Preclinical evaluation of novel synthesised nanoparticles based on tyrosine poly(ester amide) for improved targeted pulmonary delivery.

Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines-fluticasone propionate (FP) and salmeterol xinafoate (SAL)-for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency- > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.

Development of Aerosol Dry Powder Chemotherapeutic-Loaded Microparticles for the Treatment of Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, resulting in the highest mortality rates among both men and women with respect to all other types of cancer. Difficulties in treating lung cancer arise from late-stage diagnoses and tumor heterogeneity and current treatment involves a combination of chemotherapeutics, surgery, and radiation. Chemotherapeutics administered systemically can lead to undesirable side effects and severe off-site toxicity. For example, chronic administration of the chemotherapeutic doxorubicin (DOX) leads to cardiotoxicity, thereby limiting its long-term use. Systemic administration of the highly lipophilic molecule paclitaxel (PTX) is hindered by its water solubility, necessitating the use of solubilizing agents, which can induce side effects. Thus, in this investigation, formulations consisting of spray-dried microparticles (MP) containing DOX and PTX were produced to be administered as dry powder aerosols directly to the lungs. Acetalated dextran (Ac-Dex) was used as the polymer in these formulations, as it is a biocompatible and biodegradable polymer that exhibits pH-responsive degradation. Solid-state characterization revealed that DOX and PTX remained in solubility favoring amorphous states in the MP formulations and that both drugs remained thermally stable throughout the spray drying process. In vitro release studies demonstrated the pH sensitivity of the formulations due to the use of Ac-Dex, as well as the release of both therapeutics over the course of at least 48 h. In vitro aerosol dispersion studies demonstrated that both formulations exhibited suitable aerosol dispersion properties for deep lung delivery.

Inhalable paclitaxel nanoagglomerate dry powders for lung cancer chemotherapy: Design of experiments-guided development, characterization and in vitro evaluation.

Conventional intravenous chemotherapy for lung cancer frequently results in inefficient drug penetration into primary lung tumors and severe systemic toxicities. This study reports the development of inhalable paclitaxel (PTX) nanoagglomerate dry powders (PTX-NADP) for enhanced pulmonary delivery of PTX chemotherapy to lung tumors using full factorial Design of Experiments. PTX nanoparticles were fabricated by flash nanoprecipitation with the aid of N-polyvinylpyrrolidone (PVP) and curcumin (CUR) as stabilizer and co-stabilizer respectively, and subsequently agglomerated into inhalable dry powders via co-spray drying with methylcellulose. The optimized PTX-NADP formulation exhibited acceptable aqueous redispersibility (redispersibility index = 1.17 ± 0.02) into âˆ¼ 150 nm nanoparticles and superb in vitro aerosol performance [mass median aerodynamic diameter (MMAD) = 1.69 ± 0.05 µm and fine particle fraction (FPF) of 70.89 ± 1.72 %] when dispersed from a Breezhaler® at 90 L/min. Notably, adequate aerosolization (MMAD < 3.5 µm and FPF > 40 %) of the optimized formulation was maintained when dispersed at reduced inspiratory flow rates of 30 - 60 L/min. Redispersed PTX nanoparticles from PTX-NADP demonstrated enhanced in vitro antitumor efficacy and cellular uptake in A549 lung adenocarcinoma cells without compromising tolerability of BEAS-2B normal lung epithelial cells towards PTX chemotherapy. These findings highlight the potential of inhaled PTX-NADP therapy to improve therapeutic outcomes for lung cancer patients with varying levels of pulmonary function impairment.

Development of favipiravir dry powders for intranasal delivery: An integrated cocrystal and particle engineering approach via spray freeze drying.

