Orientador: Ricardo de Lima Zollner / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T18:58:24Z (GMT). No. of bitstreams: 1 ZanellatoFabbri_Natalia_D.pdf: 35087770 bytes, checksum: d1d79dc3e2bc0a5a2a05b4261a363a74 (MD5) Previous issue date: 2014 / Resumo: Apesar das diversas terapias disponíveis para o tratamento da rinite alérgica (RA), muitos pacientes não obtêm alívio dos sintomas com uso de um único fármaco e apresentam frequentemente queixa da manutenção dos sintomas mesmo sob tratamento. Estudos clínicos aleatorizados compararam a eficácia de anti-histamínicos e corticoides intranasais, isolados e associados e demonstraram que as terapias com drogas combinadas apresentam melhores resultados. A RA é um fator de risco para o desenvolvimento de obstrução de VAI e estudos clínicos com pacientes asmáticos demostraram redução da responsividade brônquica e sintomas de asma apenas com tratamento tópico nasal. O objetivo do presente estudo foi avaliar (1) o efeito do tratamento tópico nasal com azelastina (AZE), budesonida (BUD) e combinação AZE/BUD na obstrução nasal e sintomas de RA; (2) o efeito do estímulo nasal inespecífico com histamina na função pulmonar; e (3) o efeito dos tratamentos tópicos nasais na função pulmonar de pacientes com RA. O desenho do presente trabalho foi aleatorizado, cruzado e cego composto por 3 tratamentos. 28 pacientes participaram do estudo, com tratamento tópico nasal de 30 dias e intervalo de 7 dias entre os tratamentos. Os pacientes foram submetidos ao protocolo de TPN com histamina, avaliado por escore de sintomas, rinometria acústica e espirometria. Nossos resultados mostraram que a terapia com AZE/BUD é mais efetiva na prevenção da obstrução nasal e sintomas da RA comparada ao tratamento com as drogas isoladas. Além disso, encontramos indivíduos com alterações na função pulmonar após estímulo nasal inespecífico e controle destas alterações após tratamento tópico nasal, sugerindo influência positiva do tratamento nasal na função pulmonar de indivíduos com hiperreatividade brônquica / Abstract: Despite the several therapies available for the treatment of allergic rhinitis (AR) many patients do not get relief of symptoms using a single drug and often have the maintenance of symptoms even under treatment. Randomized clinical trials comparing the efficacy of antihistamines and intranasal corticosteroids, isolated and associates, show that the combination drug therapies have better outcomes. The AR is a risk factor for the development of obstruction in lower airways and clinical studies with asthmatic patients demonstrated reduction of bronchial hyperresponsiveness and asthma symptoms after just nasal topical treatment. The aim of this study was to evaluate (1) the effect of treatment with topical nasal azelastine (AZE), budesonide (BUD) and combined drugs (AZE/BUD) in nasal obstruction and symptoms of RA; (2) the effect of non-specific nasal challenge with histamine in lung function; and (3) the effect of topical nasal treatment on lung function in patients with RA. The design of this study was randomized, crossover and blind consisting of 3 periods of treatment with nasal sprays. 28 patients participated in the study, composed for 3 periods of treatment (30 days) and 7-day interval between treatments. Patients underwent protocol nasal provocation test with histamine assessed by symptom scores, acoustic rhinometry and spirometry. Our results showed that therapy with AZE/BUD is more effective in preventing nasal obstruction and symptoms of RA compared to treatment with drugs isolated. Furthermore, we find individuals with changes in pulmonary function after nonspecific nasal stimulation and control of these changes after nasal topical treatment, suggesting a positive influence of nasal treatment on lung function in subjects with bronchial hyperreactivity / Doutorado / Clinica Medica / Doutora em Clínica Médica

It has always been a challenge to imitate the lung environment, therefore there is a constant development of standardized in vitro dissolution methods for inhaled products. Dissolution in vitro has been considered as an important parameter, because low solubility determines the bioavailability of inhaled drugs. The in vitro dissolution data generated by the dissolution test experiment can be correlated with in vivo pharmacokinetic data through in vitro-in vivo correlation (IVIVC), because a completed predictive IVIVC model is very useful for drug formulation design and manufacturing changes after approval. The aim of this study was to investigate the effect of the membrane on the dissolution profile of orally inhaled drugs with different solubility, Budesonide (BUD) and Fluticasone propionate (FP) in the different pore sizes of the membrane 8.0 μm, 3.0 μm and 0.4 μm. The method in this study builds on previous dissolution methods, a Transwell® setup to dissolve the drugs with a small amount of dissolution medium, which mimics more the limited lung fluid capacity in vivo. In order to collect the dose from the drugs, Andersen Cascade Impact was used. The dissolution rate of BUD was first in the ranking in all of the pore sizes in the membrane.

