Fabrication and Characterization of Pectin Films Containing Solid Lipid Nanoparticles for Buccal Delivery of Fluconazole.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Design of nanoparticle-based systems for the systemic delivery of chemotherapeutics: Alternative potential routes via sublingual and buccal administration for systemic drug delivery.

Conventional therapeutic approaches for cancer generally involve chemo- and radiation therapies that often exhibit low efficacy and induce toxic side effects. Recent years have seen significant advancements in the use of protein biologics as a promising alternative treatment option. Nanotechnology-based systems have shown great potential in providing more specific and targeted cancer treatments, thus improving upon many of the limitations associated with current treatments. The unique properties of biomaterial carriers at the nanoscale have been proven to enhance both the performance of the incorporated therapeutic agent and tumor targeting; however, many of these systems are delivered intravenously, which can cause hazardous side effects. Buccal and sublingual delivery systems offer an alternative route for more efficient delivery of nanotechnologies and drug absorption into systemic circulation. This review concentrates on emerging buccal and sublingual nanoparticle delivery systems for chemo- and protein therapeutics, their development, efficacy, and potential areas of improvement in the field. Several factors contribute to the development of effective buccal or sublingual nanoparticle delivery systems, including targeting efficiency of the nanoparticulate carriers, drug release, and carrier biocompatibility. Furthermore, the potential utilization of buccal and sublingual multilayer films combined with nanoparticle chemotherapeutic systems is outlined as a future avenue for in vitro and in vivo research.

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.

Boosting systemic absorption of peptides with a bioinspired buccal-stretching patch.

Biopharmaceuticals, including proteins and peptides, have revolutionized the treatment of a wide range of diseases, from diabetes and cardiovascular disorders to virus infections and cancer. Despite their efficacy, most of these macromolecular drugs require parenteral administration because of their high molecular weight and relative instability. Over the past 40 years, only a few oral peptide drugs have entered clinical trials, even when formulated with substantial amounts of permeation enhancers. To overcome the epithelial barrier, devices that inject drugs directly into the gastrointestinal mucosa have been proposed recently. However, the robustness and safety of those complex systems are yet to be assessed. In this study, we introduced an innovative technology to boost drug absorption by synergistically combining noninvasive stretching of the buccal mucosa with permeation enhancers. Inspired by the unique structural features of octopus suckers, a self-applicable suction patch was engineered, enabling strong adhesion to and effective mechanical deformation of the mucosal tissue. In dogs, this suction patch achieved bioavailability up to two orders of magnitude higher than those of the commercial tablet formulation of desmopressin, a peptide drug known for its poor oral absorption. Moreover, systemic exposure comparable to that of the approved oral semaglutide tablet was achieved without further optimization. Last, a first-in-human study involving 40 healthy participants confirmed the dosage form's acceptability, thereby supporting the clinical translatability of this simple yet effective platform technology.

Pediatric and Geriatric-Friendly Buccal Foams: Enhancing Omeprazole Delivery for Patients Encountering Swallowing Difficulties.

Buccal foams containing omeprazole (OME) have been developed as potential drug delivery systems for individuals encountering swallowing difficulties, particularly pediatric and geriatric patients. The buccal foams were formulated from lyophilized aqueous gels of maltodextrin, used as a sweetener, combined with various polymers (alginate, chitosan, gelatin, tragacanth) to fine tune their structural, mechanical, and physicochemical properties. Consistent with the requirements for efficient drug delivery across buccal epithelium, the foam comprised of hydroxypropyl methylcellulose and alginate (HPMC-Alg-OME), exhibited moderate hardness and high mucoadhesion resulting to prolonged residence and increased transport of the active across porcine epithelium. The HPMC-Alg-OME foam induced a 30-fold increase in the drug's apparent permeability across porcine buccal tissue, compared to the drug suspension. The developed buccal foams exhibited excellent stability, as evidenced by the unchanged omeprazole content even after six months of storage under ambient conditions (20 °C and 45% RH). Results indicate that buccal foams of omeprazole may address the stability and ease of administration issues related to oral administration of the drug, particularly for children and elderly patients who have difficulty swallowing solid dosage forms.

Metoclopramide loaded buccal films for potential treatment of migraine symptoms: in vitro and in vivo study.