The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity. The cocrystal formation was characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy, and unit cell determination through Rietveld refinement of powder X-ray analysis. FAV-INA crystalized in a monoclinic space group P21/c with a unit cell volume of 1223.54(3) Å3, accommodating one FAV molecule and one INA molecule in the asymmetric unit. The cocrystal was further reproduced as intranasal dry powders by SFD, of which the morphology, particle size, in vitro drug release, and nasal deposition were assessed. The non-porous flake shaped FAV-INA powders exhibited a mean particle size of 19.79 ± 2.61 µm, rendering its suitability for intranasal delivery. Compared with raw FAV, FAV-INA displayed a 3-fold higher cumulative fraction of drug permeated in Franz diffusion cells at 45 min (p = 0.001). Dose fraction of FAV-INA deposited in the nasal fraction of a customized 3D-printed nasal cast reached over 80 %, whereas the fine particle fraction remained below 6 % at a flow rate of 15 L/min, suggesting high nasal deposition whilst minimal lung deposition. FAV-INA was safe in RPMI 2650 nasal and SH-SY5Y neuroblastoma cells without any in vitro cytotoxicity observed. This study demonstrated that combining the merits of cocrystallization and particle engineering via SFD can propel the development of advanced dry powder formulations for intranasal drug delivery.

A quality-by-design strategic approach for the development of bedaquiline-pretomanid nanoparticles as inhalable dry powders for TB treatment.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M.tb) and is the second leading cause of death from an infectious disease globally. The disease mainly affects the lungs and forms granulomatous lesions that encapsulate the bacteria, making treating TB challenging. The current treatment includes oral administration of bedaquiline (BDQ) and pretomanid (PTD); however, patients suffer from severe systemic toxicities, low lung drug concentration, and non-adherence. In this study, we developed BDQ-PTD loaded nanoparticles as inhalable dry powders for pulmonary TB treatment using a Quality-by-Design (QbD) approach. The BDQ-PTD combination showed an additive/synergistic effect for M.tb inhibition in vitro, and the optimized drug ratio (1:4) was successfully loaded into polymeric nanoparticles (PLGA NPs). The QbD approach was implemented by identifying the quality target product profile (QTPPs), critical quality attributes (CQAs), and critical process parameters (CPPs) to develop efficient design space for dry powder preparation using spray drying. The three-factorial and three-level Box-Behnken Design was used to assess the effect of process parameters (CPPs) on product quality (CQAs). The Design of Experiments (DoE) analysis showed different regression models for product quality responses and helped optimize process parameters to meet QTPPs. The optimized dry powder showed excellent yield (72 ± 2 % w/w), high drug (BDQ-PTD) loading, low moisture content (<1% w/w), and spherical morphology. Further, aerosolization performance revealed the suitability of powder for deposition in the respiratory airways of the lungs (MMAD 2.4 µm and FPF > 75 %). In conclusion, the QbD approach helped optimize process parameters and develop dry powder with a suitable quality profile for inhalation delivery in TB patients.

Inhaled dry powder liposomal azithromycin for treatment of chronic lower respiratory tract infection.

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.

Inhalable dry powders of microRNA-laden extracellular vesicles prepared by thin-film freeze-drying.

Extracellular vesicles (EVs) are endogenous vesicles that comprise a variety of submicron vesicular structures. Among these, exosomes have been widely investigated as delivery systems for small and large molecules. Herein, the thin-film freeze-drying technology was utilized to engineer aerosolizable dry powders of miR-335-laden induced EVs (iEV-335) generated in B cells for potential delivery into the lung to treat primary lung cancer and/or pulmonary metastases. The size distribution, structure, and morphology of iEV-335 were preserved after they were subjected to thin-film freeze-drying with the proper excipients. Importantly, iEV-335, in liquid or reconstituted from thin-film freeze-dried powders, were equally effective in downregulating SOX4 gene expression in LM2 human triple-negative mammary cancer cells. The iEV-335 dry powder compositions showed mass median aerodynamic diameters (MMAD) of around 1.2 µm with > 60 % of the emitted doses had an MMAD of ≤ 3 µm, indicating that the powders can potentially achieve efficient deposition within the alveolar region following oral inhalation, which is desirable for treatment of primary lung cancer and pulmonary metastases. Overall, it is concluded that it is feasible to apply thin-film freeze-drying to prepare aerosolizable dry powders of iEVs for pulmonary delivery.