Modified-release oral drug delivery dosage forms are widely used in the pharmaceutical field to overcome all the potential issues imposed by the physiological variabilities of the gastrointestinal tract as well as to maintain drug concentrations within the therapeutic window. In the market, they are available only as solid dosage forms such as capsules or tablets. The development of a liquid oral dosage form with modified-release properties has been keenly awaited. This form could increase the compliance of patients with a swallowing impairment (i.e. paediatric, older or critically ill patients) and, consequently, the efficacy of the therapeutic treatment. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup. Omeprazole and budesonide have been employed as model drugs. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a median diameter below 500 µm. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days). / Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie) / info:eu-repo/semantics/nonPublished

Today, orally inhaled drugs found on the market suffer from variable and discontinuous pulmonary drug release which lowers efficacy and patience compliance. This is usually a consequence of the poor understanding of the interaction and dissolution behavior of drug particles in the lung environment. Thus, the aim of this project was to investigate the effect of the dissolution medium on dissolution profiles for the well-known orally inhaled drug budesonide (BD) and fluticasone propionate (FP), in order to assess the importance of a proper selection of dissolution media for in vitro dissolution methods. In order to achieve this a modified Andersen Cascade Impactor was used to simulate deposition of particles onto filters. The dissolution was measured using a Transwell set up with polycarbonate membranes that can hold the filters with the deposited drug on it. Different media were prepared, from simple to more biorelevant. The samples taken during the dissolution experiments were analyzed quantitatively using UPLC-UV and the experimental data was processed by fitting to the Weibull function. The aim of this project was successfully achieved and the dissolution media that worked best for both BD and FP was PBS with the addition of 0.5% SDS. On the other hand, the dissolution media that performed the least for both BD and FP was the simulated lung fluid (SLF) with presence of 0.02% (w/v) DPPC. This may be due to the fact that DPPC forms liposomal aggregates which probably results in the media becoming more viscous and hence the dissolution time becomes slower.

<p>Allergic asthma is a disease involving airway inflammation, commonly linked to allergen exposure. Computed tomography (CT) is used to quantitatively assess changes in density, hence inflammation, in the lung. CT imaging provides the ability to non-invasively and longitudinally study disease progression and evaluate treatment efficacy. The objective of this study was to determine the sensitivity of CT to detect the anti-inflammatory effects of budesonide (BUD) by measuring airway tissue density in a rat model of allergic airway disease.</p> <p>Female<strong> </strong>Brown Norway rats were exposed intratracheally to house dust mite (HDM) extract (250 µg in 100µL saline) or saline control every other day for a total of five administrations (inflammatory phase). ABUD dose and temporal response study was performed usingBUD 0, 10, 100, and 300 µg/kg administered concurrently with HDM for three and six treatments (treatment phase). CT scanning was performed at baseline, post inflammatory phase, and after three and six BUD treatments. From the CT, density was measured in a defined volume of interest surrounding the major airways. Bronchoalveolar lavage (BAL) and histological samples were collected at the same time points.</p> <p>After the inflammatory phase, a significant increase in peribronchial density was found in the HDM group compared to controls. This corresponded to a significant increase in inflammation by histology andBALtotal cell count (TCC), specifically eosinophils. Within the treatment phase after three treatments,BUD100 and 300 µg/kg led to a significant shift in lung density compared to HDM exposure alone, to a state similar to baseline. All BUD treated groups expressed a significant reduction in peribronchial density after six treatments. However, histology andBALTCC only showed a significant decrease in inflammation after six treatments for all three BUD doses.</p> <p>CT densitometry is a sensitive, non-invasive method of evaluating the anti-inflammatory effects of budesonide and can be used for future screening of therapies in allergic lung models. Airway segmentation of CT permits the localized assessment of peribronchial inflammation, while other outcome measurements, such as BAL cytology, provide whole lung assessment which may not accurately reflect important regional changes.</p> / Master of Science (MSc)

Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, measuring the surface energies of a set of single drug and carrier (budesonide or theophylline with either mannitol or lactose) with different levels of surfactant using Inverse Gas Chromatography, and comparing them to their lung deposition performance using a Next Generation Impactor established a relationship between the two. A 1:10 mixing ratio of budesonide with either carrier was found to have the highest FPF. Coating the carriers with 0.05% sodium lauryl sulphate resulted in a further increase in the FPF when using either budesonide or theophylline as the API, and the same results were seen when a sonocrystallised version of the API was substituted for the micronised form. The calculated IGC values then showed that the highest performing formulations had the lowest dispersive energy and total free surface energy. Furthermore, a trend was observed in the work of adhesion (Wa) and work of cohesion (Wc) for each set of formulations depending on which API was chosen, where for the less polar drug (budesonide) a higher Wa/Wc ratio was associated with the highest formulation performance, and for the more polar drug (theophylline) a smaller Wa/Wc ratio was associated with the highest formulation performance, enabling the estimation of lung performance for a set of single drug and carrier using their surface energy data. / Kuwait’s government and the Ministry of Health of Kuwait

