Dans les produits laitiers, les cultures bioprotectrices et leurs métabolites représentent une alternative d’intérêt aux conservateurs chimiques pour lutter contre les contaminations fongiques. L’objectif de cette thèse était de développer des ingrédients antifongiques, issus de la fermentation d’un substrat laitier par différents microorganismes, bactéries ou champignons, utilisables dans des produits laitiers variés. Pour ce faire, nous avons dans un premier temps caractérisé la diversité des contaminants fongiques des produits laitiers et de leur environnement afin de sélectionner les cibles fongiques les plus pertinentes pour le reste de notre étude. Ensuite, nous avons criblé, in vitro, l’activité antifongique de fermentats issus de la fermentation de 2 substrats laitiers par 698 souches de bactéries lactiques, propioniques et de champignons grâce à une nouvelle méthode de criblage haut-débit, dans une matrice mimant le fromage. Après optimisation des conditions de fermentation pour améliorer l’activité antifongique de ces fermentats, les plus actifs ont été testés à l’échelle du laboratoire sur des fromages blancs et des fromages à pâte pressée à croûte morgée (PPCM) avant d’être testés à l’échelle pilote dans des crèmes fraiches et des fromages à PPCM. Cette étape nous a permis (i) de valider l’activité antifongique des fermentats en produits réels en mettant en place des challengetests et des tests d’usage et (ii) d’évaluer leur impact sur les qualités organoleptiques des produits grâce à des analyses sensorielles. Les molécules impliquées dans l’activité antifongique ont ensuite été identifiées grâce à différentes méthodes (chromatographie en phase gazeuse ou liquide couplée ou non à la spectrométrie de masse) et l’impact de ces composés sur la croissance des cibles fongiques a été évalué. Le criblage in vitro a permis la sélection de 3 ingrédients antifongiques qui se sont tous révélés actifs in situ. Les tests de durabilité ont révélé que le fermentat issu de Lactobacillus rhamnosus CIRM-BIA 1952 avait une activité prometteuse dans les crèmes fraiches. Pour le fromage à PPCM, le fermentat issu de Propionibacterium jensenii CIRM-BIA 1774, qui retarde jusqu’à 16 jours la croissance de Mucor racemosus et Penicillium commune pourrait être utilisé à la place de la natamycine. La caractérisation des composés antifongiques dans les fermentats a mis en évidence certains acides organiques, des acides gras, des composés volatils et un peptide qui, ensemble, jouent très probablement un rôle dans l’activité antifongique de ces fermentats. Nous avons enfin montré l’effet fongistatique du fermentat le plus actif sur Rhodotorula mucilaginosa UBOCC-A-216004 et Mucor racemosus UBOCC-A-109155 ainsi que son impact sur la physiologie des spores de M. racemosus. L’ensemble de ces résultats devrait donc conduire au développement de nouveaux ingrédients laitiers antifongiques qui pourraient remplacer avantageusement les conservateurs dans les produits laitiers, ils apportent en outre des éléments d’information sur les molécules et les mécanismes mis en œuvre dans l’inhibition antifongique. / In dairy products, bioprotective cultures and their metabolites represent an interesting alternative to chemical preservatives. The aim of this PhD thesis was to develop antifungal dairy ingredients, derived from the fermentation of dairy substrates by different microorganisms, bacteria and fungi, which could be used in various dairy products. To do so, we first studied the diversity of spoilage fungi in a large variety of dairy products and their environment in order to select the most appropriate fungal targets. Then, we screened the in vitro antifungal activity of fermentates obtained from the fermentation of 2 dairy substrates by 698 lactic acid bacteria, propionibacteria and fungal strains using a novel high-throughput method in a cheese mimicking model. After optimizing fermentation conditions to enhance antifungal activity, the most active fermentates were tested at a lab scale in semi-hard and fresh cheese before evaluation at a pilot scale in semi-hard cheese and sour cream. This step allowed us (i) to validate the fermentate antifungal activities in real products using challenge- and durability-tests and (ii) to evaluate their impact on the products’ organoleptic properties using sensorial analysis. Antifungal molecules were then identified using different analytical methods (high performance liquid chromatography, gas chromatography coupled or not with mass spectrometry) and impact of these compounds on fungal growth was studied. The in vitro screening allowed selecting 3 antifungal ingredients that were also active in situ. Durability tests revealed that Lactobacillus rhamnosus CIRMBIA 1952 fermentate had a promising activity in sour cream. In semi-hard cheese, Propionibacterium jensenii CIRMBIA 1774 fermentate, which delayed Mucor racemosus and Penicillium commune growth for up to 16 days, could be used instead of natamycin. Antifungal compounds present in fermentates consisted of organic acids, free fatty acids, volatile compounds and peptides which altogether might play a role in the antifungal activity of these fermentates. Finally, the fungistatic effect of P. jensenii CIRM-BIA 1774 fermentate against R. mucilaginosa UBOCC-A-216004 and M. racemosus UBOC-A-109155 was demonstrated, as well as its impact on the physiology of M. racemosus spores. Together, these results should lead to the development of new antifungal dairy ingredients which could replace preservatives in dairy products. Finally, these results gave us new information concerning antifungal molecules and their action mechanisms.

