Finally, the pharmacodynamic effects of propranolol powder formulation with different buffering were carried out in two healthy male subjects. The maximal reduction in heart rate was found at the saliva pH of 7.6, which corresponded to the pHmax of propranolol. A buffered propranolol sublingual tablet was then prepared to achieve the saliva pH around 7.6. The preliminary investigation confirmed that the sublingually administrated buffered propranolol tablet produced a faster and more pronounced heart rate reduction than the non-buffered commercial propranolol tablet. / Firstly, the use of the HO-1-u-1 cell culture for screening sublingual drug delivery was validated. The cells were seeded on cell culture inserts. The integrity of cell layers, inter-passage variation and directionality were assessed by measuring the resistance and the permeability of standard markers, beta-blockers and calcium channel blockers. The effect of pH, osmolarity and a permeation enhancer (GDC) were also studied. The results showed that HO-1-u-1 cells grown on inserts formed stratified and epithelial-like structure that preserved the typical histological feathers of the normal human sublingual epithelium. The maximal integrity was reached in 23 days. The Papp of beta-blockers and calcium channel blockers ranged from 2.89+/-0.17 x 10 -6 cm/s to 6.37+/-0.37 x 10-6 cm/s. The permeability of selected beta-blockers under different pH, osmolarity and GDC revealed that enhancing effects were significant for hydrophilic compounds but less for lipophilic compounds. / Secondly, fresh porcine sublingual mucosa was prepared and compared to the cell line model. Good correlations were obtained for both the Papp of beta-blockers and the enhancement ratios of pH and GDC between the two models. / The aims of the present study are (1) to develop and validate a human sublingual epithelial cell line model and (2) to demonstrate the application in sublingual development of cardiovascular drugs. / Thirdly, the steady-state flux (Jss) at various pH levels were measured. Results show that saturated propranolol solution at pH 7.0--7.6 resulted in a much higher Jss than the solution at other pHs. These data led to the development of theoretical equations for predicting the optimum pH (pHmax) for ionizable compounds. The calculation fitted well with the experimental data. / Wang Yanfeng. / Advisers: Moses S. S. Chow; Zhong Joan Zuo. / Source: Dissertation Abstracts International, Volume: 73-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 184-). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Les vaccins des muqueuses s'administrent facilement et favorisent une immunité humorale et cellulaire au niveau des muqueuses. Ainsi, ils offrent une protection optimale contre les pathogènes envahissant par les muqueuses. Cependant, la mise sur le marché de nouveaux vaccins des muqueuses est entravée par le manque d'adjuvants des muqueuses efficaces et sans effets secondaires. La toxine cholérique (CT) est une entérotoxine à fort pouvoir adjuvant mais sa toxicité empêche son utilisation chez l'homme. En tant que modèle expérimental, elle a permis de comprendre l'importance de l'activité enzymatique et des récepteurs dans l'adjuvanticité. Notre travail se base sur l'observation que des doses sublétales de la toxine œdémateuse de Bacillus anthracis (EdTx) n'inhibent pas la réponse immune à des vaccins « nasaux » contenant CT comme adjuvant. Nous avons montré que les dérivés EdTx représentent une nouvelle classe d'adjuvants qui donnent des réponses systémiques et des muqueuses à des protéines vaccinales administrées par de multiples voies, notamment nasale. Contrairement à CT qui se fixe aux gangliosides, EdTx se fixe aux récepteurs des toxines de l'anthrax et ne cible pas les tissus du système nerveux central après administration nasale. Le facteur inné nerve growth factor intervient dans les réponses des muqueuses induites par CT mais n'affecte pas l'adjuvanticité d'EdTx in vivo. L'activité adjuvante d'EdTx implique aussi l'augmentation des fonctions de présentation de l'antigène. Enfin, nous avons montré qu'EdTx est un adjuvant efficace par les voies transcutanée et sublinguale, bien que les IgA des muqueuses ne soient induits qu'après immunisation sublinguale.

