.e., hydroxypropyl methylcellulose (HPMC), starch, and hydroxypropyl starch as buccal films of amorphous CUR-chitosan nanoplex at high CUR payload. Both HPMC and starch films could accommodate high CUR payload without adverse effects on the films' characteristics. Starch films exhibited far superior CUR release profiles at high CUR payload as the faster disintegration time of starch films lowered the precipitation propensity of the highly supersaturated CUR concentration generated by the nanoplex. Compared to unmodified starch, hydroxypropyl starch films exhibited superior CUR release, with sustained release of nearly 100% of the CUR payload in 4 h. Hydroxypropyl starch films also exhibited good payload uniformity, minimal weight/thickness variations, high folding endurance, and good long-term storage stability. The present results established hydroxypropyl starch as the suitable mucoadhesive polysaccharide for high-payload buccal film applications.

Micellar buccal film for safe and effective control of seizures: Preparation, in vitro characterization, ex vivo permeation studies and in vivo assessment.

The current research article focused on formulating an easily applied, water-based buccal film loaded with the antiepileptic drug, lamotrigine (LTG). The designed film can be comfortably administered by epileptic patients to ensure a controllable therapeutic efficacy against seizures. The solubility of LTG in water was significantly improved by micellar solubilization. Upon testing several surfactants, three of them (Synperonic PE/P84, Brij L23, and Brij 78) achieved maximum possible solubility for LTG and were characterized for their micellar size, cloud point, and % transmittance. Selected micellar systems were incorporated within a buccal film prepared using solvent casting method based on either gelatin or polyvinylpyrrolidone (3%w/v) with 1.5%w/v propylene glycol as a plasticizer. Different micellar films were characterized for their physicochemical characteristics, swelling index, folding endurance, drug content uniformity, and in vitro LTG release. From the tested formulations, one formulation; LTG-BF1 (in which Brij 78 was used for the micellar solubilization and gelatin as the matrix former), was selected as the optimum and extensively studied for mucoadhesion, ex vivo permeation studies by Franz diffusion cells and confocal laser scanning microscopy. Results showed superior enhanced permeation of micellar film. LTG-BF1 was evaluated for the in vivo performance using rats. Status epilepticus was induced in rats by injecting Pentylenetetrazol (PTZ) i.p. at an initial dose of 30 mg/kg, followed by 10 mg/kg every10 min till 60 min. A group of rats receiving the designed buccal formulation (20 mg/kg) was compared with a group receiving the same dose of the oral market product and the normal control and PTZ groups. Rats receiving LTG-BF1 recorded reduced seizure scores at all stages, longer latency time, and higher threshold PTZ dose compared to PTZ and market product groups. In addition, LTG-BF1 reduced brain concentrations of TNF-α and TGF-ß with an elevation of EAAT2 and GABA brain contents compared to PTZ and market product groups and ameliorated neuronal damage. In conclusion, LTG-loaded buccal micellar film proved a superior antiepileptic effect in PTZ induced acute epileptic model.

Facilitated Buccal Insulin Delivery via Hydrophobic Ion-Pairing Approach: In vitro and ex vivo Evaluation.

BACKGROUND: 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.

Current Status of Mucoadhesive Gel Systems for Buccal Drug Delivery.

BACKGROUND: Buccal drug delivery is a fascinating research field. Gel-based formulations present potent characteristics as buccal systems since they have great physicochemical properties. METHODS: Among the various gels, in situ gels are viscous colloidal systems consisting of polymers; when physiological conditions change (pH, temperature, ion activation), they are transformed into the gel phase. These systems can improve bioavailability. Other systems, such as nanogels or emulgels can also be applied for buccal delivery with promising results. Polymeric gel-based systems can be produced by natural, semisynthetic, and synthetic polymers. Their main advantage is that the active molecules can be released in a sustained and controllable manner. Several gels based on chitosan are produced for the entrapment of drugs demonstrating efficient retention time and bioavailability due to chitosan mucoadhesion. Besides polysaccharides, poloxamers and carbopol are also used in buccal gels due to their high swelling ability and reversed thermal gelation behavior. RESULTS: Herein, the authors focused on the current development of mucoadhesive gel systems used in buccal drug delivery. After explaining buccal drug delivery and mucoadhesion, various studies with hydrogels, in situ gels, and nanogels were analyzed as buccal gel systems. Various mucoadhesive gel studies with mucoadhesive polymers have been studied and summarized. This review is presented as valuable guidance to scientists in formulating buccal mucoadhesive drug delivery systems. CONCLUSION: This review aimed to assist researchers working on buccal drug delivery by summarizing buccal drug delivery, mucoadhesion, and buccal mucoadhesive gel systems recently found in the literature.

Development and characterization of thermopressed polyvinyl alcohol films for buccal delivery of benznidazole.

