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Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer’s disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.

Dry powder inhalation offers a well-established administration route for either local or systemic drug delivery. Lactose-based powder blends still build the basis of respiratory drug delivery, despite of numerous emerging formulation approaches. The amount of fine lactose excipients, either extrinsic or intrinsic, crucially influences the aerodynamic performance of the corresponding blend. This study highlights the role of intrinsic fines as a fundamental performance affecting parameter during storage and expiry of lactose carrier bulk. We showed that intrinsic fines play an inferior role after expiring compared to fresh batches. If strongly adhering or even merged fines regain their mobility and contribute to the dispersion (by removal and re-addition), it will significantly enhance drug delivery. Furthermore, we provide evidence for decreased mobility of intrinsic fines caused by humidity (e.g., during inappropriate storage) resulting in decreased powder fluidisation.

Fungal β-glucans are compounds with the potential to activate the innate immune system, in part through binding to the receptor dectin-1. In the present study, small-scale methods for preparing dectin-1a binding microparticles from Albatrellus ovinus alkali-soluble β-glucans were investigated. Mechanical milling was time-consuming and yielded large particles with wide size distributions. Precipitation was more successful: the β-glucan was dissolved in 1 M NaOH, diluted, and precipitated in 1:1 mol equiv HCl. This yielded particles in sizes ranging from 0.5–2 μm. The dectin-1a binding activity was determined using HEK-Blue reporter cells. The prepared particles were able to bind to dectin-1a to the same extent as baker’s-yeast-derived β-glucan particles. The precipitation method was convenient as a quick method for small-scale preparation of β-glucan microparticle dispersions from mushroom β-glucans.

Purpose Membrane engineering has versatile applications in adoptive cell therapies, immune therapy or drug delivery. Incorporation of lipidated antibody-derived ligands into cells may enforce supraphysiological cell interactions that offer new therapeutic approaches. A challenge is the defined synthesis of lipidated ligands that effectively interact with such membranes. Methods Sortase-A was used to attach a PEGylated, dimyristyl lipid-anchor on single-domain antibodies (VHH). The membrane insertion was investigated on liposomal bilayers, myeloid-derived suppressor cells (MDSC) and T cells. Results The lipidated VHHs remodeled liposomal as well as cellular membranes. The VHH carrying liposomes were successfully targeted towards antigen-positive cells. MDSC and T cells were both modified with lipidated VHHs as detected with an FITC-anti-llama antibody. T cells that carried an anti-CD11b VHH showed cellular association in vitro with CD11b+Gr-1+ MDSC in a two-dimensional magnetic activated cell sorting / flow-cytometry assay. Conclusion The applied combination of chemoenzymatic ligation, PEGylated lipid anchors and single-domain antibodies delivers water-soluble and chemically defined lipidated ligands, which readily associate with liposomal and cellular membranes. This enables liposomal drug targeting and artificial cell-cell interactions. Hence, the presented concept for lipidation of single-domain antibodies is promising for further application in the field of drug delivery or cell-based therapies.

Pharmaceutical tablet quality is tightly controlled to ensure the patient’s safety. Though the tableting process is a well-known and accepted approach, process understanding is frequently built upon long-time experience of the operators. This is also true for the first step in tableting, the die filling where the powder is fed from the hopper through a force feeding system into the rotating dies of the turret. The current study considers a three-chambered force feeder of a FETTE 1200i, with the focus to evaluate the influence of the paddle wheel shape, which may either be of cylindrical or cuboid shaped blades, on tablet quality. A numerical approach utilizing the discrete element method allowed to compute the powder transfer in the tablet press which helps in identifying the optimal paddle wheel shape configuration. For instance, at a low turret – high paddle wheel speed, the cylindrical configuration revealed highest quality with respect to tablet mass, tablet mass variation, and content uniformity. In contrast, the cuboid configuration indicated better quality at a high turret – low paddle wheel speed. In addition, the detailed analysis of macroscopic and microscopic powder flow phenomena within the force feeder was performed which improves general process understanding in pharmaceutical development.