Nivel de adhesión y prevalencia a inhaladores en pacientes ambulatorios con Asma y Enfermedad Pulmonar Obstructiva Crónica / Level of inhaler adhesion and prevalence in outpatients with Asthma and Chronic Obstructive Pulmonary Disease

INTRODUCCIÓN. Para el tratamiento farmacoterapéutico de enfermedades respi-ratorias, el uso de herramientas para abordar la vía inhalatoria es de elección por su mayor eficacia y menos efectos secundarios; registrar su adhesión y prevalencia es importante. OBJETIVO. Determinar el nivel y la prevalencia de adhesión al uso de inhaladores en pacientes con Asma y Enfermedad Pulmonar Obstructiva Cróni-ca. MATERIALES Y MÉTODOS. Estudio analítico transversal. Población de 215 y muestra de 121 Historias Clínicas. Se aplicó el Test de Adhesión a Inhaladores, que consistió en dos cuestionarios complementarios: el de 10 ítems, que valoró el nivel de adhesión, y el de 12 que identificó el tipo de incumplimiento en pacientes de Consulta Externa de la Unidad Técnica de Neumología del Hospital de Especialidades Carlos Andrade Marín, periodo julio 2018 - enero 2019. La tabulación y análisis de datos se realizó con el programa Excel. RESULTADOS. La prevalencia de mala adhesión en asmáticos fue de 83,33% y en Enfermedad Pulmonar Obstructiva Crónica 13,33%. En cuanto al sexo, la prevalencia de mala adhesión fue de 15,28% en hombres y de 40,82% en mujeres, con una p<0,05. No se encontró diferencia significativa respecto a los niveles de instrucción. CONCLUSIÓN. La prevalencia de mala adhesión al uso de inhaladores en pacientes con Asma y Enfermedad Pulmonar Obstructiva Crónica fue alta sobre todo en los asmáticos.

INTRODUCTION. For respiratory diseases and their pharmacotherapeutic treatment, the use of tools to address the inhalation route is chosen due to its greater efficacy and fewer secondary effects; then record the adherence and prevalence is important. OBJECTIVE. To determine both level and prevalence of adherence to the use of inhalers in patients with Asthma and Chronic Obstructive Pulmonary Disease. MATE-RIALS AND METHODS. Cross-sectional analytical study. Population of 215 and sam-ple of 121 patients. The Inhaler Adherence Test was applied, which consisted of two complementary questionnaires: a 10-item questionnaire, which assessed the level of adherence, and a 12-item questionnaire that identified the type of non-compliance in patients of the Pneumology Technical Unit of the Hospital de Especialidades Carlos Andrade Marín, period July 2018 - January 2019. The tabulation and data analysis was performed with Microsoft Excel program. RESULTS. The prevalence of poor ad-herence in asthmatics was 83.33% and in Chronic Obstructive Pulmonary Disease was 13.3%. Regarding gender, the prevalence of poor adherence was 15.28% in men and 40.82% in women, with a p <0.05. No significant differences were found regarding the levels of instruction. CONCLUSION. The prevalence of poor adherence to the use of inhalers in patients with Asthma and Chronic Obstructive Pulmonary Disease was high, especially in asthmatics

Peak inspiratory flow in children and adolescents with asthma using dry powder inhalers: a cross-sectional study / Pico de fluxo inspiratório de crianças e adolescentes com asma que utilizam inaladores de pó: um estudo transversal

ABSTRACT Objective: To measure peak inspiratory flow (PIF) and assess dynamic lung function in children and adolescents with asthma, as well as to determine the association of PIF with dynamic lung function and clinical variables. Methods: This was a cross-sectional study of children and adolescents with asthma using dry powder inhalers (DPIs) regularly. The control group included sex-, age-, weight-, and height-matched individuals without lung disease. Socioeconomic and clinical variables were collected. PIF and dynamic lung function variables were obtained with a specific device. Between-group comparisons were made with the Student's t-test and ANOVA. Multiple linear regression analysis was performed, and Pearson's correlation coefficients were calculated to assess associations between PIF and the other variables. Results: A total of 88 individuals (44 asthma patients and 44 controls) participated in the study. PIF and respiratory muscle strength (S-index) values were lower in the asthma patients than in the controls. PIF correlated positively with age, weight, height, and S-index in the asthma group. After controlling for height, we found an increase of 0.05 units in PIF associated with an increase of 1 unit in the S-index in the asthma group. Conclusions: PIF appears to be lower in children and adolescents with asthma than in those without asthma, correlating positively with age, height, weight, and respiratory muscle strength.