One of the most common reasons people seek primary care and emergency care is to reduce the symptoms of allergies, such as hay fever. To meet this high demand, several recent FDA-approved methods for treating seasonal and perennial allergies have been developed, including sublingual immunotherapy tablets. Furthermore, no longer must a patient endure allergy shots; this can now be delivered sublingually. Although this method has been shown to have high safety and efficacy, very few clinicians actually utilize this form of therapy. The purpose of this paper is describe the use of sublingual immunotherapy among Nurse Practitioners (NPs) and discuss barriers that may prevent its use. Nurse Practitioners working in primary care settings were surveyed regarding their use of sublingual immunotherapy. Although many nurse practitioners treat patients with allergic disease, not one participant reported using sublingual immunotherapy. This discussion outlines some of the reasons NPs are not currently utilizing this method of allergy treatment and the findings are compared with the extant literature. This paper culminates in an evidence-based algorithm to outline best practices for utilizing sublingual immunotherapy to reduce allergy symptoms.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22035号 / 医博第4520号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 佐藤 俊哉, 教授 福原 俊一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

A cárie dental é uma doença bacteriana infecciosa considerada como um dos principais problemas de saúde pública. O principal agente etiológico para o desenvolvimento da doença é o Streptococcus mutans. A proteína P1, também conhecida como antígeno I/II, do S. mutans é fundamental para a etapa inicial de adesão à superfície dental (sacarose-independente), sendo, portanto, considerada essencial para o processo de colonização deste patógeno. Algumas regiões dessa proteína vêm sendo empregadas como antígenos em estratégias vacinais contra a cárie, entre elas a região A, localizada na porção N-terminal, conhecida como região de ligação à saliva Saliva Binding Region (SBR). No entanto, apesar dos avanços, não existe vacina para a prevenção da cárie licenciada para uso em humanos. Diante disso, o presente trabalho tem como objetivo o desenvolvimento e caracterização de uma nova estratégia vacinal contra o S. mutans baseada em esquema de dose-reforço heterólogo, utilizando o fragmento P139-512, na forma de proteína purificada, expressa a partir de linhagens recombinantes de Bacillus subtilis. A proteína P139-512 compreende os aminoácidos 39-512 da proteína nativa, o que corresponde a toda região A e uma pequena porção da região variável da proteína P1. Utilizamos esporos de B. subtilis 1012, modificados para expressar o antígeno P139-512 (LDV702). A linhagem LDV704, além de expressar o antígeno, foi modificada para expressar uma invasina (InvA) com capacidade de se ligar a epitélios de mucosa. Camundongos da linhagem BALB/c foram imunizados por via sublingual com uma dose de esporos de B. subtilis (linhagens 1012, LDV702, LDV704 ou PBS) seguidos por dois reforços com a proteína P139-512, associada ou não com o adjuvante LTK63. Níveis significativos de anticorpos séricos foram induzidos pelas formulações em associação com o adjuvante após a terceira dose, e mostraram-se capazes de reconhecer os epítopos em diferentes linhagens de S. mutans. No entanto, nenhuma das formulações mostrou-se capaz de ativar respostas de mucosa (S-IgA). Porém, observamos que o adjuvante LTK63 empregado na estratégia dose-reforço heterólogo potencializou a resposta sérica de anticorpos IgG, sendo capaz de modular e melhorar qualitativamente as respostas induzidas. Assim, a administração das formulações na presença do adjuvante representa uma alternativa promissora para o controle do S. mutans. / Dental caries is an infectious bacterial disease considered as one of the main public health problems. The main etiological agent for the development of the disease is the Streptococcus mutans. The P1 protein, also known as S. mutans Ag I / II antigen, is essential for the initial stages of adhesion to the dental surface (sucrose-independent) and is, therefore, considered essential for the colonization process of this pathogen. Some regions of this protein have been used as antigens in vaccine strategies against caries, among them the A region, located at the amino terminal region also known as the Saliva Binding Region (SBR). However, despite the advances, there is no licensed anti-caries vaccine for human use. Therefore, the present work aims to develop and characterize a new vaccine strategy against S. mutans based on a heterologous priming/boost immunization regimen using the recombinant P139-512 fragment, expressed and purified from a Bacillus subtilis strain. The P139-512 protein comprises amino acids that encompasses the entire A region and a small portion of the variable region of the P1 protein. We used spores of B. subtilis 1012 (wild-strain) and recombinants that were modified to express the antigen P139-512 (LDV702). In addition to express the antigen, the LDV704 strain was modified to express a surface-exposed bacterial invasin (InvA) capable of binding to the mucosal epithelia. BALB/c mice were primed via the sublingual route with a dose of B. subtilis spores (1012, LDV702, or LDV704 strains) followed by two boosting doses with the purified protein P139-512, associated or not with the LTK63 adjuvant, by the same administration route. Significant serum antibody levels were induced by the formulations with the adjuvants after the third dose and the antibodies were shown to recognize epitopes exposed on the surface of different S. mutans strains. However, none of the formulations were capable to activate mucosal responses (S-IgA). Nevertheless, we observed that the LTK63 enhanced the serum IgG responses and qualitatively improved the induced antibody response. Thus, the administration of the formulations in the presence of the adjuvant represents a promising alternative for the control of S. mutans.

Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-04-04T20:45:16Z No. of bitstreams: 1 DAYSE DE LOURDES MADRGA ESPÍNOLA GUEDES - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2225179 bytes, checksum: ad9f795a81034cb79500cb575de58f73 (MD5) / Made available in DSpace on 2018-04-04T20:45:16Z (GMT). No. of bitstreams: 1 DAYSE DE LOURDES MADRGA ESPÍNOLA GUEDES - DISSERTAÇÃO PPG-CEMat 2014..pdf: 2225179 bytes, checksum: ad9f795a81034cb79500cb575de58f73 (MD5) Previous issue date: 2014-12-12 / A presente pesquisa tem como objetivo, caracterizar filmes de quitosana, de aplicação sublingual, para uso em sistemas de liberação controlada de fumarato de formoterol., buscando uma nova alternativa para o tratamento emergencial das crises de asma. Sabemos que a asma é uma patologia de grande incidência no Brasil e no mundo, pois existem cerca de 300 milhões de pessoas acometidas pela doença a nível mundial e 20 milhões de brasileiros .É uma doença de caráter hereditário, crônica que não tem cura e que se apresenta muitas vezes como uma emergência médica , pois nas crises da doença o socorro deve ser imediato com o intuito de evitar o óbito do paciente. Hoje utiliza-se apenas a via inalatória como preferencial para administração dos broncodilatadores, visto que essa via tem rapidez de ação. No entando, deparamo-nos com a difícil técnica de utilização dos inaladores que veiculam o medicamento o que muitas vezes impossibilita a sua utilização especialmente em crianças, idosos e pacientes muito debilidados. Vendo esta dificuldade, propusemos com o nosso trabalho buscar uma nova via de utilização dos medicamentos broncodilatadores, que tivesse a mesma eficácia da via inalatória, dispensando a difícil técnica de utilização dos fármacos .Para isso , escolhemos a via sublingual de rápida ação e facilidade de utilização, podendo ser empregada mais adequadamente em uma crise de asma . Selecionamos a quitosana, por ser um biopolímero versátil e muito utilizado em sistema de liberação controlada de fármaco para veicular o formoterol , que é um potente broncodilatador, através da produção de um filme para deposição sublingual. E os resultados obtidos através das caracterizações apresentaram membranas com variações de cristalinidade (por DRX) de acordo com o processo de reticulação, além de apresentarem uma possível relação entre reticulação e liberação. Por FTIR pode-se observar certa interação entre o fármaco e os grupos amina da quitosana, assim como possível isomerização do fármaco pela reticulação com 5% de TPP. Pelas microscopias ótica e eletrônica, pode-se observar que o acréscimo de fármaco proporcionou alguma rugosidade a membrana. Também pelas microscopias verificou-se a reticulação não homogênea da superfície da membrana. Por EDS não se verificou nenhum elemento estranho a estrutura da quitosana e do fármaco. Por medida do ângulo de molhabilidade pode-se verificar aumento do perfil hidrofílico da membrana por adição do fármaco, perfil este que não foi modificado pelo processo de reticulação. O ensaio de citotoxicidade apresentou resultados que indicam a membrana como promissora candidata a testes in vivo. / This research aims to characterize chitosan films, sublingual application, for use in controlled release of formoterol fumarate systems., Looking for a new alternative for the emergency treatment of asthma attacks. We know that asthma is a disease of high incidence in Brazil and in the world, because we have about 300milhões of people with the disease worldwide and 20 million Brazilians .It is one hereditary disease, chronic that has no cure and that often presents as a medical emergency, because the crisis of the disease the relief should be immediate in order to prevent the death of the patient. Today only is used inhalation as preferred for administration of bronchodilators, since this route has faster action .In entando, we are faced with the difficult technique for using inhalers that deliver the medicine which often makes it impossible to use especially in children, the elderly and very debilidados patients. Buy this difficulty, we proposed in our work to seek a new route for the use of bronchodilators, which had the same effectiveness of inhaled, eliminating the difficult technique of using drugs .For this, choose the sublingual route of fast action and ease of use and can be used more appropriately in an asthma attack. Chitosan selected because it is a versatile and widely used biopolymer for controlled drug delivery system for conveying formoterol, which is a potent bronchodilator, by producing a film for sublingual deposition. And the results obtained from the characterization showed