OBJECTIVE: Developing mucoadhesive buccal films loaded with metoclopramide for the treatment of migraine-associated vomiting. METHODS: Buccal films were prepared using the solvent casting method. Several tests were conducted, including measurement of film weight, thickness, drug content, moisture uptake, swelling index, and DSC analysis. The bioadhesion properties were also assessed. Furthermore, in vitro release profiles and in human bioavailability were studied. RESULTS: The developed films were transparent, homogeneous, and easy to remove. Film weight and thickness increased with higher drug content. The drug entrapment exceeded 90%. Film weight increased with moisture uptake, and DSC analysis indicated the absence of drug crystallinity. Bioadhesion properties and swelling index decreased with increasing drug content. In vitro release demonstrated that drug release depended on the drug-polymer ratio. The in vivo study showed significant improvements in Tmax (from 1.21 ± 0.33 to 0.50 ± 0.0) and Cmax (from 45.29 ± 14.66 to 63.27 ± 24.85) compared to conventional tablets. CONCLUSION: The prepared mucoadhesive buccal films exhibited the desired characteristics and demonstrated enhanced drug absorption, evidenced by the significantly reduced Tmax and increased Cmax compared to conventional tablets. The results indicate the successful achievement of the study objectives in selecting and designing an effective pharmaceutical dosage form. as cm2.

Development of a buccal in vitro permeation method - exploring aQbD implementation.

The buccal mucosa is arising within the pharmaceutical landscape as an attractive option for local and systemic drug delivery, mostly due to its high vascularization, inherent permeability and robustness. Still, one of the major challenges in bringing oromucosal preparations to market remains the accurate evaluation of permeability. During pre-clinical drug development, in vitro permeation assessment is essential, and methodologies, based on the selection of a proper membrane in a diffusion cell, have become appealing alternatives to the conventional cell-based models. The development of such methods is being constrained by the number of variables - related to study conditions, setup and formulation - that need to be optimized to accurately estimate buccal permeation. The gap of knowledge over the mentioned variables may lead to long costly developments and poorly accurate methods, especially if the empirical analytical approach is used. In this paper, a systematic risk-based analytical quality by design approach was applied to the development of a buccal in vitro permeation method, ensuring that all sources of variability affecting permeation process were identified, explained and managed by appropriate measures. Researchers are guided through a step by step model, successfully demonstrating with experimental data the impact of critical variables on method's performance.

Formulation and characterization of pramipexole containing buccal films for using in Parkinson's disease.

Parkinson's disease (PD) is neurodegenerative chronic illness which affects primarily the elderly over 45 years of age. The symptoms can be various, both non-motor and motor symptoms can appear. The biggest problem in the treatment of the disease is the difficulty in swallowing for the patients. However, buccal patches can solve this problem because the patients do not have to swallow the dosage form, and during application, the API can absorb from the area of the buccal mucosa quickly without causing a foreign body sensation. In our present study, we focused on the development of buccal polymer films with pramipexole dihydrochloride (PR). Films with different compositions were formulated and their mechanical properties and chemical interactions were investigated. The biocompatibility of the film compositions was examined on the TR146 buccal cell line. The permeation of PR was also monitored across the TR146 human cell line. It can be stated that the plasticizer can enhance the thickness and the breaking hardness of the films, while not decreasing their mucoadhesivity significantly. All formulations proved to have cell viability higher than 87%. Finally, we found the best composition (3% SA+1% GLY-PR-Sample1) which can be applied on the buccal mucosa in the treatment of PD.

Candesartan exhibits low intrinsic permeation capacity and affects buccal tissue viability and integrity: An ex vivo study in porcine buccal mucosa.

Candesartan is a nonpeptide angiotensin II receptor blocker that selectively binds to angiotensin II receptor subtype 1. It is administered orally in its ester form (candesartan cilexetil). However, its poor aqueous solubility results in its low bioavailability; therefore, other routes of administration must be explored. The buccal mucosa has been extensively studied as an alternative route for drug delivery as it improves the bioavailability of drugs administered via the peroral route. Porcine buccal mucosa has been widely used as an ex vivo model to study the permeability of various diffusants; however, studies on candesartan are limited. This study aimed to evaluate the ex vivo permeation profile of candesartan and its effects on the viability and integrity of porcine buccal mucosa. Initially, we evaluated the viability, integrity, and barrier function of the buccal tissue before performing permeability tests using freshly excised tissues or tissues after 12 h of resection. Here, three indicators were used: caffeine, ß-estradiol, and FD-20 penetration; mucosal metabolic activity, as determined using MTT reduction assay; and haematoxylin and eosin staining. Our results indicated that the porcine buccal mucosa preserved its viability, integrity, and barrier function before the permeation assay, allowing the passage of molecules with a molecular mass of less than 20 kDa, such as caffeine, but not ß-estradiol and FD-20. Furthermore, we analyzed the intrinsic capacity of candesartan to diffuse through the fresh porcine buccal mucosa under two pH conditions. The concentration of candesartan in the receptor chamber of Franz diffusion cell was quantified using ultra-high liquid chromatography. In the permeation assay, candesartan exhibited a low intrinsic permeation capacity that impacted the buccal tissue viability and integrity, suggesting that using the buccal mucosa as an alternative route of administration requires developing a pharmaceutical formulation that reduces the adverse effects on mucosa and increasing the buccal permeability of candesartan.