This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam. The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected. The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam. The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam. The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples. The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.

A partir de 1980, els canvis polítics, socials i administratius van provocar la desaparició gradual del Servei d’Extensió Agrària a Catalunya, establint-se grups d’assessorament, aliens a l’administració pública, bé adscrits a cases comercials o a grans empreses, o bé formats per professionals en exercici lliure. Aquesta situació, i pel que fa a les explotacions de vaques de llet, fou considerada satisfactòria, tant per l’administració com per altres organismes o estaments socials i econòmics, tot i que hi ha algunes opinions de professionals i ramaders que ho qüestionen. Per aquest motiu, es va plantejar la hipòtesi que les explotacions de vaques de llet, estan necessitades d’un model d’extensió que les ajudi a detectar i a solucionar problemes, per si mateixes. A través d’un mostreig estratificat d’explotacions, es va realitzar un estudi descriptiu del maneig dels sistema productiu, i, alhora, una enquesta de coneixements, dirigida als titulars de 57 explotacions. A la descripció s’insistí en la valoració nutritiva de les racions alimentàries, i en aquells aspectes destacats del racionament – tipus de ració, distribució de la ració, espai per vaca a la menjadora, el confort, els abeuradors, etc. – El tractament estadístic de les dades, fet mitjançant el paquet estadístic SAS (2002), va requerir de la transformació prèvia de la informació recollida, tant de la descripció com de l’enquesta de coneixements. En el pla teòric, mitjançant la revisió bibliogràfica, es demostra la necessitat del model d’extensió per fer front, en general, als canvis d’orientació exigits per la societat a l’agricultura. Tanmateix, es fa palès la idoneïtat del model d’extensió per a la resta de la societat. Dels resultats de l’anàlisi realitzat, cal destacar que en el 70% de les explotacions no es fa cap tipus d’examen o anàlisi dels resultats econòmics, i, només, el 26% dels titulars coneixen, aproximadament, el cost d’un litre de llet. A la majoria de les explotacions, el titular ha perdut el control del factor alimentació, i les racions, subministrades per al conjunt de vaques lactants, es formulen per a valors alts de producció, amb independència de la producció real. En general, són deficitàries en energia en relació a la potencialitat que s’exigeix al contingut proteic, i a les de quota superior, es formula en contingut PDIN per a una producció superior en 14 litres a la mitjana per vaca en lactació i dia. El ramader d’explotacions petites i mitjanes, l’únic estímul que rep, és el d’ampliar o deixar l’activitat. Mentre que, el de les explotacions d’estrats superiors de quota, es veu forçat a delegar el control dels factors de producció en els serveis tècnics, privats. El model d’extensió, esdevé necessari, ja que dóna formació i informació per tal que el ramader decideixi, com empresari, sense delegar aquesta funció. / A partir de 1980, los cambios políticos, sociales y administrativos, condujeron a la paulatina desaparición del Servicio de Extensión Agraria en Cataluña; oportunidad que fue aprovechada para el establecimiento de grupos de asesoramiento, ajenos a la administración pública, unos adscritos a casas comerciales o a grandes empresas, y otros formados por profesionales en ejercicio libre. Esta situación, considerada satisfactoria por la administración y otros estamentos sociales y económicos, se está cuestionando por algunos profesionales y agricultores. Por lo cual se planteó la hipótesis de que las explotaciones de vacas de leche están necesitadas de un modelo de extensión, que les ayuden a detectar y a solucionar problemas por si mismas. A través de un muestreo estratificado de 57 explotaciones, se realizó un estudio descriptivo del manejo del sistema productivo, y del estado de conocimientos de los titulares de las mismas. Dentro del estudio descriptivo se incidió en la valoración nutritiva de las raciones alimenticias, y en los aspectos destacados del racionamiento – tipo de ración, modo de distribución, espacio por vaca en el comedero, confort, distribución de los bebederos, etc. – El tratamiento estadístico de los