Systemic drug application is the main approach in epilepsy treatment. However, the central nervous system (CNS) is a challenging target for drug delivery as the blood-brain barrier (BBB) restricts the transfer of drugs into the brain. Accordingly, there is a general interest in developing new therapeutic strategies to improve CNS drug accessibility. Intrathecal administration of antiseizure drugs (ASDs) e.g. via pumps or advanced materials could be a possible approach to bypass the BBB and increase the availability of neuroactive compounds in the CNS. The aim of this study was the evaluation of intracerebroventricular (i.c.v.) compared to systemic drug application in generalized epilepsy. The i.c.v. administration of the established ASD ethosuximide (ETX) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) caused a robust and dose-dependent reduction of spike-wave discharges (SWDs) without causing obvious behavioral abnormalities. Additionally, we could show that i.c.v. treatment with ETX is significantly more effective in seizure suppression than systemic treatment with the same dose. The localized application resulted in reduced systemic drug exposure compared to standard systemic ETX therapy. The tracing of dye distribution throughout the CNS supported the view that i.c.v. applied drugs cross into brain tissue surrounding the ventricles but largely remain restricted to the site of injection. Our data suggest that intrathecal application represents a possible route for the treatment in generalized epilepsy through direct drug penetration from CSF into brain tissue.

Additive Manufacturing (AM) comprises a variety of techniques that enable fabrication of customised objects with specific attributes. The versatility of AM procedures and constant technological improvements allow for their application in the development of medicinal products and medical devices. This review provides an overview of AM applications related to respiratory sciences. For this purpose, both fields of research are briefly introduced and the potential benefits of integrating AM to respiratory sciences at different levels of pharmaceutical development are highlighted. Tailored manufacturing of microstructures as a particle design approach in respiratory drug delivery will be discussed. At the dosage form level, we exemplify AM as an important link in the iterative loop of data driven inhaler design, rapid prototyping and in vitro testing. This review also presents the application of bioprinting in the respiratory field for design of biorelevant in vitro cellular models, followed by an overview of AM-related processes in preventive and therapeutic care. Finally, this review discusses future prospects of AM as a component in a digital health environment.

Lung tuberculosis (TB) is the most deadly infectious disease worldwide although it is treatable. High doses of antibiotics are used for therapy over a period of at least 6 months. Since in many treated patients only subtherapeutic concentrations are reached in the infected tissue of the lung, about half a million cases of multi drug resistant tuberculosis (MDR TB) occur every year. In order to increase the concentration of the active pharmaceutical ingredient (API) at the site of the primary infection, inhalation of antibiotics seems to be promising. In this study, we show the capability of softpellets, engineered dry powder agglomerates, to deliver high doses to the lungs. For this, the antibiotic rifampicin was milled and processed into softpellets which were then dispersed utilising a novel high dose dry powder inhaler, the 8Shot from Hovione Technology. Aerodynamic assessment resulted in a fine particle dose of 21.35 mg with a device retention of 15% after loading all eight chambers of the inhaler with 10 mg softpellet formulation. At the same time, we present a new process design to produce softpellets, namely vibro-pelletisation.

The combined approach of quality by design (QbD) framework and discrete element method (DEM) is applied to force feeding process within the tableting machine to assess the influence of potential critical process conditions (CPPs) and critical material attributes (CMAs) on tablet quality. The numerical model considers the three paddled force feeder of a FETTE 1200i tableting machine. The influence of the selected potential CPPs: turret speed and paddle wheels speed and CMAs: API dose strength, inter-particle cohesion, and particle-wall friction on the critical quality attributes (CQAs) tablet mass, tablet mass variation, and content uniformity are evaluated by using a fractional-factorial screening design. In addition to the CQAs, the DEM provides the opportunity to shed light on the powder flow phenomena within the force feeder thus an understanding on the impact of the paddle wheels on powder over-lubrication and particle attrition is provided. Such a combined approach of QbD and DEM helps in identifying the significance of selected CPPs and CMAs and thereby to generate the design space providing an optimal tablet quality.

High-shear mixer coatings as well as mechanofusion processes are used in the particle-engineering of dry powder inhalation carrier systems. The aim of coating the carrier particle is usually to decrease carrier–drug adhesion. This study comprises the in-depth comparison of two established dry particle coating options. Both processes were conducted with and without a model additive (magnesium stearate). In doing so, changes in the behaviour of the processed particles can be traced back to either the process or the additive. It can be stated that the coarse model carrier showed no significant changes when processed without additives. By coating the particles with magnesium stearate, the surface energy decreased significantly. This leads to a significant enhancement of the aerodynamic performance of the respective carrier-based blends. Comparing the engineered carriers with each other, the high-shear mixer coating shows significant benefits, namely, lower drug–carrier adhesion and the higher efficiency of the coating process.

