Thesis (Ph. D.)--University of Texas at Austin, 1999. / Vita. Includes bibliographical references (leaves 232-252). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 263-280). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Pharmaceutics. Bibliography : leaves 198-208. Also available online via the Internet.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Pharmaceutics. Title from thesis description page. Includes bibliographical references.

Background: Evidence on aerosol delivery via tracheostomy is lacking. The purpose of this study was to evaluate the effect of aerosol device and administration technique on drug delivery in a simulated spontaneously breathing pediatric model with tracheostomy. Methods: Delivery efficiencies during spontaneous breathing with assisted and unassisted administration techniques were compared using the jet nebulizer (JN- MicroMist), vibrating mesh nebulizer (VMN- Aeroneb Solo) and pressurized metered-dose inhaler (pMDI- ProAirHFA). The direct administration of aerosols in spontaneously breathing patients (unassisted technique) was compared to administration of aerosol therapy via a manual resuscitation bag (assisted technique) attached to the aerosol delivery device and synchronized with inspiration. An in-vitro lung model consisted of an uncuffed tracheostomy tube (4.5 mmID) was attached to a collecting filter (Respirgard) which was connected to a dual-chamber test lung (TTL) and a ventilator (Hamilton). The breathing parameters of a 2 years-old child were set at an RR of 25 breaths/min, a Vt of 150 mL, a Ti of 0.8 sec and PIF of 20 L/min. Albuterol sulfate was administered with each nebulizer (2.5 mg/3 ml) and pMDI with spacer (4 puffs, 108 µg/puff). Each aerosol device was tested five times with both administration techniques (n=5). Drug collected on the filter was eluted with 0.1 N HCl and analyzed via spectrophotometry. Results: The amount of aerosol deposited in the filter was quantified and expressed as inhaled mass and inhaled mass percent. The pMDI with spacer had the highest inhaled mass percent, while the VMN had the highest inhaled mass. The results of this study also found that JN had the least efficient aerosol device used in this study. The trend of higher deposition with unassisted versus assisted administration of aerosol was not significant (p>0.05). Conclusions: Drug deposited distal to the tracheostomy tube with JN was lesser than either VMN or pMDI. Delivery efficiency was similar with unassisted and assisted aerosol administration technique in this in vitro pediatric model.

Existem evidências na literatura de que a administração de medicações, como corticosteróides inalatórios e broncodilatadores, utilizando inaladores pressurizados dosimetrados, é mais eficaz e segura do que com os nebulizadores convencionais. Entretanto, há evidências de que não só pacientes, mas também profissionais de saúde têm dificuldade no manejo dos inaladores pressurizados dosimetrados. A hipótese do presente estudo é que o conhecimento da técnica inalatória entre os profissionais da nossa Instituição é heterogêneo, sendo que não há informações sobre o nível deste conhecimento entre as diversas categorias profissionais. OBJETIVOS: Avaliar o conhecimento prático e teórico de profissionais da área médica, de enfermagem e fisioterapia sobre a utilização do inalador dosimetrado através de testes padronizados. MÉTODOS: Avaliações teóricas e práticas sobre o conhecimento do uso de inaladores pressurizados dosimetrados foram realizadas com médicos, fisioterapeutas, enfermeiras e auxiliares de enfermagem, atribuindo-se uma nota de 0 a 10 para cada avaliação. Calcularam-se as medianas das notas obtidas pelos profissionais de cada categoria, as questões com maiores e menores índices de erros e feita a comparação descritiva do desempenho das diversas categorias profissionais. Após as avaliações, instrução verbal e escrita sobre a utilização correta dos dispositivos foi fornecida a todos os participantes. A análise estatística foi feita através do método de Kruskal-Wallis de comparação de medianas. Também