Introdução: A lavagem nasal com budesonida em solução salina de alto volume (BAV) tem sido utilizada no tratamento de rinossinusite crônica (RSC). Atualmente, não existem evidências de superioridade da BAV sobre o placebo (PLA). Objetivo: O estudo avalia a eficácia da lavagem nasal com BAV na RSC com polipose nasossinusal de difícil controle e asma brônquica. Métodos: Os indivíduos foram prospectivamente recrutados e randomizados em dois grupos: budesonida (1mg/dia) ou placebo, diluídos em 250mL de Soro Fisiológico a 0,9%, e orientados para aplicar 125mL dessa solução em cada narina de 12 em 12 horas, por 12 semanas. Os pacientes foram avaliados quanto a: qualidade de vida doença-específica (SNOT-20, NOSE), endoscopia nasossinusal (Lund-Kennedy) e olfato (UPSIT). Efeitos adversos foram avaliados por meio do cortisol sérico e urinário, feita a avaliação da opacidade do cristalino e teste de sobrecarga hídrica para aferição da pressão ocular. Resultados: Trinta e oito pacientes foram randomizados: 20 no grupo budesonida e 18 no grupo placebo; 3 pacientes do grupo placebo não concluíram o tratamento. O grupo BAV apresentou melhora estatisticamente significativa evidenciada nos questionários NOSE e Lund-Kennedy, enquanto no SNOT observou-se melhora em ambos os grupos. Não houve diferença estatisticamente significativa na comparação entre os grupos em nenhum parâmetro. Entretanto, o grupo BAV mostrou uma redução maior da obstrução nasal (NOSE), comparado ao grupo PLA, cuja análise dos dados apresentou uma tendência para significância estatística (p=0,0593) que poderia ter sido evidenciada caso houvesse um tamanho amostral maior. Pacientes com doença respiratória exacerbada por aspirina no grupo BAV apresentaram melhora mais importante da obstrução nasal (NOSE) quando comparada ao placebo (p=0,0030). Não ocorreu aumento significativo dos eventos adversos após os tratamentos. Conclusão: A lavagem nasal com budesonida em alto volume de solução salina na rinossinusite crônica com polipose nasossinusal de difícil controle e asma brônquica não mostrou ser eficaz na melhora da qualidade de vida doença-específica para rinossinusite (SNOT-20) quando comparada ao placebo, mas uma tendência para melhora significativa da obstrução nasal (NOSE) foi observada / Introduction: Nasal irrigation with high-volume budesonide (HVB) in saline solution has been utilized in the treatment of chronic rhinosinusitis (CRS). Currently, there is no evidence of the superiority of HVB over placebo (PLA). The efficacy and safety of this treatment in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma still needs to be better established. Objective: This study evaluated the efficacy of nasal irrigation with HVB in patients with difficult-to-control CRS with nasal polyposis and bronchial asthma. Methods: Subjects were prospectively recruited and randomized into two groups: budesonide (1 mg/day) or placebo, diluted in 250 mL of 0.9% saline solution. Patients were instructed to irrigate each nostril with 125 mL of this solution every 12 hours for 12 weeks. Patients were evaluated for disease-specific quality of life (SNOT-20, NOSE) and underwent sinonasal endoscopy (Lund-Kennedy score) and an olfactory test (UPSIT). Adverse effects were evaluated by measurement of serum and urinary cortisol levels, assessment of lens opacity, and a water-drinking test for measurement of intraocular pressure. Results: Thirty-eight patients were randomized: 20 to the budesonide and 18 to the placebo group. Three patients in the placebo group did not complete treatment. The HVB group exhibited statistically significant improvement in NOSE and Lund-Kennedy scores, while improvement in NOSE scores was observed in both groups. There were no statistically significant differences in any parameter on between-group comparison. However, the HVB group exhibited a greater reduction in nasal obstruction scores (NOSE) as compared to the PLA group, with data analysis showing a trend toward statistical significance (p=0.0593) if the sample size had been larger. Patients with aspirin-exacerbated respiratory disease in the HVB group exhibited greater improvement in nasal obstruction (NOSE) than those in the placebo group (p=0.0030). There was no increase in adverse effects after treatment. Conclusion: In patients with difficult-to-control chronic rhinosinusitis with nasal polyposis and bronchial asthma, nasal irrigation with high-volume saline solution plus budesonide was not effective in improving disease-specific quality of life (SNOT-20) as compared with placebo, but was associated with a trend toward significant improvement in nasal obstruction (NOSE)

