Shaping and enhancing resilient forests for a resilient society.

The world is currently facing uncertainty caused by environmental, social, and economic changes and by political shocks. Fostering social-ecological resilience by enhancing forests' ability to provide a range of ecosystem services, including carbon sequestration, habitat provision, and sustainable livelihoods, is key to addressing such uncertainty. However, policy makers and managers currently lack a clear understanding of how to operationalise the shaping of resilience through the combined challenges of climate change, the biodiversity crisis, and changes in societal demand. Based on a scientific literature review, we identified a set of actions related to ecosystem services, biodiversity conservation, and disturbance and pressure impacts that forest managers and policy makers should attend to enhance the resilience of European forest systems. We conclude that the resilience shaping of forests should (1) adopt an operational approach, which is currently lacking, (2) identify and address existing and future trade-offs while reinforcing win-wins and (3) attend to local particularities through an adaptive management approach.

Characterizing interregional differences in the rheological properties and composition of rat small intestinal mucus.

The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs.

Assessing acute colitis induced by dextran sulfate sodium in rats and its impact on gastrointestinal fluids.

Dextran sulfate sodium (DSS) is commonly used to induce colitis in rats. While the DSS-induced colitis rat model can be used to test new oral drug formulations for the treatment of inflammatory bowel disease, the effect of the DSS treatment on the gastrointestinal tract has not been thoroughly characterized. Additionally, the use of different markers to assess and confirm successful induction of colitis is somewhat inconsistent. This study aimed to investigate the DSS model to improve the preclinical evaluation of new oral drug formulations. The induction of colitis was evaluated based on the disease activity index (DAI) score, colon length, histological tissue evaluation, spleen weight, plasma C-reactive protein, and plasma lipocalin-2. Furthermore, the study investigated how the DSS-induced colitis affected the luminal pH, lipase activity, and concentrations of bile salts, polar lipids, and neutral lipids. For all evaluated parameters, healthy rats were used as a reference. The DAI score, colon length, and histological evaluation of the colon were effective disease indicators in DSS-induced colitis rats, while spleen weight, plasma C-reactive protein, and plasma lipocalin-2 were not. The luminal pH of the colon and bile salt- and neutral lipid concentrations in regions of the small intestine were lower in DSS-induced rats compared to healthy rats. Overall, the colitis model was deemed relevant for investigating ulcerative colitis-specific formulations.

A balancing act: Principles, criteria and indicator framework to operationalize social-ecological resilience of forests.

Against a background of intensifying climate-induced disturbances, the need to enhance the resilience of forests and forest management is gaining urgency. In forest management, multiple trade-offs exist between different demands as well as across and within temporal and spatial scales. However, methods to assess resilience that consider these trade-offs are presently lacking. Here we propose a hierarchical framework of principles, criteria, and indicators to assess the resilience of a social-ecological system by focusing on the mechanisms behind resilience. This hierarchical framework balances trade-offs between mechanisms, different parts of the social-ecological system, ecosystem services, and spatial as well as temporal scales. The framework was developed to be used in a participatory manner in forest management planning. It accounts for the major parts of the forest-related social-ecological system and considers the multiple trade-offs involved. We demonstrate the utility of the framework by applying it to a landscape dominated by Norway spruce (Picea abies (L.) Karst.) in Central Europe, managed for three different management goals. The framework highlights how forest resilience varies with the pursued management goals and related management strategies. The framework is flexible and can be applied to various forest management contexts as part of a participatory process with stakeholders. It thus is an important step towards operationalizing social-ecological resilience in forest management systems.

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.

An Evaluation of the Physicochemical Properties of Preservative-Free 0.005% (w/v) Latanoprost Ophthalmic Solutions, and the Impact on In Vitro Human Conjunctival Goblet Cell Survival.