Drug administration by inhalation is a well-established approach to treat respiratory and systemic diseases. To deliver a drug into the lung dry powder inhalation (DPI) is an advantageous, but yet challenging option. A variety of strategies is available for developing DPI formulations. These formulation strategies should address the present disadvantage of insufficient drug delivery and enable therapies in general or to reach new targets (e.g. mucosal vaccination). To increase therapy safety and efficacy scientists challenge the limits of technical feasibility to engineer respiratory medicines. In this review, we provide a concise overview of particle engineering as enabling formulation technique or as an optimisation approach for existing strategies in pulmonary drug delivery. It comprehensively describes different techniques for particle engineering in carrier-based blends for inhalation. This covers considerations on which attributes are beneficial for carriers, followed by methods to modify such attributes or directly manufacture the desired carriers. Furthermore, this work comprises the current state of knowledge on nanocrystal and nanoparticle production as well as other carrier-free technologies and their applications. This review is completed by a glance in the future of carrier engineering using additive manufacturing.

Nasal drug delivery has specific challenges which are distinct from oral inhalation, alongside which it is often considered. The next generation of nasal products will be required to deliver new classes of molecule, e.g. vaccines, biologics and drugs with action in the brain or sinuses, to local and systemic therapeutic targets. Innovations and new tools/knowledge are required to design products to deliver these therapeutic agents to the right target at the right time in the right patients. We report the outcomes of an expert meeting convened to consider gaps in knowledge and unmet research needs in terms of (i) formulation and devices, (ii) meaningful product characterization and modeling, (iii) opportunities to modify absorption and clearance. Important research questions were identified in the areas of device and formulation innovation, critical quality attributes for different nasal products, development of nasal casts for drug deposition studies, improved experimental models, the use of simulations and nasal delivery in special populations. We offer these questions as a stimulus to research and suggest that they might be addressed most effectively by collaborative research endeavors.

Localized therapy of the highly malignant brain tumor glioblastoma multiforme (GBM) could help to drastically improve the treatment efficiency and increase the patient’s median survival. Here, a macroscopic PDMS matrix composed of interconnected microchannels for tailored drug release and localized GBM therapy is introduced. Based on a simple bottom-up fabrication method using a highly versatile sacrificial template, the presented strategy solves the scaling problem associated with the previously developed microchannel-based drug delivery systems, which were limited to two dimensions due to the commonly employed top-down microfabrication methods. Additionally, tailoring of the microchannel density, the fraction of drug-releasing microchannels and the macroscopic size of the drug delivery systems enabled precise adjustment of the drug release kinetics for more than 10 days. As demonstrated in a long-term GBM in vitro model, the release kinetics of the exemplarily chosen GBM drug AT101 could be tailored by variation of the microchannel density and the initial drug concentration, leading to diffusion-controlled AT101 release. Adapting a previously developed GBM treatment plan based on a sequential stimulation with AT101, measured anti-tumorigenic effects of free versus PDMS-released AT101 were comparable in human GBM cells and demonstrated efficient biological activity of PDMS-released AT101.

Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.

Active targeting with ligand coated liposomal drug delivery systems is a means to increase the therapeutic index of drugs. Stable ligand coating requires bilayer anchorage of the commonly proteinaceous ligands and hence a conjugation of lipid structures towards amino acids. This often leads to heterogeneous reaction products especially when chemical coupling methods are employed. Chemoenzymatic Sortase-A mediated transpeptidation (sortagging) is a useful tool to avoid this protein heterogeneity through its site-specific, bioorthogonal ligation mechanism. Manufacturing of such sortaggable, pentaglycine modified liposomes was developed by adaption of a scalable solvent injection technique. The pentaglycine liposomes were prepared with different degrees of PEGylation and steric accessibility of the pentaglycine motif. Comparable hydrodynamic diameters (146–188 nm) of the different formulations were obtained after a flow rate screening. The sortagging reactivity of a single-domain antibody (VHH) towards the pentaglycine liposomes was strongly dependent on the steric accessibility of the pentaglycine nucleophile. Adjusting the pentaglycine to ligand ratio improved conversion rates up to 80%. The liposome bound VHH was accessible for its soluble antigen as shown by a chromatography-based binding assay. Mono- and granulocytes could be selectively targeted in vitro by conjugation of BMX1, a VHH directed towards human myeloid cell surface marker CD11b. Confocal microscopy revealed intracellular localization of the targeted liposomes. The developability of those pentaglycine liposomes as well as their proof of principle for targeted drug delivery shows their potential for further investigation, for example as delivery platform for diagnostics or drugs into the tumor microenvironment.