Introdução: A lavagem nasal com budesonida em solução salina de alto volume (BAV) tem sido utilizada no tratamento de rinossinusite crônica (RSC). Atualmente, não existem evidências de superioridade da BAV sobre o placebo (PLA). Objetivo: O estudo avalia a eficácia da lavagem nasal com BAV na RSC com polipose nasossinusal de difícil controle e asma brônquica. Métodos: Os indivíduos foram prospectivamente recrutados e randomizados em dois grupos: budesonida (1mg/dia) ou placebo, diluídos em 250mL de Soro Fisiológico a 0,9%, e orientados para aplicar 125mL dessa solução em cada narina de 12 em 12 horas, por 12 semanas. Os pacientes foram avaliados quanto a: qualidade de vida doença-específica (SNOT-20, NOSE), endoscopia nasossinusal (Lund-Kennedy) e olfato (UPSIT). Efeitos adversos foram avaliados por meio do cortisol sérico e urinário, feita a avaliação da opacidade do cristalino e teste de sobrecarga hídrica para aferição da pressão ocular. Resultados: Trinta e oito pacientes foram randomizados: 20 no grupo budesonida e 18 no grupo placebo; 3 pacientes do grupo placebo não concluíram o tratamento. O grupo BAV apresentou melhora estatisticamente significativa evidenciada nos questionários NOSE e Lund-Kennedy, enquanto no SNOT observou-se melhora em ambos os grupos. Não houve diferença estatisticamente significativa na comparação entre os grupos em nenhum parâmetro. Entretanto, o grupo BAV mostrou uma redução maior da obstrução nasal (NOSE), comparado ao grupo PLA, cuja análise dos dados apresentou uma tendência para significância estatística (p=0,0593) que poderia ter sido evidenciada caso houvesse um tamanho amostral maior. Pacientes com doença respiratória exacerbada por aspirina no grupo BAV apresentaram melhora mais importante da obstrução nasal (NOSE) quando comparada ao placebo (p=0,0030). Não ocorreu aumento significativo dos eventos adversos após os tratamentos. Conclusão: A lavagem nasal com budesonida em alto volume de solução salina na rinossinusite crônica com polipose nasossinusal de difícil controle e asma brônquica não mostrou ser eficaz na melhora da qualidade de vida doença-específica para rinossinusite (SNOT-20) quando comparada ao placebo, mas uma tendência para melhora significativa da obstrução nasal (NOSE) foi observada / Introduction: Nasal irrigation with high-volume budesonide (HVB) in saline solution has been utilized in the treatment of chronic rhinosinusitis (CRS). Currently, there is no evidence of the superiority of HVB over placebo (PLA). The efficacy and safety of this treatment in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma still needs to be better established. Objective: This study evaluated the efficacy of nasal irrigation with HVB in patients with difficult-to-control CRS with nasal polyposis and bronchial asthma. Methods: Subjects were prospectively recruited and randomized into two groups: budesonide (1 mg/day) or placebo, diluted in 250 mL of 0.9% saline solution. Patients were instructed to irrigate each nostril with 125 mL of this solution every 12 hours for 12 weeks. Patients were evaluated for disease-specific quality of life (SNOT-20, NOSE) and underwent sinonasal endoscopy (Lund-Kennedy score) and an olfactory test (UPSIT). Adverse effects were evaluated by measurement of serum and urinary cortisol levels, assessment of lens opacity, and a water-drinking test for measurement of intraocular pressure. Results: Thirty-eight patients were randomized: 20 to the budesonide and 18 to the placebo group. Three patients in the placebo group did not complete treatment. The HVB group exhibited statistically significant improvement in NOSE and Lund-Kennedy scores, while improvement in NOSE scores was observed in both groups. There were no statistically significant differences in any parameter on between-group comparison. However, the HVB group exhibited a greater reduction in nasal obstruction scores (NOSE) as compared to the PLA group, with data analysis showing a trend toward statistical significance (p=0.0593) if the sample size had been larger. Patients with aspirin-exacerbated respiratory disease in the HVB group exhibited greater improvement in nasal obstruction (NOSE) than those in the placebo group (p=0.0030). There was no increase in adverse effects after treatment. Conclusion: In patients with difficult-to-control chronic rhinosinusitis with nasal polyposis and bronchial asthma, nasal irrigation with high-volume saline solution plus budesonide was not effective in improving disease-specific quality of life (SNOT-20) as compared with placebo, but was associated with a trend toward significant improvement in nasal obstruction (NOSE)

Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted. / text