PURPOSE: To examine the physicochemical properties of five preservative-free (PF) 0.005% latanoprost ophthalmic products; Monoprost®, Latanest®, Gaap Ofteno®, Xalmono®, and Xaloptic® Free. Furthermore, the study investigated the mucin production and cell survival of primary cultured human conjunctival goblet cells when treated with PF eye drops. METHOD: The pH value, osmolality, and surface tension were examined. Cell survival was analyzed using lactate dehydrogenase and tetrazolium dye colorimetric assays. Mucin production was analyzed with immunohistochemical staining. RESULTS: Monoprost® (pH value 6.84 ± 0.032) had a pH value closest to the pH value of tear fluid (pH value 7.4-7.6), whereas Gaap Ofteno® (pH value 6.34 ± 0.004) and Latanest® (pH value 6.33 ± 0.003) had the lowest pH values. Gaap Ofteno® (325.9 ± 2.9 mosmol/kg) showed iso-osmolar probabilities, whereas the other products were hypo-osmolar. Gaap Ofteno® (60.31 ± 0.35 mN/m) had a higher surface tension compared to the tear fluid (40 to 46 mN/m), as described in the literature. No significant differences in goblet cell survival or mucin release were observed between the treatments and control. CONCLUSION: Significant differences in pH value, osmolality, and surface tension were observed. However, this did not affect the viability of the goblet cells or the release of mucin. Clinical studies are required to evaluate the long-term effects of use on efficacy and safety.

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

PURPOSE: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics. METHODS: The effect of travoprost eye drops was evaluated on GC cultures. Cell viability was assessed through lactate dehydrogenase (LDH) and tetrazolium dye (MTT) colorimetric assays. Mucin secretion was evaluated by immunohistochemical staining. Secretion of interleukin (IL)-6 and IL-8 was measured using BD Cytometric Bead Arrays. pH, viscosity, droplet mass, osmolality and surface tension were measured for all included eye drops. RESULTS: In the LDH assay, BAK travoprost caused significant GC loss after 2 hrs of incubation compared to the control. PQ travoprost caused no GC loss at any time point. Both PQ- and BAK travoprost caused secretion of mucin to the cytoplasma. No difference in IL-6 and IL-8 secretion was identified compared to controls. The pH values for the generics were lower (pH 6.0) than the pH value for Travatan (pH 6.7; p < 0.0001). The viscosity was lowest for Travatan, while the mean droplet mass was higher for Travatan (35 mg) than the generics (28-30 mg; p ≤ 0.0318). The osmolality and surface tension did not differ between the eye drops investigated. CONCLUSION: BAK travoprost caused GC loss, indicating that PQ preservation may be preferable in treatment of glaucoma. Furthermore, physicochemical properties of branded and generic travoprost eye drops can not be assumed to be identical.

Mucoadhesive Electrospun Nanofiber-Based Hybrid System with Controlled and Unidirectional Release of Desmopressin.

The sublingual mucosa is an attractive route for drug delivery, although challenged by a continuous flow of saliva that leads to a loss of drug by swallowing. It is of great benefit that drugs absorbed across the sublingual mucosa avoid exposure to the harsh environment of the gastro-intestinal lumen; this is especially beneficial for drugs of low physicochemical stability such as therapeutic peptides. In this study, a two-layered hybrid drug delivery system was developed for the sublingual delivery of the therapeutic peptide desmopressin. It consisted of peptide-loaded mucoadhesive electrospun chitosan/polyethylene oxide-based nanofibers (mean diameter of 183 ± 20 nm) and a saliva-repelling backing film to promote unidirectional release towards the mucosa. Desmopressin was released from the nanofiber-based hybrid system (approximately 80% of the loaded peptide was released within 45 min) in a unidirectional manner in vitro. Importantly, the nanofiber-film hybrid system protected the peptide from wash-out, as demonstrated in an ex vivo flow retention model with porcine sublingual mucosal tissue. Approximately 90% of the loaded desmopressin was retained at the surface of the ex vivo porcine sublingual mucosa after 15 min of exposure to flow rates representing salivary flow.

Multi-material 3D printing of programmable and stretchable oromucosal patches for delivery of saquinavir.

Oromucosal patches for drug delivery allow fast onset of action and ability to circumvent hepatic first pass metabolism of drugs. While conventional fabrication methods such as solvent casting or hot melt extrusion are ideal for scalable production of low-cost delivery patches, these methods chiefly allow for simple, homogenous patch designs. As alternative, a multi-material direct-ink-write 3D printing for rapid fabrication of complex oromucosal patches with unique design features was demonstrated in the present study. Specifically, three print-materials: an acidic saquinavir-loaded hydroxypropyl methylcellulose ink, an alkaline effervescent sodium carbonate-loaded ink, and a methyl cellulose backing material were combined in various designs. The CO2 content and pH of the microenvironment were controlled by adjusting the number of alkaline layers in the patch. Additionally, the rigid and brittle patches were converted to compliant and stretchable patches by implementing mesh-like designs. Our results illustrate how 3D printing can be used for rapid design and fabrication of multifunctional or customized oromucosal patches with tailored dosages and changed drug permeation.