RESUMO Objetivo: Analisar o pico de fluxo inspiratório (PFI) e a função pulmonar dinâmica de crianças e adolescentes asmáticos e verificar sua associação com variáveis clínicas. Métodos: Estudo transversal com crianças e adolescentes asmáticos que faziam uso regular de inaladores de pó. O grupo controle foi composto por participantes sem doença pulmonar, pareados por sexo, idade, peso e altura. Foram coletadas variáveis socioeconômicas e clínicas. O PFI e variáveis de função pulmonar dinâmica foram obtidos através de um dispositivo específico. As associações entre os dois grupos foram estudadas utilizando-se o teste t de Student e ANOVA. Realizou-se um modelo de regressão linear múltipla e foram calculados os coeficientes de correlação de Pearson para estimar associações entre o PFI e as demais variáveis. Resultados: Foram incluídos no estudo 88 participantes (44 em cada grupo). Nos asmáticos, os valores do PFI e de força muscular respiratória (S-índex) foram menores que os dos controles. O PFI nos asmáticos apresentou correlações positivas com as variáveis idade, peso, altura e S-índex. Controlando-se a altura, houve um aumento de 0,05 unidades no PFI associado ao aumento de 1 unidade de S-índex nos asmáticos. Conclusões: O PFI é menor em crianças e adolescentes com asma em comparação àqueles sem asma com características antropométricas semelhantes e apresenta correlações positivas com idade, altura, peso e força dos músculos respiratórios.

Influencia del uso de inhaladores sobre la caries dental en pacientes pediátricos asmáticos: Estudio de casos y controles / Impact of inhaler use on dental caries in asthma pediatrics patients: A case-control study

Introducción. El asma es una enfermedad inflamatoria crónica con alta prevalencia en pacientes pediátricos. Existen resultados contradictorios respecto al efecto de esta enfermedad en los índices de caries dental. El objetivo del estudio fue determinar la prevalencia de caries dental en pacientes pediátricos asmáticos con medicación inhalatoria. Población y métodos. Estudio de casos y controles cuya muestra estuvo conformada por pacientes pediátricos que acudieron al Centro Médico Naval "Cirujano Mayor Santiago Távara" de diciembre de 2014 a marzo de 2015. Se dividieron en dos grupos: el primero (casos), integrado por pacientes asmáticos que utilizaban inhaladores en su tratamiento; el segundo (controles), por pacientes sanos del mismo nosocomio. Se realizó una evaluación médica para determinar tipo, tiempo y frecuencia del tratamiento y un examen oral para determinar la prevalencia de caries dental y el índice de dientes cariados, perdidos y obturados (CPOD). Resultados. Se encontró que la prevalencia de caries dental en el grupo control fue del 34,2 %, mientras, en el grupo casos, fue del 28,3 % (p = 0,094). Con respecto al índice de caries dental, el grupo control presentó CPOD de 4,73 ± 0,32, y el grupo casos, de 3,98 ± 0,31 (p = 0,08). Sin embargo, se evidenció que, a mayor tiempo de tratamiento con los inhaladores, el índice CPOD aumentaba significativamente (p = 0,04).Conclusiones. La medicación inhalatoria no incrementa la prevalencia de caries dental en pacientes pediátricos asmáticos. Sin embargo, existe una relación directa entre la duración del tratamiento y la prevalencia de caries dental