membranes crystallinity variations (XRD) according to the crosslinking process, besides presenting a possible relationship between cross-linking and release. By FTIR one can observe some interaction between the drug and amino groups of chitosan, and can isomerization of drug by crosslinking with 5% TPP. Through optical and electronic microscopy, it can be seen that addition of drug has provided some roughness to the membrane. Also by microscopy verified the inhomogeneous crosslinking of the membrane surface. EDS there was no foreign object the structure of chitosan and the drug. By measuring the wetting angle can be checked increase the hydrophilic profile of the membrane by addition of the drug, this profile has not been modified by crosslinking process. The cytotoxicity assay results presented indicate that the membrane as a promising candidate for in vivo testing.

<p>This thesis presents two new concepts in oral drug administration and the results of evaluation of some relevant formulation factors.</p><p>Investigation into improving the homogeneity of mixtures for tableting indicated that it may be possible to obtain interactive dry mixtures of micronised drugs containing drug proportions as low as 0.015% w/w. By studying the relationship between disintegration time and tensile strength, it was found that the microstructure surrounding the disintegrant particles may influence the disintegration process. Therefore, avoidance of excipients which are highly deformable or very soluble in water will result in more rapid disintegration. Further, it is possible to increase the bioadhesive properties of a non-bioadhesive carrier material by forming interactive mixtures containing a fine particulate bioadhesive material.</p><p>The new sublingual tablet concept presented is based on interactive mixtures consisting of a water-soluble carrier covered with fine drug particles and a bioadhesive component. With this approach, it is possible to obtain rapid dissolution in combination with bioadhesive retention of the drug in the oral cavity. Clinical data indicate that this allows rapid sublingual absorption while simultaneously avoiding intestinal absorption. </p><p>An individualised dose administration system is also presented. This system is based on the use of standardised units (microtablets), each containing a sub-therapeutic amount of the active ingredient. The required dose is fine-tuned by electronically counting out a specific number of these units using an automatic dose dispenser. A patient handling study supported the suggestion that the dosage of some medications can be more easily and safely individualised for each patient with this method than by using traditional methods of mixing different standard tablet strengths or dividing tablets.</p>

This thesis presents two new concepts in oral drug administration and the results of evaluation of some relevant formulation factors. Investigation into improving the homogeneity of mixtures for tableting indicated that it may be possible to obtain interactive dry mixtures of micronised drugs containing drug proportions as low as 0.015% w/w. By studying the relationship between disintegration time and tensile strength, it was found that the microstructure surrounding the disintegrant particles may influence the disintegration process. Therefore, avoidance of excipients which are highly deformable or very soluble in water will result in more rapid disintegration. Further, it is possible to increase the bioadhesive properties of a non-bioadhesive carrier material by forming interactive mixtures containing a fine particulate bioadhesive material. The new sublingual tablet concept presented is based on interactive mixtures consisting of a water-soluble carrier covered with fine drug particles and a bioadhesive component. With this approach, it is possible to obtain rapid dissolution in combination with bioadhesive retention of the drug in the oral cavity. Clinical data indicate that this allows rapid sublingual absorption while simultaneously avoiding intestinal absorption. An individualised dose administration system is also presented. This system is based on the use of standardised units (microtablets), each containing a sub-therapeutic amount of the active ingredient. The required dose is fine-tuned by electronically counting out a specific number of these units using an automatic dose dispenser. A patient handling study supported the suggestion that the dosage of some medications can be more easily and safely individualised for each patient with this method than by using traditional methods of mixing different standard tablet strengths or dividing tablets.