Predicting in vivo performance of fenofibrate amorphous solid dispersions using in vitro non-sink dissolution and dissolution permeation setup.

Amorphous solid dispersion (ASD) is emerging as a useful formulation strategy to increase the bioavailability of active pharmaceutical ingredients with poor solubility. In vitro dissolution testing under non-sink conditions has often been used to evaluate the ability of ASDs to generate and maintain supersaturation to predict the in vivo performance. However, such a single compartment dissolution setup can fail to predict the oral bioavailability, due to an interdependence between precipitation and permeation. Hence, the use of two compartment dissolution-permeation setups is emerging. In this study, three ASDs containing fenofibrate as model drug substance were developed using Soluplus®, and Hypromellose Acetate Succinate in two different grades (high and low), respectively. The aim was to compare the use of a small-scale in vitro non-sink dissolution setup and a small-scale in vitro dissolution-permeation setup to predict the in vivo oral exposure of the ASDs in rats. The maximum concentration (Cmax) and area under curve (AUC) obtained in the in vitro studies were used to predict the in vivo rank order of the formulations. The results showed that the two in vitro studies resulted in the same rank order based on both Cmax and AUC. Interestingly, Cmax resulted in a better in vitro/in vivo correlation than the in vitro AUC, and based on the in vitro Cmax, the in vivo rank order was predicted.

Exploration of in vitro drug release testing methods for saquinavir microenvironmental pH modifying buccal films.

Buccal films containing a pH modifying excipient may be able to increase bioavailability of drugs with pH-dependent solubility such as saquinavir. Access to suitable in vitro drug release testing methods may facilitate buccal formulation development. This study aimed to explore two release testing methods for characterising buccal films and to elucidate the relationship between microenvironmental pH (pHM, i.e. the pH around the swelling films) and saquinavir release. The Franz diffusion cell method was applicable to investigate the effect of hydroxypropyl methylcellulose (HPMC) grade on saquinavir release. Films containing HPMC K3 LV had a faster saquinavir release than films containing HPMC K100 LV. A UV/Vis imaging method was developed to visualise saquinavir release and pHM changes during the initial dissolution. Within 5 min, the pHM decreased from 6.8 to around 5.4 for HPMC K100 LV-based films containing 11.1 % or 16.6 % (w/w) malic acid. Subsequently, the pHM increased due to increasing concentrations of saquinavir. An increase in malic acid content led to a faster saquinavir release. The combination of methods may be broadly applicable for excipient screening in development of buccal formulations. The imaging approach holds promise for characterizing other pH modifying formulation principles.

Impact of benzalkonium chloride-preserved and preservative-free latanoprost eye drops on cultured human conjunctival goblet cells upon acute exposure and differences in physicochemical properties of the eye drops.

OBJECTIVE: To investigate the short-term impact on human conjunctival goblet cell (GC) survival and mucin release of acute exposure to benzalkonium chloride (BAK) preserved and preservative-free (PF) 0.005% (w/v) latanoprost (LT) eye drops, and to compare the eye drops' physicochemical properties. METHODS AND ANALYSIS: Primary GC cultures were established from human conjunctival donor tissue. The impact of eye drops on GC survival was assessed using a lactate dehydrogenase assay. Mucin release was evaluated through mucin-specific immunostaining. pH value, osmolality, drop mass and surface tension for all LT eye drops were measured. RESULTS: After application with PF-LT for 30 min (min), the GC survival was maintained compared with control (p=0.9941), while all BAK-LT eye drops reduced survival with approximately 30% (p<0.02). Following application with PF-LT for 30 min, mucin was found around the GC nucleus, as seen in the vehicle control, indicating no secretion. In contrast, BAK-LT caused diffuse staining of mucin, similar to the secretagogue histamine, indicating stimulation of secretion. The pH value of the BAK-LT and PF-LT eye drops were 6.0-6.9 and 6.8, respectively. The osmolality was 258-288 mOsm/kg for the BAK-LT eye drops and 276 for PF-LT eye drops. The mean drop mass was 26-31 mg for the BAK-LT eye drops and 30 mg for PF-LT. The surface tension was lower for all BAK-LT eye drops (31.1-32.1 mN/m) compared with PF-LT (42 mN/m). CONCLUSION: PF-LT compared with various branded and generic LT preparations containing BAK are less cytotoxic when applied to cultured GCs.

Effect of decision rules in choice experiments on hunting and bushmeat trade.