The quantification of lipids and assessment of lipid composition is an indispensable step during the pharmaceutical development of novel lipid based drug delivery systems such as liposomes. Broad excipient screenings of such formulations raise the need for versatile analytical methods. Even more demanding complexity is generated by introduction of targeted systems requiring functionalized lipids. We addressed this demand by developing an rp-HPLC based analytical method with evaporative light scattering detection (ELSD) for the simultaneous analysis of commonly used phosphatidylcholines, cholesterol and bilayer surface-modifying cationic, anionic or PEGylated lipids, which can be analyzed in combination with novel pentaglycine lipids suitable as targeting ligand anchor. The method was validated for specificity, precision, accuracy and sample stability. We monitor the continuous and scalable manufacturing of two pentaglycine-modified liposomal formulations and track the modification of these drug delivery systems with a single-domain antibody utilizing bioorthogonal Sortase-A technology. Both the presented analytical and preparative techniques can help to improve the quality control and to accelerate the pharmaceutical development of such targeted drug delivery systems.

The die filing process within a lab-scale rotary tablet press is simulated using the Discrete Element Method (DEM). Powder is transferred from a gravity feeder (comprising of a cylindrical pipe, an inclined chute, and a rectangular box) into rotating dies. Spherical shape micro-crystalline cellulose particles serve as an experimental pendant to measure the particle size distribution (PSD) and to calibrate the micro-mechanical material properties entering in the DEM calculations. At first, the die filling process of the particles having poly-dispersity in size is explored by analyzing the basic metrics such as tablet mass, tablet mass variation, and mass flow rate. Particle size segregation is investigated by computing the PSD development in different locations of the feeding system and in the filled dies. In addition, particles’ velocity and coloring analysis (both qualitative and quantitative) are performed. Results show that different zones of the system are involved in various powder flow phenomena constituting varying particle size segregation causes. Next, the micro-mechanical properties, namely inter-particle cohesion, particle-particle and particle-wall friction, are varied one at a time to shed light on their influence on the particle size segregation and tablet quality. Finally, the influence of different material properties on various metrics are compared with each other providing a guide towards formulation optimization resulting in optimal tableting process performance.

The focus of this study is to establish a characterization method determining the powder flowability in context of tableting. At first, flowability of different materials is measured using the ring shear tester, and its prediction from particle size is established. Next, the model die-filling system is presented which is a modified version of previous studies. Using this system, flowability of different materials is measured at varying die speeds. A new curve fit to assess die fill ratio vs die speed is suggested improving predictability, and a novel flowability metric, "Die Fill Index" (DFI), is derived. The DFI is appropriate to describe flowability for most of the tested materials, and sensitivity of a material with respect to tableting speed. A correlation is generated predicting DFI from particle size. Additionally, it is shown that model die filling is the preferable method to assess flowability for tableting compared to ring shear tester.

This study was dealing with the spray drying of tailored mannitol particles as carriers in dry powder inhalation formulations. A self-constructed spray tower equipped with a laminar rotary ...

Background: Nanoparticle imaging and tracking the release of the loaded material from the nanoparticle system have attracted significant attention in recent years. If the release of the loaded molecules could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. Methods: Here, we test a system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo from the lipid iron nanoparticle delivery system. The ICG spectral properties like its concentration dependence, sensitivity and the fluctuation of the absorption and emission wavelengths can be utilized for gathering information about the change of the ICG surrounding. Results: We have found that the absorption, fluorescence, and photoacoustic spectra of ICG in lipid iron nanoparticles differ from the spectra of ICG in pure water and plasma. We followed the ICG containing liposomal nanoparticle uptake into squamous carcinoma cells (SCC) by fluorescence microscopy and the in vivo uptake into SCC tumors in an orthotopic xenograft nude mouse model under a surgical microscope. Conclusion: Absorption and emission properties of ICG in the different solvent environment, like in plasma and human serum albumin, differ from those in aqueous solution. Photoacoustic spectral imaging confirmed a peak shift towards longer wavelengths and an intensity increase of ICG when bound to the lipids. The SCC cells showed that the ICG containing liposomes bind to the cell surface but are not internalized in the SCC-9 cells after 60 minutes of incubation. We also showed here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice.

In dry powder inhalation (DPI), larger carrier particles, typically lactose, are blended with micronised active pharmaceutical ingredient (API) particles to improve handling, processability and inhalable fraction. Alternative carrier materials were researched for years, but did not enter the market yet. In this study, a common lactose carrier for DPI formulations and a spray granulated mannitol carrier were compared to evaluate if the particle engineered mannitol can be considered a serious alternative. Blends with five different API concentrations (0.1 to 4%) were prepared with two APIs. Physical carrier and blend characterisation regarding particle size, morphology, density, shear cell testing and dosing behaviour were performed. Aerodynamic assessment was done using two different inhaler devices (one capsule-based inhaler and one reservoir-based inhaler). In addition, the influence of different flow rates was examined. Results indicated that uniform dosing in metered mass and delivered dose over this API concentration range was achieved due to good flowability of the blends. Furthermore, linear dose delivery could be seen over the added API concentrations. Impaction analysis showed that the respirable fractions of mannitol blends were comparable (for salbutamol sulphate blends) or higher (for budesonide blends) than with a standard lactose carrier.