Chitosan-based buccal mucoadhesive patches to enhance the systemic bioavailability of tizanidine.

Tizanidine hydrochloride (TZN) is a muscle relaxant used to treat a variety of disorders such as painful muscle spasms and chronic spasticity. TZN has low oral bioavailability due to extensive first-pass metabolism and is used orally at a dose of 6-24 mg per day. In the present study, buccal patches were prepared by solvent casting method using chitosan glutamate (Chi-Glu) and novel chitosan azelate (Chi-Aze) which was synthesised in-house for the first time, to enhance the bioavailability of TZN by bypassing first-pass metabolism. The characterisation, mucoadhesion and drug release studies were performed. Chi-Aze patches retained their integrity longer in the buccal medium and showed higher ex vivo drug permeability compared to that prepared with Chi-Glu. In vivo studies revealed that buccal formulation fabricated with Chi-Aze (3%) showed approx 3 times more bioavailability than the orally administered commercial product. Results of the studies indicate that Chi-Aze, prepared by conjugation of chitosan and a fatty acid, the patch formulation is a promising buccal mucoadhesive system due to the physical stability in buccal medium, the good mucoadhesiveness and the high TZN bioavailability. Moreover, Chi-Aze patch might be an alternative to oral formulations of TZN to reduce the dose and frequency of drug administration.

Mucoadhesive buccal tablet of leuprolide and its fatty acid conjugate: Design, in vitro evaluation and formulation strategies.

This study aimed to design mucoadhesive buccal tablets of leuprolide (LEU) and to manufacture and evaluate the properties of buccal tablets containing LEU-oleic acid conjugate (LOC) and self-assembled LEU-oleic acid nanoparticles (LON), which were developed in a previous study. Hydroxypropyl methylcellulose (HPMC 4000) was used as the mucoadhesive polymer, and tablets were prepared by direct compression. The formulations were characterized by weight, content uniformity, thickness, hardness, swelling index, disintegration time, mucoadhesion time, and drug release. The chosen formulation maintained an adhesion time of up to 6.43 h and a disintegration time of 4.10 h. Drug stability in the mucoadhesive tablets was confirmed after 2 h of storage in human mimic saliva (Phosphate buffer solution pH 6.8). Furthermore, the designed LEU formulation and the LOC and LON developed in a previous study were prepared as buccal tablets and compared. In the dissolution and permeation studies, LON-loaded buccal tablets showed the highest permeation rate. This study suggests that mucoadhesive buccal tablets containing self-assembled LON may effectively increase the medication adherence for pediatric and geriatric patients by improving the bioavailability and permeation rate of LEU.

Buccal delivery of small molecules and biologics: Of mucoadhesive polymers, films, and nanoparticles - An update.

Buccal delivery of small and large molecules is an attractive route of administration that has been studied extensively over the past few decades. This route bypasses first-pass metabolism and can be used to deliver therapeutics directly to systemic circulation. Moreover, buccal films are efficient dosage forms for drug delivery due to their simplicity, portability, and patient comfort. Films have traditionally been formulated using conventional techniques, including hot-melt extrusion and solvent casting. However, newer methods are now being exploited to improve the delivery of small molecules and biologics. This review discusses recent advances in buccal film manufacturing, using the latest technologies, such as 2D and 3D printing, electrospraying, and electrospinning. This review also focuses on the excipients used in the preparation of these films, with emphasis on mucoadhesive polymers and plasticizers. Along with advances in manufacturing technology, newer analytical tools have also been used for the assessment of permeation of the active agents across the buccal mucosa, the most critical biological barrier and limiting factor of this route. Additionally, preclinical and clinical trial challenges are discussed, and some small molecule products already on the market are explored.

Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action.