Providing insight on decisions to hunt and trade bushmeat can facilitate improved management interventions that typically include enforcement, alternative employment, and donation of livestock. Conservation interventions to regulate bushmeat hunting and trade have hitherto been based on assumptions of utility- (i.e., personal benefits) maximizing behavior, which influences the types of incentives designed. However, if individuals instead strive to minimize regret, interventions may be misguided. We tested support for 3 hypotheses regarding decision rules through a choice experiment in Tanzania. We estimated models based on the assumptions of random utility maximization (RUM) and pure random regret maximization (P-RRM) and combinations thereof. One of these models had an attribute-specific decision rule and another had a class-specific decision rule. The RUM model outperformed the P-RRM model, but the attribute-specific model performed better. Allowing respondents with different decision rules and preference heterogeneity within each decision rule in a class-specific model performed best, revealing that 55% of the sample used a P-RRM decision rule. Individuals using a P-RRM decision rule responded less to enforcement, salary, and livestock donation than did individuals using the RUM decision rule. Hence, 3 common strategies, enforcement, alternative income-generating activities, and providing livestock as a substitute protein, are likely less effective in changing the behavior of more than half of respondents. Only salary elicited a large (i.e. elastic) response, and only for one RUM class. Policies to regulate the bushmeat trade based solely on the assumption of individuals maximizing utility, may fail for a significant proportion of the sample. Despite the superior performance of models that allow both RUM and P-RRM decision rules there are drawbacks that must be considered before use in the Global South, where very little is known about the social-psychology of decision making.

Efecto de las Reglas de Decisión en los Experimentos de Selección sobre la Cacería y el Mercado de la Carne de Animales Silvestres Resumen La obtención de conocimiento del porqué se elige cazar o comerciar con carne de animales silvestres puede facilitar mejoras en el manejo de las intervenciones que típicamente incluyen el cumplimiento de leyes, el empleo alternativo y la donación de ganado. Las intervenciones de conservación para regular la cacería y el comercio hasta ahora han estado basadas en suposiciones de comportamiento de maximización de la utilidad (es decir, los beneficios personales), las cuales influyen sobre los tipos de incentivos que son diseñados. Sin embargo, si los individuos en lugar de eso buscan minimizar el arrepentimiento, las intervenciones pueden ser erróneas. Evaluamos el apoyo para tres hipótesis con respecto a las reglas de decisión mediante un experimento de selección en Tanzania. Estimamos los modelos con base en las suposiciones de la maximización aleatoria de la utilidad (MAU) y la maximización aleatoria pura del arrepentimiento (MAPA) y las combinaciones de estas. Uno de estos modelos tuvo una regla de decisión específica de atributo y otro modelo tuvo una regla de decisión específica de clase. El modelo MAU tuvo un mucho mejor desempeño que el modelo MAPA, pero el modelo específico de atributo fue el que tuvo el mejor desempeño de todos. El mejor desempeño se observó cuando permitimos a los respondientes con diferentes reglas de decisión y con heterogeneidad de preferencia dentro de cada regla de decisión en un modelo específico de clase, lo que revela que el 55% de las muestras usaron una regla de decisión MAPA. Los individuos que usaron una regla de decisión MAPA respondieron menos al cumplimiento de leyes, el salario y la donación de ganado que aquellos individuos que usaron la regla de decisión MAU. Por esto, las tres estrategias comunes (cumplimiento de leyes, actividades alternativas generadoras de ingresos y el sustento de ganado como sustituto de la proteína) probablemente sean menos efectivas en el cambio del comportamiento de más de la mitad de los respondientes. Solamente el salario provocó una respuesta elástica, y solamente fue para una clase MAU. Las políticas que regulan el mercado de la carne de animales silvstres basadas solamente en la suposición de que los individuos maximizan la utilidad pueden fallar para una proporción significativa de la muestra. A pesar del desempeño superior de los modelos que permiten las reglas de decisión MAU y MAPA, existen desventajas que deben ser consideradas antes del uso de los modelos en el hemisferio sur, en donde se conoce muy poco sobre la psicología social de las decisiones.

Electrospun α-Lactalbumin Nanofibers for Site-Specific and Fast-Onset Delivery of Nicotine in the Oral Cavity: An In Vitro, Ex Vivo, and Tissue Spatial Distribution Study.