Introduction. Asthma is a chronic inflammatory disease that is highly prevalent among pediatric patients. The results about the effect of asthma on the rate of dental caries are contradictory. The objective of this study was to determine the prevalence of dental caries in asthma pediatric patients using inhaled drugs. Population and methods. Case-control study in a sample made up of pediatric patients who attended Centro Médico Naval "Cirujano Mayor Santiago Távara" between December 2014 and March 2015. Patients were divided into two groups: group A (cases) included asthma patients using inhalers as part of their treatment; group B (controls), healthy subjects who attended the same facility. A medical examination was done to determine the type, time, and frequency of treatment and an oral exam, to establish the prevalence of dental caries and the decayed, missing, and filled teeth (DMFT) index. Results. The prevalence of dental caries was 34.2 % in the control group and 28.3 % in the case group (p = 0.094). In relation to the rate of dental caries, the DMFT index in the control group was 4.73 ± 0.32, and 3.98 ± 0.31 in the case group (p = 0.08). However, it was evidenced that a longer duration of inhaler use led to a significantly higher DMFT index (p = 0.04).Conclusions. Inhaled drugs do not increase the prevalence of dental caries in asthma pediatric patients. However, there is a direct relationship between treatment duration and the prevalence of dental caries.

Most frequent errors in inhalation technique of patients with asthma treated at a tertiary care hospital / Erros mais frequentes na técnica inalatória de pacientes com asma brônquica em tratamento em hospital terciário

ABSTRACT Objective: To demonstrate the most frequent errors in inhalation technique in patients with asthma undergoing treatment at a tertiary care hospital. Methods: A cross-sectional study with a convenience sample of asthma patients aged 18 years or over, treated at a pulmonology outpatient clinic of a tertiary care hospital. The assessment of inhalation technique of users of the dry powder inhalers Aerolizer®, Aerocaps and Diskus®, or metered-dose inhalers was based on the manufacturer's instructions for use of each inhaler device. Patients demonstrated the inhalation technique with empty inhaler devices, and it was considered correct when all stages were performed properly, or when errors probably did not interfere with the treatment outcome. Results: Among 71 participants, 43 (60.5%) performed inhalation technique incorrectly. Among metered-dose inhalers and dry powder inhalers users, inhalation technique errors were found in 84.2% and 51.9%, respectively (p=0.013). Errors were more frequent at the exhalation stage (67.4%), followed by breathing in (58.1%) and apnea (51.2%). In the group using dry powder inhalers, the most common errors occurred during exhalation and, for those using metered-dose inhalers, the most compromised stage was aspiration. Conclusion: Errors were more frequent among those using metered-dose inhalers compared with dry powder inhalers. Misconceptions are more common at the expiration stage among users of dry powder inhalers and in aspiration among those on metered-dose inhalers.

RESUMO Objetivo: Demonstrar os erros mais frequentes na técnica inalatória de pacientes com asma brônquica em tratamento em hospital terciário. Métodos: Estudo transversal, com amostra de conveniência de pacientes com asma, com 18 anos ou mais, em tratamento em ambulatório de pneumologia de um hospital terciário. A avaliação da técnica inalatória dos usuários dos dispositivos de pó seco Aerolizer ®, Aerocaps® ou Diskus®, ou de aerossóis dosimetrados teve como base as orientações da bula do fabricante de cada dispositivo inalatório. Os pacientes demonstraram a técnica inalatória com dispositivos inalatórios vazios, e ela foi considerada correta quando todas as etapas foram realizadas de forma apropriada, ou quando os equívocos provavelmente não interferiam no resultado do tratamento. Resultados: Entre os 71 participantes, 43 (60,5%) realizaram a técnica inalatória de forma incorreta. Dentre os usuários de aerossóis dosimetrados e dispositivos de pó seco, ocorreram erros de técnica inalatória em 84,2% e 51,9%, respectivamente (p=0,013). Os erros foram mais frequentes na etapa da expiração (67,4%), seguidos da aspiração (58,1%) e da apneia (51,2%). No grupo que usava dispositivos de pó seco, os erros mais comuns aconteceram na expiração e, nos que utilizavam aerossóis dosimetrados, a etapa mais comprometida foi a aspiração. Conclusão: Os erros foram mais frequentes entre os que usavam aerossóis dosimetrados em comparação com dispositivos de pó seco. Os equívocos foram mais comuns na etapa da expiração entre os usuários de dispositivos de pó seco e na aspiração entre os que usavam aerossóis dosimetrados.