The highly effective phosphodiesterase type 5 inhibitor (avanafil; AVA) is routinely prescribed to treat erectile dysfunction. The drug has poor oral bioavailability and undergoes a significant first-pass metabolism. Therefore, altering AVA's solubility and choosing a different delivery method may boost its effectiveness. Nine different solid dispersion formulations utilizing polyvinylpyrrolidone (PVP) at three different ratios were prepared and characterized. The Box-Behnken design was employed to optimize AVA-buccal tablets. The pre-compression and post-compression characteristics of the tablets were assessed. The mucoadhesion strength of the optimized tablet was investigated using cow buccal mucosal tissue. In vivo performance of the optimized tablets was examined on human volunteers compared to the commercial tablets. PVP K90 at 2:1 drug to polymer ratio showed the highest solubilization capacity. The mucoadhesive polymer type and percentage and the mucopenetration enhancer percentage were significantly affect the mucoadhesion strength, tablet hardness, and the initial and cumulative AVA released from the prepared tablets. The optimized AVA-buccal tablet showed 4.96 folds increase in the mean residence time, higher plasma exposure, and an improvement in the relative bioavailability of AVA by 1076.27% compared with the commercial tablet. Therefore, a successful approach to deal with AVA first-pass metabolism and low bioavailability could be to employ buccal tablets containing a solubility-enhanced form of AVA.

Predicting tolerability of high-dose fentanyl buccal tablets in cancer patients.

BACKGROUND & AIMS: Fentanyl buccal tablets (FBTs) are a rapid-onset opioid indicated for breakthrough cancer pain (BTcP) and FBT titration is needed to optimize BTcP management. We aimed to predict which patients could tolerate a high dose of FBT (400 µg or more at a time). METHODS: A retrospective analysis was performed to assess the final FBT dose. The final FBT doses were compared according to the clinical features. The prediction accuracy of patients tolerant of 400 µg or higher FBT was compared using the area under the receiver operating characteristic (ROC) curves. A risk scoring model based on the odds ratio (OR) was developed from the final multivariable model, and patients were assigned into two groups: low tolerance (0-1 point) and high tolerance (2-3 points). RESULTS: Among 131 patients, the most frequently effective dose of FBT was 200 µg (54%), followed by 100 µg (30%). The median value of morphine equivalent daily doses (MEDD) was 60 mg/day, and the most common daily use was 3-4 times/day. In multivariable analysis, male sex, younger age, and use of FBTs three or more times per day were independently associated with high-dose FBT. According to the risk scoring model, the patients with a final FBT of 400 µg or higher were significantly more in the high tolerance group (17%) compared to the low tolerance group (3%; p = 0.023). CONCLUSIONS: According to the dose relationship between the final FBT dose and the clinical features, three factors (sex, age, daily use of FBT) were independently associated with the final dose of FBT. Our risk score model could help predict tolerance to high-dose FBT and guide the titration plan for BTcP.

Mucoadhesive chitosan- and cellulose derivative-based nanofiber-on-foam-on-film system for non-invasive peptide delivery.

Oromucosal administration is an attractive non-invasive route. However, drug absorption is challenged by salivary flow and the mucosa being a significant permeability barrier. The aim of this study was to design and investigate a multi-layered nanofiber-on-foam-on-film (NFF) drug delivery system with unique properties and based on polysaccharides combined as i) mucoadhesive chitosan-based nanofibers, ii) a peptide loaded hydroxypropyl methylcellulose foam, and iii) a saliva-repelling backing film based on ethylcellulose. NFF displays optimal mechanical properties shown by dynamic mechanical analysis, and biocompatibility demonstrated after exposure to a TR146 cell monolayer. Chitosan-based nanofibers provided the NFF with improved mucoadhesion compared to that of the foam alone. After 1 h, >80 % of the peptide desmopressin was released from the NFF. Ex vivo permeation studies across porcine buccal mucosa indicated that NFF improved the permeation of desmopressin compared to a commercial freeze-dried tablet. The findings demonstrate the potential of the NFF as a biocompatible drug delivery system.

Water-soluble chitosan eases development of mucoadhesive buccal films and wafers for children.