Nicotine replacement therapy (NRT) formulations for oromucosal administration induce a delayed rise in nicotine blood levels as opposed to the immediate nicotine increase obtained from cigarette smoking, this being a shortcoming of the therapy. Here, we demonstrate that α-lactalbumin/polyethylene oxide (ALA/PEO) electrospun nanofibers constitute an efficient oromucosal delivery system for fast-onset nicotine delivery of high relevance for acute dosing NRT applications. In vitro, nicotine-loaded nanofibers showed fast disintegration in water, with a weight loss up to 40% within minutes, and a faster nicotine release (26.1 ± 4.6% after 1 min of incubation) of the loaded nicotine compared to two relevant marketed NRT formulations with a comparable nicotine dose (i.e., 7.9 ± 5.1 and 2.2 ± 0.3% nicotine was released from a lozenge and a sublingual tablet, respectively). Model-fitting of the release data indicated that the release mechanism of nicotine from the hydrophilic nanofibers was possibly governed by more than one type of release phenomena. Remarkably, ex vivo studies using porcine buccal mucosa demonstrated a more efficient permeation of the nicotine released from the nanofibers [flux of 1.06 ± 0.22 nmol/(cm2·min)] compared to when dosing even a ten-fold concentrated nicotine solution [flux of 0.17 ± 0.14 nmol/(cm2·min)]. Moreover, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MS) imaging of ex vivo porcine buccal mucosa exposed to nicotine-loaded nanofibers clearly revealed higher amounts of nicotine throughout the epithelium, as well as in the lamina propria and submucosa of the tissue. Our findings suggest that nicotine-loaded ALA/PEO nanofibers have potential as a mucosal, fast-releasing, and biocompatible delivery system for nicotine, which can overcome the limitations of the currently marketed NRTs.

Swelling of mucoadhesive electrospun chitosan/polyethylene oxide nanofibers facilitates adhesion to the sublingual mucosa.

Mucoadhesive chitosan-based electrospun nanofibers are promising candidates for overcoming challenges associated with sublingual drug delivery, yet studies focusing on evaluating the mucoadhesive properties of nanofibers for sublingual administration are limited. The aim was to elucidate the mucoadhesive properties of chitosan/polyethylene oxide (PEO) nanofibers focusing on how the degree of deacetylation (DDA, 53-96 %) of chitosan influenced their morphological and mucoadhesive properties. The mechanism of mucoadhesion was explained by the intermolecular interactions of chitosan with mucin from bovine submaxillary glands using quartz-crystal microbalance with dissipation monitoring and by adhesion of the nanofibers to ex vivo porcine sublingual mucosa. An increase in chitosan DDA improved the morphological stability of the nanofibers in water, but did not contribute to altered mucoadhesive properties. This study demonstrates excellent mucoadhesive properties of chitosan/PEO nanofibers and shows that the strong mucoadhesiveness of the nanofibers is attributed to their swelling ability.

Fabrication of Mucoadhesive Buccal Films for Local Administration of Ketoprofen and Lidocaine Hydrochloride by Combining Fused Deposition Modeling and Inkjet Printing.

In the area of developing oromucosal drug delivery systems, mucoadhesive buccal films are the most promising formulations for either systemic or local drug delivery. The current study presents the fabrication of buccal films, by combining fused deposition modeling (FDM) and inkjet printing. Hydroxypropyl methylcellulose-based films were fabricated via FDM, containing the non-steroidal anti-inflammatory drug ketoprofen. Unidirectional release properties were achieved, by incorporating an ethyl cellulose-based backing layer. The local anesthetic lidocaine hydrochloride, combined with the permeation enhancer l-menthol, was deposited onto the film by inkjet printing. Physicochemical analysis showed alterations in the characteristics of the films, and the mucoadhesive and mechanical properties were effectively modified, due to the ink deposition on the substrates. The in vitro release data of the active pharmaceutical compounds, as well as the permeation profiles across ex vivo porcine buccal mucosa and filter-grown TR146 cells of human buccal origin, were associated with the presence of the permeation enhancer and the backing layer. The lack of any toxicity of the fabricated films was demonstrated by the MTT viability assay. This proof-of-concept study provides an alternative formulation approach of mucoadhesive buccal films, intended for the treatment of local oromucosal diseases or systemic drug delivery.

Microenvironmental pH modifying films for buccal delivery of saquinavir: Effects of organic acids on pH and drug release in vitro.