datos, realizado mediante el paquete estadístico SAS (2002), requirió la transformación previa, en variables cualitativas y cuantitativas, de la información recogida, tanto de la descripción como de la encuesta de conocimientos. En el plano teórico, y mediante la revisión bibliográfica, se evidencia la necesidad del modelo de extensión, en general, ante los cambios de orientación exigidos por la sociedad a la agricultura. Asimismo, se hace patente la idoneidad del modelo de extensión para el resto de la sociedad. De los resultados del análisis realizado, se destaca que en el 70% de las explotaciones no se realiza ningún tipo de análisis sobre los resultados económicos, y, sólo, el 26% de los titulares conocen, de manera aproximada, el coste de un litro de leche. En la mayoría de las explotaciones, el titular ha perdido el control del factor alimentación; las raciones, suministradas para el conjunto de vacas en lactación, se formulan para valores altos de producción, con independencia de la producción real. En general, son deficitarias en energía en relación con la potencialidad exigida al contenido proteico; en las explotaciones de mayor cuota, se formula en contenido PDIN para una producción superior en 14 litros a la media por vaca en lactación y día. El titular de explotaciones pequeñas y medianas, el único estimulo que recibe, de la administración pública, es el de ampliar o de dejar la actividad. Mientras, el ganadero de las explotaciones mayores, se ve presionado a delegar el control de los factores de producción en los servicios técnicos privados. El modelo de extensión, se hace necesario, para dotar a los ganaderos de un nivel de formación que les permita tomar decisiones, como empresarios, sin delegar el control de la explotación. / From 1980, politics, socials and administrative changes, lead to the gradual disappearance of Agricultural Service of Extension in Catalonia, with the consequent appearance of groups of advising, free from public administration, ones assigning to commercial houses or great enterprises, and others formed by professionals in free exercise. Opposite to argument of those starting activities of dairy cows operations are well covered with the advice received, one considered the hypothesis that the operations of milk cows were needed of an extension model, which can help to detect problems and find by themselves, the solutions. Through a stratified sampling of the dairy cows, one carried out a descriptive study about management of the productive system, and the fulfilment of a knowledge inquiry to the farmer. In the descriptive study, one influenced in the nutritious valuation of the food rations, and about the outstanding aspects of the rationing - type of ration, way of distribution, space by cow in the feeding place, comfort, distribution of drink trough, etc. – Data processing was made with statistics package SAS (2002). It was necessary the previous transformation of the collected information, as much of the description as of the inquiry of knowledge. In theoretic plane, through bibliographic revision, is demonstrated the necessity of one extension model before orientation changes demanded by the agriculture society, in general. Likewise, it is obviously the suitability of the model of extension for the rest of the society. Through analysis result, one stands up that in 70% of dairy cows is not made any type of examination on the economics results, and, only, 26% of the farmers know, approximately, the cost of a litre of milk. In most operations, the framer has lost the control of the feeding factor, and the rations, provided to dairy cows, are formulated for higher values of production, independently of real production. In general, they are deficiencies in energy in relation with the potentiality demanded to the protein content, and those with the more amount of reference (quota), the ration is formulated in content PDIN, average, for a bigger 14 litres production, average by cow in lactation and day. The farmer of small and medium dairy cows, the only stimulus that he receives, is in the possibility of extending or leaving his activity. However, the farmer of dairy cows with more production or quota, must, unavoidably, delegate the control of the production factors to the private service of experts. The extension model appears like necessary, because it helps to trust and to lean in the expert, without delegating theirs functions of decision.