Repercussões cardiorrespiratórias agudas no uso correto de inaladores aerossóis de pó seco / Acute cardiopulmonary repercussions in the correct use of the dry-powder inhalers

Modelo do estudo: Trata-se de estudo original, transversal, clínico e comparativo. Objetivo do estudo: Avaliar as repercussões cardiorrespiratórias agudas no uso correto de inaladores aerossóis de pó seco (IPS) em pacientes com asma. Metodologia: Foram avaliados, em dois momentos, 17 pacientes adultos asmáticos em uso de IPS (Formoterol e Budesonida). As variáveis avaliadas, pré e pós-uso do IPS, foram: antropométrica, cognitiva, força muscular, sinais vitais, saturação de oxigênio, pressões respiratórias e pico de fluxo. No primeiro momento (M1) foi avaliada e monitorada a execução rotineira antes e imediatamente após uso do IPS e entregue folheto explicativo sobre o uso correto. No segundo momento (M2), 30 dias após M1, houve a mesma avaliação, entretanto, com execução correta do IPS. Resultados: No M2 ocorreram aumentos significativos da pressão inspiratória de 64,2±2,03 para 74,1±31,7 (cmH2O); pressão expiratória de 71,05±33,8 para 80±31,4 (cmH2O); capacidade vital de 3,3±0,9 para 3,9±0,9 (l) e reduções na frequência de pulso de 80,310,7 para 72,2±9,4 (bpm) e do duplo produto de 10001±1693 para 8846±1416 (teste t-Student pareado, p<0,05). Conclusões: O uso correto de IPS traz ao paciente repercussões cardiorrespiratórias positivas, melhorando as condições respiratórias e reduzindo o trabalho cardíaco.

Study model: It is a cross-over, clinical and comparative study. Objective: To evaluate the acute respiratory and cardiac respercussions in correct use of the dry powder inhalers (DPI) in patients with asthma. Methodology: Seventeen adult patients with asthma using DPI (Formoterol and Budesonide)were evaluated in two moments. The mensuared variables, before and after use of DPI, were: anthropometric, cognitive, muscle strength, vital signs, periferic oxygen saturation, respiratory pressures and peak expiratory flow. In the first moment (M1) was evaluated and monitored the usual performance before and immediately after using DPI and delivered an explicative leaflet about the correct use. In the second moment (M2), 30 days after M1, there was the same evaluation, however, with correct use ofthe DPI. Results: In the M2 there were increases to inspiratory pressure of 64,2±2,03 to 74,1±31,7(cmH2O); expiratory pressure of 71,05±33,8 to 80±31,4 (cmH2O); vital capacity of 3,3±0,9 to 3,9±0,9(l) and reductions in the pulse frequence of 80,3±10,7 to 72,2±9,4 (bm) and double product of 10001±1693 to 8846±1416 (paired t test, p<0,05). Conclusions: The correct use of the DPI promoves the positive respiratory and cardiac repercussions, improving respiratory conditions and reducing cardiac work.

Validation of scores of use of inhalation devices: valoration of errors / Validação de escores de uso de dispositivos para inalação: valoração dos erros cometidos

AbstractObjective: To validate two scores quantifying the ability of patients to use metered dose inhalers (MDIs) or dry powder inhalers (DPIs); to identify the most common errors made during their use; and to identify the patients in need of an educational program for the use of these devices.Methods: This study was conducted in three phases: validation of the reliability of the inhaler technique scores; validation of the contents of the two scores using a convenience sample; and testing for criterion validation and discriminant validation of these instruments in patients who met the inclusion criteria.Results: The convenience sample comprised 16 patients. Interobserver disagreement was found in 19% and 25% of the DPI and MDI scores, respectively. After expert analysis on the subject, the scores were modified and were applied in 72 patients. The most relevant difficulty encountered during the use of both types of devices was the maintenance of total lung capacity after a deep inhalation. The degree of correlation of the scores by observer was 0.97 (p < 0.0001). There was good interobserver agreement in the classification of patients as able/not able to use a DPI (50%/50% and 52%/58%; p < 0.01) and an MDI (49%/51% and 54%/46%; p < 0.05).Conclusions: The validated scores allow the identification and correction of inhaler technique errors during consultations and, as a result, improvement in the management of inhalation devices.