Buccal delivery of saquinavir has the advantage to bypass the gastrointestinal enzymatic degradation and the hepatic first-pass metabolism. Saquinavir has a pH-dependent solubility and is poorly soluble in human saliva at the physiological pH. Decreasing microenvironmental pH (pHM) in saliva may increase saquinavir release from buccal formulations. The present study aimed to investigate the effects of organic acids on the pHM, saquinavir release in vitro and the solid-state form of saquinavir. An UV/Vis imaging method was used to measure pHM. After 5 min of swelling of the buccal films containing malic acid, pHM was reduced from 6.8 to 5.4. The films containing malic acid were more efficient in maintaining low pHM than films containing citric acid and succinic acid. Addition of organic acids in the buccal films resulted in a faster drug release than films without acids due to the reduced pHM. However, the enhancement of saquinavir release was limited by the fast release of organic acids. Addition of malic acid and citric acid suppressed the crystallization of saquinavir during 3 months storage at the elevated temperature (40 °C) and humidity (RH 75%) respectively. These results suggest that pHM modifying film is a potential formulation strategy for buccal delivery of saquinavir.

Characterization of burning mouth syndrome profiles based on response to a local anaesthetic lozenge.

OBJECTIVE: Burning mouth syndrome (BMS) is a chronic oral pain condition with unknown aetiology but assumed to involve peripheral/central neuropathological and immune-mediated inflammatory factors. We aimed at characterizing inflammatory and neurogenic profiles and oral symptomatology of patients with BMS based on response to a local anaesthetic lozenge. METHODS: Patients with BMS were divided into an Effect (n = 13), No effect (n = 8) or Unspecified (n = 2) group according to their response to a local anaesthetic lozenge on oral pain. Inflammation was assessed in blood plasma and saliva by analyses of IL-6, IL-8, IL-17A, IL-23 and TNF-α levels. The degree of inflammation and distribution of oestrogen receptor, NGF, NGF-receptor, TRPV-1 and IL-17F in buccal mucosal tissue were investigated by immunohistochemistry. RESULTS: Immunoreactivity to the oestrogen receptor was most intense in the Effect group, whereas the No effect group tended to have higher plasma levels of the pro-inflammatory cytokines. CONCLUSIONS: Our findings indicate that the response to treatment with local anaesthesia enables subgrouping of patients with BMS according to the potential pathogenic mechanisms. Effect of local anaesthesia indicates a peripheral neuropathology involving lack of oestrogen and upregulation of oestrogen receptors, and no effect indicates a systemic inflammation-induced mechanism leading to increased levels of plasma cytokines.

Mucoadhesive Electrospun Patch Delivery of Lidocaine to the Oral Mucosa and Investigation of Spatial Distribution in a Tissue Using MALDI-Mass Spectrometry Imaging.

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a noninjectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anesthetics from this system and their uptake by oral tissue have not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fiber patches, drug release, and subsequent uptake and permeation through the porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 min (0.16 ± 0.04 mg) compared to that from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 min, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionization-mass spectrometry imaging was used to investigate localization of lidocaine within the oral tissue. Lidocaine in the solution as well as from the mucoadhesive patch penetrated into the buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 min. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anesthetic drug delivery to treat or prevent oral pain.

Polymeric Lids for Microcontainers for Oral Protein Delivery.

Oral delivery of proteins and peptides is one of the main challenges in pharmaceutical drug development. Microdevices have the possibility to protect the therapeutics until release is desired, avoiding losses by degradation. One type of microdevice is polymeric microcontainers. In this study, lysozyme is chosen as model protein and loaded into microcontainers with the permeation enhancer sodium decanoate (C10). The loaded microcontainers are sealed and functionalized by applying polymeric lids onto the cavity of the devices. The first lid is poly(lactic-co-glycolic) acid (PLGA) and on top of this either polyethylene glycol (PEG) or chitosan is applied (PLGA+PEG or PLGA+chitosan, respectively). The functionalization is evaluated in vitro for morphology, drug release, and mucoadhesive properties. These are coupled with in vitro and ex vivo studies using Caco-2 cells, Caco-2/HT29-MTX-E12 co-cultures, and porcine intestinal tissue. PLGA+chitosan shows slower release compared to PLGA+PEG or only PLGA in buffer and the transport of lysozyme across cell cultures is not enhanced compared to the bulk powder. Microcontainers coated with chitosan or PEG demonstrate a three times stronger adhesion during ex vivo mucoadhesion studies compared to samples without coatings. Altogether, functionalized microcontainers with mucoadhesive properties and tunable release for oral protein delivery are developed and characterized.