This study is an exploratory examination of the perceptions of chefs affiliated with Relais & Chateaux properties in Canada with respect to their relationships with suppliers, the importance of local ingredients in menu design, and other issues associated with their work as chefs in some of the top restaurants in Canada. Their understanding of the concept of “culinary tourism” is also explored. For the purpose of this study, culinary tourism is conceptually defined to be “any tourism experience in which one learns about, appreciates, or consumes branded local culinary resources” (Smith and Xiao, 2006, p. 4). Data for this study were obtained from three sources: (1) a closed-ended questionnaire, which inquired about acquisition, production and consumption issues associated with restaurant chefs (2) in-depth personal interviews with chefs that enabled the researcher to gain a holistic view of the role and results of chefs interaction with local food producers, and (3) a content analysis of Relais & Chateaux menus that served as a template to how chefs brand producers in their restaurants. A total of 11 chefs completed the survey and were interviewed between the months of June, 2007 and August, 2007. The comments by the chefs in the interviews were classified into 9 themes. The themes that emerged include producer relationships, producer communication, local ingredients, cuisine, restaurant staff, culinary tourism, knowledge of clientele, culinary products and Relais & Chateaux brand. The interviews resulted in a number of insights into chef relations with local food producers as well as the potential of culinary tourism as a tourism experience provided by Relais & Chateaux chefs. Chefs spend considerable time and effort facilitating relationships with local producers in order to create quality. These chefs expressed the importance of quality and relationships with local producers while highlighting the need for communication among properly trained waiters. Chefs used both menus and guests’ interaction with waiters to communicate the use of local ingredients in their restaurants. The chefs focus on local affiliations to products as a way to promote local producers. However, once relationships with a local producer are developed, some chefs maintain that relationship even if the move out of the area. Many chefs reported that increased interaction among culinary tourism stakeholders, at a regional level, was needed in order for regional producers to brand their products in the market place. With this it was recommended that bi-yearly meetings involving restaurateurs, producers, farmers and artisans is needed to better network their product offerings. In each case, the goal of the Canadian Relais & Chateaux chef is to improve upon the branding of Canadian food ingredients. The research revealed the positive impact that this group of chefs has had in promoting grass roots food products for an increasingly popular tourism market. Findings of this research suggest that chefs are involved in the production, education, facilitation and communication of local ingredients in the restaurant setting which raises issues of their role in the branding of local food ingredients for the culinary tourist in order to promote a healthy culinary tourism product. The study concludes with suggestions for further research in this area.

This study is an exploratory examination of the perceptions of chefs affiliated with Relais & Chateaux properties in Canada with respect to their relationships with suppliers, the importance of local ingredients in menu design, and other issues associated with their work as chefs in some of the top restaurants in Canada. Their understanding of the concept of “culinary tourism” is also explored. For the purpose of this study, culinary tourism is conceptually defined to be “any tourism experience in which one learns about, appreciates, or consumes branded local culinary resources” (Smith and Xiao, 2006, p. 4). Data for this study were obtained from three sources: (1) a closed-ended questionnaire, which inquired about acquisition, production and consumption issues associated with restaurant chefs (2) in-depth personal interviews with chefs that enabled the researcher to gain a holistic view of the role and results of chefs interaction with local food producers, and (3) a content analysis of Relais & Chateaux menus that served as a template to how chefs brand producers in their restaurants. A total of 11 chefs completed the survey and were interviewed between the months of June, 2007 and August, 2007. The comments by the chefs in the interviews were classified into 9 themes. The themes that emerged include producer relationships, producer communication, local ingredients, cuisine, restaurant staff, culinary tourism, knowledge of clientele, culinary products and Relais & Chateaux brand. The interviews resulted in a number of insights into chef relations with local food producers as well as the potential of culinary tourism as a tourism experience provided by Relais & Chateaux chefs. Chefs spend considerable time and effort facilitating relationships with local producers in order to create quality. These chefs expressed the importance of quality and relationships with local producers while highlighting the need for communication among properly trained waiters. Chefs used both menus and guests’ interaction with waiters to communicate the use of local ingredients in their restaurants. The chefs focus on local affiliations to products as a way to promote local producers. However, once relationships with a local producer are developed, some chefs maintain that relationship even if the move out of the area. Many chefs reported that increased interaction among culinary tourism stakeholders, at a regional level, was needed in order for regional producers to brand their products in the market place. With this it was recommended that bi-yearly meetings involving restaurateurs, producers, farmers and artisans is needed to better network their product offerings. In each case, the goal of the Canadian Relais & Chateaux chef is to improve upon the branding of Canadian food ingredients. The research revealed the positive impact that this group of chefs has had in promoting grass roots food products for an increasingly popular tourism market. Findings of this research suggest that chefs are involved in the production, education, facilitation and communication of local ingredients in the restaurant setting which raises issues of their role in the branding of local food ingredients for the culinary tourist in order to promote a healthy culinary tourism product. The study concludes with suggestions for further research in this area.

Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles. Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824. This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.</p>

Vaistiniai augalai šiuolaikinėje medicinoje turi labai didelę reikšmę. Šiuo metu Lietuvoje – tradicinėje ir liaudies medicinoje naudojama apie 460 augalų rūšių. Rausvažiedė ežiuolė yra vienas iš populiariausių vaistinių augalų. Iš jos pagaminti vaistai vartojami odos, onkologinių ir peršalimo ligų gydymui. Vaistinei žaliavai naudojamos įvairios rausvažiedės ežiuolės dalys: lapai, žiedai, stiebai, šaknys ir t.t. Nuimta vaistinė augalinė žaliava yra labai drėgna. Susidaro ypač palanki terpė mikroorganizmams vystytis. Todėl vaistinės augalinės žaliavos paruošimui dažniausiai naudojamas džiovinimas. Džiovinimo būdai didžia dalimi nulemia vaistinės augalinės žaliavos kokybę. Tyrimų tikslas – ištirti ir palyginti džiūvimo sąlygų įtaką rausvažiedės ežiuolės žolės ir skirtingų jos dalių drėgmės mainams su aplinka. Nustatyta, kad standžios augalo morfologinės dalys lemia stabilesnę ir poringesnę vaistinės augalinės žaliavos sampilo struktūrą, todėl džiovinant rausvažiedės ežiuolės žiedus ir ypač smulkintus stiebus bei žolę susiformuoja palankesnės džiūvimui sąlygos nei, pavyzdžiui, skintų lapų sampile. / Medicinal plants are of great importance in modern medicine. Currently, Lithuania - traditional and folk medicine used for about 460 species of plants. Echinacea purpurea is one of the most popular medicinal plants. From these plants made drugs are used to treat skin diseases, oncological diseases and cold diseases. Various parts of Echinacea purpurea an used for medicinal materials: leaves, flowers, stems, roots, etc. Been harvested herbal ingredients are very moist. There is a particularly favorable environment for the development of microorganisms. Therefore, the preparation of medicinal plant raw materials commonly used in drying. Drying methods are largely determined by the quality of raw materials. Purposes of the study - to investigate and compare the drying conditions on Echinacea purpurea herbs and different parts of moisture exchange with the environment. It was found that the rigid parts of the plant determines the morphological stability and more porous medicinal plant raw materials layer structure, therefore drying purple cone flowers, and especially the chopped stems and grass formed favorable drying conditions than cutted leaves layer.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

The United States possesses a well intentioned but misguided lunch program, leaving children overfed but malnourished. Currently, a revolution is under way to transform programs around the country by incorporating locally grown and fresh ingredients, as well as integrating hands-on educational experiences with gardening and nutrition. The Claremont Unified School District (CUSD) makes up a group of schools that once heavily relied on unhealthy processed foods for providing lunch. Through a series of modifications in the past three years, CUSD’s program has been remodeled to feature more local produce and fresh ingredients, independent of USDA commodities or large scale agriculture. This has led to a healthier student body as well as a more cohesive school community.