Given that oral preparations of benznidazole (BZN) have demonstrated limited efficacy in the treatment of Chagas' disease due to pharmacokinetic or toxicological problems, the development of buccal polymeric films was purposed in this study. These systems ensure high patient acceptability and direct access to the systemic circulation, improving drug bioavailability and toxicological profile. Polymer films were prepared through a thermopressing method by mixing BZN and polyvinyl alcohol (PVAL). In some preparations, propylene glycol (PG) and thymol (TM) were also included as plasticizer and chemical absorption enhancer, respectively. Morphology, X-ray diffraction, spectroscopic, thermal, mechanical, and water uptake properties, as well as ex vivo permeability studies, were performed to characterize the film formulations. BZN remained stable and in an amorphous form over 90 days. The addition of PG and TM improved the mechanical properties of the films, making them soft, flexible and tear-resistant. Also, these additives increased the water sorption rate of the films at 50 and 75% relative humidity and the TM increased the film erosion properties and drug permeability (close to 6×) compared to control. It was hypothesized that the permeability improvement of thymol-based films that follow a drug release profile through erosion is also associated with the inhibition of the crystallization of BNZ when the film is in contact with the buccal mucosa. Once the thymol has previously demonstrated a significant in vivo and in vitro trypanocidal action and even improved film characteristics, these systems may be considered promising for Chagas' disease treatment.

In Vitro and Ex Vivo Evaluation of Penetratin as a Non-invasive Permeation Enhancer in the Penetration of Salmon Calcitonin through TR146 Buccal Cells and Porcine Buccal Tissues.

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.

Biopolymer Substrates in Buccal Drug Delivery: Current Status and Future Trend.

BACKGROUND: This paper provides a critical review of biopolymer-based substrates, especially the cellulose derivatives, for their application in buccal drug delivery. Drug delivery to the buccal mucous has the benefits of immobile muscle, abundant vascularization and rapid recovery, but not all the drugs can be administered through the buccal mucosa (e.g., macromolecular drugs), due to the low bioavailability caused by their large molecular size. This shortfall inspired the rapid development of drug-compounding technologies and the corresponding usage of biopolymer substrates. METHODS: Cellulose derivatives have been extensively developed for drug manufacturing to facilitate its delivery. We engaged in structured research of cellulose-based drug compounding technologies. We summarized the characteristic cellulose derivatives which have been used as the biocompatible substrates in buccal delivery systems. The discussion of potential use of the rapidly-developed nanocellulose (NC) is also notable in this paper. RESULTS: Seventy-eight papers were referenced in this perspective paper with the majority (sixty-five) published later than 2010. Forty-seven papers defined the buccal drug delivery systems and their substrates. Fifteen papers outlined the properties and applications of cellulose derivatives. Nanocellulose was introduced as a leading edge of nanomaterial with sixteen papers highlighted its adaptability in drug compounding for buccal delivery. CONCLUSION: The findings of this perspective paper proposed the potential use of cellulose derivatives, the typical kind of biopolymers, in the buccal drug delivery system for promoting the bioavailability of macromolecular drugs. Nanocellulose (NC) in particular was proposed as an innovative bio-binder/carrier for the controlled-release of drugs in buccal system.

Design and Evaluation of pH-Dependent Nanosystems Based on Cellulose Acetate Phthalate, Nanoparticles Loaded with Chlorhexidine for Periodontal Treatment.

This work aimed to develop and evaluate pH-dependent systems based on nanospheres (NSphs) and nanocapsules (NCs) loaded with chlorhexidine (CHX) base as a novel formulation for the treatment of periodontal disease. Cellulose acetate phthalate (CAP) was employed as a pH-dependent polymeric material. The NSphs and NCs were prepared using the emulsion-diffusion technique and then characterized according to encapsulation efficiency (EE), size, zeta-potential, morphology, thermal properties, release profiles and a preliminary clinical panel test. The formulations showed 77% and 61% EE and 57% and 84% process efficiency (PE), respectively. Both systems were spherical with an average size of 250-300 nm. Differential scanning calorimetry (DSC) studies showed that the drug has the potential to be dispersed molecularly in the NSph matrix or dissolved in the oily center of the NCs. The CHX release test revealed that the release of NSphs-CHX follows Fickian diffusion involving diffusion-erosion processes. The NCs showed a slower release than the NSphs, following non-Fickian diffusion, which is indicative of anomalous transport. These nanosystems may, therefore, be employed as novel formulations for treating periodontal disease, due to (1) their coverage of a large surface area, (2) the controlled release of active substances at different pH, and (3) potential gingival tissue infiltration.

A preliminary study for the development and optimization by experimental design of an in vitro method for prediction of drug buccal absorption.

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 (Papp) 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 (Papp) 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 Papp 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.

Development of Triamcinolone Acetonide-Loaded Nanostructured Lipid Carriers (NLCs) for Buccal Drug Delivery Using the Box-Behnken Design.

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.

Buccal administration of mucoadhesive blend films saturated with propranolol loaded nanoparticles.

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.