Oromucosal films and wafers are user-friendly solid dosage forms offering easy and convenient administration, as well as rapid or controlled drug delivery. The aim of this study was to develop prednisolone containing child-friendly chitosan-based mucoadhesive films and wafers with a prolonged residence time on the buccal mucosa. Four different chitosan types (different molecular weights, degree of deacetylation (DDA), pattern of deacetylation) were studied for films prepared by solvent-cast-evaporation and wafers by freeze-drying. Mucoadhesive properties correlated with swelling abilities and were dependent on the chitosan type, the solvent, and the preparation method. Mucoadhesive forces were higher for formulations containing chitosan with higher DDA and for wafers compared to films. The drug release was relatively fast, especially for films (approx. 90 % in 15 minutes) and steadier for wafers (90 % in 45-120 minutes). Permeability was evaluated using artificial membranes and HT29-MTX cell-monolayers. The developed formulations exhibited good biocompatibility. Organoleptic properties can be improved by choosing a homogenously deacetylated chitosan type that provides a more neutral pH. Using hydroxypropyl-beta-cyclodextrin-complexation for taste masking of bitter drugs also reduced wafers' drug release rate. Mucoadhesive wafers are promising alternatives to films with a slower drug release rate and stronger mucoadhesion.

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.

Oromucosal delivery of macromolecules: Challenges and recent developments to improve bioavailability.

Owing to their biological diversity, high potency, good tolerability, low immunogenicity, site-specific activity, and great efficacy, macromolecular drugs (i.e., proteins and peptides, antibodies, hormones, nucleic acids, vaccines, etc.) are extensively used as diagnostics, prophylactics, and therapeutics in various diseases. To overcome drawbacks associated with parenteral (invasive) delivery of macromolecules as well as to preserve their therapeutic integrity, oromucosal route (sublingual and buccal) has been proven efficient alternate port of delivery. This review aims to summarize challenges associated with oromucosal route and overtime developments in conventional delivery systems with special emphasis on most recent delivery strategies. Over the past few decades, significant efforts have been made for improving the oromucosal absorption of macromolecules by employing chemical penetration enhancers (CPE), enzyme inhibitors, chemical modification of drug structure (i.e., lipidation, PEGylation, etc.), and mucoadhesive materials in the form of buccal tablets, films (or patches), sprays, fast disintegrating tablets, and microneedles. Adaptation of adjunct strategies (e.g., iontophoresis in conjunction with CPE) has shown significant improvement in oromucosal absorption of macromolecules; however, these approaches were also associated with many drawbacks. To overcome these shortcomings and to further improve therapeutic outcomes, specialized delivery devices called "hybrid nanosystems" have been designed in recent times. This newer intervention showed promising potential for promoting oromucosal absorption and absolute bioavailability of macromolecules along with improved thermostability (cold chain free storage), enabling self-administration, site-specific activity, improving therapeutic efficacy and patient compliance. We anticipate that tailoring of hybrid nanosystems to clinical trials as well as establishing their short- and long-term safety profile would substantiate their therapeutic value as pharmaceutical devices for oromucosal delivery of macromolecules.

Hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films with excellent mechanical properties and high bioavailability for buccal delivery.

Mucoadhesive buccal films (MBFs) become the most promising buccal mucosal delivery system duo to its advantageous properties, including simple preparation technique and better patient compliance. The mechanical properties and mucoadhesion of MBFs are crucial in their successful performance as well as manufacturing and administration. In this study, we prepared hollow mesoporous silica nanoparticles-loaded ion-crosslinked bilayer films (CCS-PVA-TPP-FSM@HMSNs) using carboxymethyl chitosan (CCS) and polyvinyl alcohol (PVA) for buccal delivery of furosemide (FSM). The FSM-loaded hollow mesoporous silica nanoparticles (FSM@HMSNs) were firstly characterized by SEM, TEM, and nitrogen adsorption/desorption. Then, we constructed an ion-crosslinked network using CCS and PVA employed with the solution casting method, and sodium tripolyphosphate (TPP) was used as a hydrogen bond crosslinking agent. The formulation was optimized through Box-Behnken design, where the impact of the proportion of the ingredients on the quality of the films was evaluated entirely. Herein, folding endurance, swelling, tensile strength, and adhesion force were selected as response variables. Morphology, mechanical, spectroscopic, thermal, and safety of CCS-PVA-TPP-FSM@HMSNs films were also investigated. The release and permeability behaviors of CCS-PVA-TPP-FSM@HMSNs films were evaluated by in vitro drug release, across isolated porcine buccal and TR146 cell model. The CCS-PVA-TPP-FSM@HMSNs films showed outstanding mechanical properties, suitable bioadhesion, high drug loading, significant sustained-release properties, and improved permeability. In pharmacokinetic study with golden hamster models, the relative bioavailability was increased by 191.54%, and the absolute bioavailability was 82.20%. In summary, this study provides evidence that this innovative CCS-PVA-TPP-FSM@HMSNs films could be a promising and industrialized buccal drug delivery system.