foi realizada a análise através de regressão logística múltipla seqüencial. RESULTADOS: foram avaliados 30 médicos residentes ou estagiários da pediatria, 23 médicos assistentes, 29 fisioterapeutas, 33 enfermeiras e 31 auxiliares de enfermagem, em um total de146 profissionais. Não foram entrevistados residentes ou assistentes do grupo de Pneumologia. Os médicos residentes, fisioterapeutas e os médicos assistentes obtiveram desempenho significativamente superior que os enfermeiros e auxiliares de enfermagem. Apenas os médicos residentes obtiveram mediana superior a seis. As questões práticas com maiores índices de erros foram as relativas à limpeza do espaçador. Questões relativas à agitação do inalador antes do uso e à limpeza da cavidade oral após a sua utilização também obtiveram alto índice de erros. A questão teórica mais errada foi a respeito do tempo necessário entre dois jatos em aplicações sucessivas do inalador pressurizado dosimetrado. CONCLUSÕES: O conhecimento teórico-prático dos profissionais de saúde da Instituição a respeito do uso de inaladores pressurizados dosimetrados é heterogêneo. Os médicos residentes, fisioterapeutas e médicos assistentes obtiveram desempenho significativamente melhor que os enfermeiros e auxiliares de enfermagem sendo que estes últimos estão diretamente envolvidos na aplicação prática destes dispositivos na rotina hospitalar. / There are data in the literature indicating that the administration of medications such as inhaled corticosteroids and bronchodilators, using metered-dose inhalers, is more effective and safer than its dispensation by conventional nebulizers. However, there is evidence that not only patients but also health care professionals have difficulty in dealing with pressurized dose inhalers. The hypothesis of the present study is that the knowledge of inhalation techniques among health professionals of our Institution is heterogeneous, and there is no information about this knowledge among the diverse categories of professionals. OBJECTIVE: To assess the practical and theoretical knowledge of medical professionals, nursing and physiotherapy on the use of metereddose inhalers by standardized testing. METHODS: Practical and written tests on the use of metered-dose inhalers were applied to physicians, physical therapists, nurses and nursing assistants. A score from 0 to 10 was assigned to each evaluation. Median scores were calculated for each professional category. Questions with higher and lower correct values were identified, and a descriptive comparison was made regarding the performance of the diverse professional categories. Following the examination, oral and written instructions on the correct use of the devices were provided for all participants. Statistical analysis was performed using the Kruskal-Wallis method for comparison of medians. A sequential logistic multiple regression analysis was also performed. RESULTS: A total of 146 professionals were assessed, including 30 fellows in pediatrics, 23 attending physicians, 29 physical therapists, 33 nurses and 31 nursing assistants. Fellows or attending physicians of the Pediatric Pulmonology Unit were not included in the study. Fellows, physical therapists and attending physicians performed significantly better than did nurses and nursing assistants. Only fellows had a median score greater than six. On the practical tests for infants and toddlers, the step most often missed was that related to cleaning the spacer. On practical tests, the steps related to shaking the inhaler and cleaning the mouth also presented high error indices. On the written tests, the question most often answered incorrectly was that related to the waiting time between puffs. CONCLUSIONS: The theoretical and practical knowledge of health professionals of our Institution on the use of metered-dose inhalers is heterogeneous. The performance of fellows, physical therapists and attending physicians was significantly better than that of nurses and nursing assistants who are directly involved in the practical application of these devices in the hospital routine.