ResumoObjetivo: Validar dois escores para medir a habilidade de pacientes em utilizar inaladores pressurizados (IPs) ou inaladores de pó (IPos), verificar os erros mais comuns na sua utilização e identificar os pacientes que necessitam de um programa educacional para o uso desses dispositivos.Métodos: Este estudo foi realizado em três etapas: validação da confiabilidade dos escores de uso dos dispositivos inalatórios; validação do conteúdo dos escores utilizando-se uma amostra de conveniência; e realização de testes para a validação de critério e a validação discriminante desses instrumentos em pacientes que preenchiam os critérios de inclusão do estudo.Resultados: A amostra de conveniência foi composta por 16 pacientes, e houve discordância interobservador em 19% e 25% para os escores de IPo e IP, respectivamente. Após a análise de expertos no assunto, os escores sofreram modificações e foram aplicados em 72 pacientes. A dificuldade mais relevante no uso de ambos os dispositivos foi a manutenção da capacidade pulmonar total após inspiração profunda. O grau de correlação dos escores por observador foi de 0,97 (p < 0,0001). Houve boa concordância interobservador na classificação dos pacientes como aptos/não aptos para uso de IPo (50%/50% e 52%/58%; p < 0,01) e de IP (49%/51% e 54%/46%; p < 0,05).Conclusões: Os escores validados permitem identificar e corrigir os erros da técnica inalatória ao longo das consultas e, em consequência, melhorar o manejo dos dispositivos para inalação.

Efficacy and safety of the single-capsule combination of fluticasone/formoterol in patients with persistent asthma: a non-inferiority trial / Eficácia e segurança da associação fluticasona/formoterol em cápsula única em pacientes com asma persistente: estudo de não inferioridade

OBJECTIVE: Fluticasone and formoterol are effective in the treatment of asthma. When a corticosteroid alone fails to control asthma, combination therapy is the treatment of choice. The objective of this study was to compare the efficacy and safety of formulations containing budesonide/formoterol (BUD/FOR), fluticasone alone (FLU), and the single-capsule combination of fluticasone/formoterol (FLU/FOR) on lung function in patients with mild-to-moderate persistent asthma. METHODS: This was a randomized, multicenter, open phase III trial conducted in Brazil. The primary efficacy analysis was the assessment of non-inferiority between FLU/FOR and BUD/FOR combinations regarding FEV1 (in L) at the final visit. The secondary analyses were PEF, level of asthma control, serum cortisol levels, frequency of adverse events, adherence to treatment, and appropriate inhaler use. RESULTS: We randomized 243 patients to three groups: FLU/FOR (n = 79), BUD/FOR (n = 83), and FLU (n = 81). In terms of the mean FEV1 after 12 weeks of treatment, the difference between the FLU/FOR and BUD/FOR groups was 0.22 L (95% CI: −0.06 to 0.49), whereas the difference between the FLU/FOR and FLU groups was 0.26 L (95% CI: −0.002 to 0.52). Non-inferiority was demonstrated by the difference between the lower limits of the two 95% CIs (−0.06 vs. −0.002). The level of asthma control and PEF were significantly greater in the FLU/FOR and BUD/FOR groups than in the FLU group. There were no significant differences among the groups regarding patient adherence, patient inhaler use, or safety profile of the formulations. CONCLUSIONS: The single-capsule combination of FLU/FOR showed non-inferiority to the BUD/FOR and FLU formulations regarding efficacy and ...