This study aimed to characterise three nasal drug delivery devices to evaluate their propensity to deliver human insulin solutions to the nasal cavity for redistribution to the central nervous system. Brain delivery was evaluated using functional magnetic resonance imaging to measure regional cerebral blood flow. Intranasal insulin administration has been hypothesised to exploit nose-to-brain pathways and deliver drug directly to the brain tissue whilst limiting systemic exposure. Three nasal pump-actuator configurations were compared for delivery of 400 IU/mL insulin solution by measuring droplet size distribution, plume geometry, spray pattern and in vitro deposition in a nasal cast. The device with optimal spray properties for nose to brain delivery (spray angle between 30° and 45°; droplet size between 20 and 50 μm) also favoured high posterior-superior deposition in the nasal cast and was utilised in a pharmacological magnetic resonance imaging study. Functional magnetic resonance imaging in healthy male volunteers showed statistically significant decreases in regional cerebral blood flow within areas dense in insulin receptors (bilateral amygdala) in response to intranasally administered insulin (160 IU) compared to saline (control). These changes correspond to the expected effects of insulin in the brain and were achieved using a simple nasal spray device and solution formulation. We recommend that a thorough characterisation of nasal delivery devices and qualitative/quantitative assessment of the administered dose is reported in all studies of nose to brain delivery so that responses can be evaluated with respect to posology and comparison between studies is facilitated.

The design of formulations intended for inhalation is a major challenge since many different factors need consideration in order to guarantee major drug delivery. This becomes especially important in dry powder inhalation. Balanced inter-particle interactions between carrier and drug particles are key factors for an optimal aerodynamic performance. This work combines an experimental approach utilising spherical glass beads as model carrier and simulations of device properties as well as particle-particle interactions to gain deeper understanding of processes during inhalation and their effect on aerodynamic performance. Surface roughness modification of the carrier proved to influence the effective drug loading of distinct drug particles. Moreover, surface topography had a major impact on the aerodynamic performance as micron-sized indentations drastically reduced the fine particle fraction (FPF). This could be linked to their ability of sheltering drug particles from the airstream during inhalation. Nano-scale roughness on the other hand led to a significant increase of the FPF. The impact of the inhalation device itself was also taken into account. The conducted numerical calculations (CFD) have provided more insight into carrier particle transport and drug detachment in the case of carrier-based formulations. A multi-scale approach was adopted to numerically analyse the performance of inhaler devices. First, the motion of carrier particles through a swirl-type inhaler was simulated to provide information on flow stresses acting on carrier and on wall collision statistics. Fully resolved simulations of carrier covered by hundreds of drug particles in connection with measured adhesion properties showed that flow-induced drug detachment will only be possible if the van der Waals force between carrier and drug is very weak (i.e. requiring surface modification). However, in the considered swirl-type inhaler the wall collision number of carriers is quite high, being the reason for an efficient drug detachment through inertia. A developed wall collision detachment model revealed that almost 100% of the drug powder is detached within the inhaler, which does not correspond to experimental observations. Consequently, also drug powder deposition on the inhaler walls needs to be accounted for, in order to allow correct predictions of the emitted dose.

From a patient-centric perspective, oromucosal drug delivery is highly attractive due to the ease of administration without the need of swallowing, and improved patient safety. The aim of the presented work was to prepare a buccal film using a self-forming micellar drug solubiliser as the film matrix, combining it with a mucoadhesive polymer for an enhanced retention on the buccal mucosa. Specifically, we propose the use of a graft co-polymer (Soluplus®), as a solubiliser and film former, supplemented with polymers with more hydrophilic properties and known mucoadhesive properties; hydroxypropyl methylcellulose (HPMC) or modified hydroxypropyl pea starch (Lycoat®). The film was manufactured by the solvent casting method. The resulting dual polymer film containing HPMC exhibited resistance to erosion and mucoadhesive properties superior to the control films of single polymers. In an in vitro oral cavity model, these properties were shown to correlate with increased residence time on simulated oral mucosa. Furthermore, all films containing the graft co-polymer showed similar permeability characteristics of furosemide towards buccal TR146 epithelial cells. This work illustrated that it is possible to manufacture dry, solid, dual polymer films containing an advanced drug delivery system with a cheap and simple method. The combination of a graft co-polymer with a mucoadhesive polymer transform into drug solubilising micelles in a mucin-retentive hydrogel scaffold with longer retention time on buccal mucosa for safe and enhanced advanced formulation.