Existem evidências na literatura de que a administração de medicações, como corticosteróides inalatórios e broncodilatadores, utilizando inaladores pressurizados dosimetrados, é mais eficaz e segura do que com os nebulizadores convencionais. Entretanto, há evidências de que não só pacientes, mas também profissionais de saúde têm dificuldade no manejo dos inaladores pressurizados dosimetrados. A hipótese do presente estudo é que o conhecimento da técnica inalatória entre os profissionais da nossa Instituição é heterogêneo, sendo que não há informações sobre o nível deste conhecimento entre as diversas categorias profissionais. OBJETIVOS: Avaliar o conhecimento prático e teórico de profissionais da área médica, de enfermagem e fisioterapia sobre a utilização do inalador dosimetrado através de testes padronizados. MÉTODOS: Avaliações teóricas e práticas sobre o conhecimento do uso de inaladores pressurizados dosimetrados foram realizadas com médicos, fisioterapeutas, enfermeiras e auxiliares de enfermagem, atribuindo-se uma nota de 0 a 10 para cada avaliação. Calcularam-se as medianas das notas obtidas pelos profissionais de cada categoria, as questões com maiores e menores índices de erros e feita a comparação descritiva do desempenho das diversas categorias profissionais. Após as avaliações, instrução verbal e escrita sobre a utilização correta dos dispositivos foi fornecida a todos os participantes. A análise estatística foi feita através do método de Kruskal-Wallis de comparação de medianas. Também foi realizada a análise através de regressão logística múltipla seqüencial. RESULTADOS: foram avaliados 30 médicos residentes ou estagiários da pediatria, 23 médicos assistentes, 29 fisioterapeutas, 33 enfermeiras e 31 auxiliares de enfermagem, em um total de146 profissionais. Não foram entrevistados residentes ou assistentes do grupo de Pneumologia. Os médicos residentes, fisioterapeutas e os médicos assistentes obtiveram desempenho significativamente superior que os enfermeiros e auxiliares de enfermagem. Apenas os médicos residentes obtiveram mediana superior a seis. As questões práticas com maiores índices de erros foram as relativas à limpeza do espaçador. Questões relativas à agitação do inalador antes do uso e à limpeza da cavidade oral após a sua utilização também obtiveram alto índice de erros. A questão teórica mais errada foi a respeito do tempo necessário entre dois jatos em aplicações sucessivas do inalador pressurizado dosimetrado. CONCLUSÕES: O conhecimento teórico-prático dos profissionais de saúde da Instituição a respeito do uso de inaladores pressurizados dosimetrados é heterogêneo. Os médicos residentes, fisioterapeutas e médicos assistentes obtiveram desempenho significativamente melhor que os enfermeiros e auxiliares de enfermagem sendo que estes últimos estão diretamente envolvidos na aplicação prática destes dispositivos na rotina hospitalar. / There are data in the literature indicating that the administration of medications such as inhaled corticosteroids and bronchodilators, using metered-dose inhalers, is more effective and safer than its dispensation by conventional nebulizers. However, there is evidence that not only patients but also health care professionals have difficulty in dealing with pressurized dose inhalers. The hypothesis of the present study is that the knowledge of inhalation techniques among health professionals of our Institution is heterogeneous, and there is no information about this knowledge among the diverse categories of professionals. OBJECTIVE: To assess the practical and theoretical knowledge of medical professionals, nursing and physiotherapy on the use of metereddose inhalers by standardized testing. METHODS: Practical and written tests on the use of metered-dose inhalers were applied to physicians, physical therapists, nurses and nursing assistants. A score from 0 to 10 was assigned to each evaluation. Median scores were calculated for each professional category. Questions with higher and lower correct values were identified, and a descriptive comparison was made regarding the performance of the diverse professional categories. Following the examination, oral and written instructions on the correct use of the devices were provided for all participants. Statistical analysis was performed using the Kruskal-Wallis method for comparison of medians. A sequential logistic multiple regression analysis was also performed. RESULTS: A total of 146 professionals were assessed, including 30 fellows in pediatrics, 23 attending physicians, 29 physical therapists, 33 nurses and 31 nursing assistants. Fellows or attending physicians of the Pediatric Pulmonology Unit were not included in the study. Fellows, physical therapists and attending physicians performed significantly better than did nurses and nursing assistants. Only fellows had a median score greater than six. On the practical tests for infants and toddlers, the step most often missed was that related to cleaning the spacer. On practical tests, the steps related to shaking the inhaler and cleaning the mouth also presented high error indices. On the written tests, the question most often answered incorrectly was that related to the waiting time between puffs. CONCLUSIONS: The theoretical and practical knowledge of health professionals of our Institution on the use of metered-dose inhalers is heterogeneous. The performance of fellows, physical therapists and attending physicians was significantly better than that of nurses and nursing assistants who are directly involved in the practical application of these devices in the hospital routine.