Sublingual administration of drugs offers advantages including avoidance of first pass metabolism and quick absorption into the systemic circulation. In spite of being one of the oldest routes of drug delivery, there is dearth of literature on characterization of the barrier properties of the sublingual mucosa. Therefore, the aim of this research was to gain an insight into the barrier properties of the porcine sublingual mucosa. The studies conducted in this dissertation research focused on an important aspect of sublingual permeation, the dependence of permeability on different physicochemical properties of the permeant such as the degree of ionization, distribution coefficient and molecular weight/size on drug transport across sublingual mucosa. Further the data from the sublingual permeation of model compounds was used in development of a predictive model which provided us with some understanding regarding the important descriptors required for sublingual drug delivery. A series of β-blockers were employed as the model drugs to study the dependence of permeability on lipophilicity across the sublingual mucosa. Eighth different β-blockers with log D (distribution coefficient) values ranging from -1.30 to 1.37 were used in this study. The most hydrophilic drug atenolol showed the lowest permeability (0.19 ± 0.04 x 10 -6 ) cm/sec and the most lipophilic drug propranolol showed the highest permeability (38.25 ± 4.30 x 10 -6 ) cm/sec. The log-log plot of permeability coefficient and the distribution coefficient showed a linear relationship. It was concluded that the increase in lipophilicity results in improved partitioning across the lipid bilayers of sublingual mucosa which results in increased permeation for the drugs. As the sublingual mucosa contains a significant amount of the polar lipids bonded with water molecules, therefore, it was hypothesized that the hydrophilic or ionized permeants will have significant permeation across the sublingual mucosa. The objective of this research was to study the effect of ionization on permeation across sublingual mucosa using a model drug nimesulide. Based on the relationship between the permeability coefficient and distribution coefficient of nimesulide at different pH, the lipoidal route was suggested as the dominant transport route for nimesulide across the sublingual mucosa. The contribution of individual ionic species of nimesulide to the total drug flux was quantitatively delineated. It was observed that the ionized species of nimesulide contributes significantly to the total flux across the sublingual mucosa. The contribution of the ionized species to total flux was almost (90%) at a pH where the drug was almost completely ionized. Polyethylene glycols (PEGs) were used as the model permeants to study the dependence of permeability on molecular weight. An inverse relationship between molecular weight and permeability coefficients was observed. This relationship was used to estimate the molecular weight cut off for the sublingual mucosa. The molecular weight cut off was estimated to be around 1675 daltons. Further, the Renkin function was used to estimate the theoretical pore size of the sublingual mucosa and the pore size of the sublingual mucosa was estimated to be around 30–53 Å based on two separate calculations using the radius of gyration and Stokes-Einstein radius for PEG molecules, respectively. No specific model is present in literature to predict the in vitro sublingual drug permeability. In this dissertation a specific model was developed and validated by performing permeation studies of 14 small molecules across the porcine sublingual mucosa. It was shown that the lipophilicity (logD 6.8 ) and the number of hydrogen bond donors (HBD) were the most significant descriptors affecting sublingual permeability. Research conducted in this dissertation provided an in-depth understanding about the barrier properties of the porcine sublingual mucosa and role of different physicochemical properties on sublingual transport. Such an understanding will hopefully expand the suitable lead candidates for sublingual delivery.