Pressurized metered dose inhalers (pMDIs) are widely utilized to manage diseases of the lungs, such as asthma and chronic obstructive pulmonary disease. They can be formulated such that the drug and/or nonvolatile excipients are dissolved or dispersed in the formulation, rendering a solution or suspension formulation, respectively. While the formulation process for solution pMDIs is well defined, the formulation process of pMDIs with any type of suspended entity can be lengthy and empirical. The use of suspended drug or the addition of a second drug or excipient in a suspension pMDI formulation may non-linearly impact the product performance of the drug of interest in the formulation; this requires iterative testing of a series of pMDIs in order to identify a formulation with the most potential for success. One of the primary attributes used to characterize the product performance and quality control of inhaled medications is the residual aerodynamic particle size distribution (APSD) of the aerosolized drug. Along with clinical factors, formulation and device parameters have a significant impact on APSD. In this study, a computational model was developed using the principles of statistics and physical chemistry to predict the residual APSD generated by suspension pMDIs based on formulation, device, and raw drug or excipient substance considerations. The formulations modeled and experimentally evaluated consist of a suspended drug or excipient with/without a dissolved drug or excipient in a cosolvent-propellant system. The in silico model enables modeling a process that is difficult to delineate experimentally and contributes to understanding the link between pMDI formulation and device to product performance. The ability to identify and understand the variables that affect atomization and/or aerosol disposition , such as initial droplet size, suspended micronized drug or excipient size, and drug or excipient concentration, facilitates defining the design space for suspension pMDIs during development and improves recognizing the sensitive of the APSD is on each hardware and formulation variable. This model can later be applied to limit batch-to-batch variation in the manufacturing process and selecting plausible suspension pMDI formulations with quality design as the end goal.

No / Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution− absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence. / This work was in part funded by a grant from the Safety and Environmental Assurance Centre, Unilever Colworth, U.K. Particle sizing was performed by Steve Ingham, Institute of Pharmaceutical Science, King’s College London.

Aerosol electrostatics is an important property of pharmaceutical aerosols. The electrostatic properties of pMDI aerosols have been shown to be a function of both formulation and packaging components. The modified ELPI enables measurement of aerosol charge as a function of particle size, and the simultaneous determination of the mass distribution using chemical analysis. However, in order to fully assess the cause and effects of aerosol electrostatics in terms of its biological and regulatory implications, it is necessary to understand the basic charging mechanisms inside the pMDI formulation. Electrical resistivity and zeta potential measurements confirmed the presence of charged species within HFA based solutions and suspensions although the nature of these species remains unknown. These measurements were influenced by the cosolvent concentration and to a lesser extent by the presence of soluble drug and surfactant. The mean electrical resistivity of a 7% ethanol / 93% HFA 134a blend (0.83 ± 0.02 MΩ.cm) was significantly lower than that reported for HFA 134a (180 MΩ.cm). Albuterol sulfate demonstrated a positive zeta potential (75.9 ± 26.2 mV) in HFA 134a. Pilot molecular modeling studies, in conjunction with the analysis of particle interactions using HINT, provided an improved understanding of the possible interactions within albuterol sulfate HFA suspension pMDIs. The predominantly negative (-7597 ± 2063) HINT score signified unfavorable interactions between albuterol sulfate and HFA 134a molecules. Systematic investigations of the electrical properties of HFA solution and suspension pMDIs using the modified ELPI demonstrated that the electrical properties were a function of the formulation type (solution/suspension), formulation components and particle size. Experimental BDP solution pMDIs produced predominantly electropositive aerosols (net charge: 160 ± 30 pC) while albuterol sulfate pMDIs produced bipolar charged aerosol clouds (net charge: -162 ± 277 pC). Finally, the modified ELPI was recalibrated using commercially available polydisperse pMDIs as calibration aerosols with a reference Andersen cascade impactor. The mean cut-off diameters for stages 4-12 obtained following recalibration of the modified ELPI were 0.44, 0.56, 0.70, 1.01, 1.40, 2.12, 3.03, 4.75, 6.37 μm, respectively in comparison to those reported by the manufacturer (0.16, 0.27, 0.39, 0.62, 0.96, 1.62, 2.42, 4.05, 6.67 μm, respectively).