OBJETIVO: A fluticasona e o formoterol são efetivos no tratamento da asma. A terapia combinada é o tratamento de escolha quando o corticosteroide isolado não controla a asma. O objetivo deste estudo foi comparar a eficácia e segurança de formulações contendo budesonida/formoterol (BUD/FOR), fluticasona (FLU) e fluticasona/formoterol (FLU/FOR) em cápsula única sobre a função pulmonar em pacientes com asma persistente leve e moderada. MÉTODOS: Estudo de fase III multicêntrico brasileiro, aleatorizado e aberto. A análise primária de eficácia foi a avaliação de não inferioridade da combinação FLU/FOR perante a combinação BUD/FOR em relação ao VEF1 (em L) na visita final. As análises secundárias foram PFE, nível de controle da asma, nível de cortisol sérico, frequência de eventos adversos, aderência ao tratamento e uso adequado do inalador. RESULTADOS: Foram randomizados 243 pacientes nos grupos FLU/FOR (n = 79), BUD/FOR (n = 83) e FLU (n = 81). Após 12 semanas de tratamento, a média da diferença do VEF1 foi de 0,22 L (IC95%: −0,06 a 0,49) entre os grupos FLU/FOR e BUD/FOR e de 0,26 L (IC95%: −0,002 a 0,52) entre os grupos FLU/FOR e FLU. A não inferioridade ficou demonstrada pela diferença de limite inferior do IC95% (−0,06 vs. −0,002). O nível de controle da asma e o PFE foram significativamente maiores nos grupos FLU/FOR e BUD/FOR em comparação com o grupo FLU. Não houve diferenças significativas em relação a adesão, uso do inalador e perfil de segurança entre os grupos. CONCLUSÕES: ...

Assessment of inhaler techniques employed by patients with respiratory diseases in southern Brazil: a population-based study / Avaliação da técnica de utilização de dispositivos inalatórios no tratamento de doenças respiratórias no sul do Brasil: estudo de base populacional

OBJECTIVE: To identify incorrect inhaler techniques employed by patients with respiratory diseases in southern Brazil and to profile the individuals who make such errors. METHODS: This was a population-based, cross-sectional study involving subjects ≥ 10 years of age using metered dose inhalers (MDIs) or dry powder inhalers (DPIs) in 1,722 households in the city of Pelotas, Brazil. RESULTS: We included 110 subjects, who collectively used 94 MDIs and 49 DPIs. The most common errors in the use of MDIs and DPIs were not exhaling prior to inhalation (66% and 47%, respectively), not performing a breath-hold after inhalation (29% and 25%), and not shaking the MDI prior to use (21%). Individuals ≥ 60 years of age more often made such errors. Among the demonstrations of the use of MDIs and DPIs, at least one error was made in 72% and 51%, respectively. Overall, there were errors made in all steps in 11% of the demonstrations, whereas there were no errors made in 13%.Among the individuals who made at least one error, the proportion of those with a low level of education was significantly greater than was that of those with a higher level of education, for MDIs (85% vs. 60%; p = 0.018) and for DPIs (81% vs. 35%; p = 0.010). CONCLUSIONS: In this sample, the most common errors in the use of inhalers were not exhaling prior to inhalation, not performing a breath-hold after inhalation, and not shaking the MDI prior to use. Special attention should be given to education regarding inhaler techniques for patients of lower socioeconomic status and with less formal education, as well as for those of advanced age, because those populations are at a greater risk of committing errors in their use of inhalers. .

OBJETIVO: Conhecer os erros na técnica de uso de dispositivos inalatórios empregada por pacientes com doenças respiratórias no sul do Brasil e o perfil daqueles que possuem dificuldades em realizá-la. MÉTODOS: Estudo transversal, de base populacional, com indivíduos com idade ≥ 10 anos e em uso de inaladores pressurizados (IPrs) ou inaladores de pó (IP) em 1.722 domicílios de Pelotas (RS). RESULTADOS: Foram incluídos 110 indivíduos que utilizavam 94 IPrs e 49 IP. Os principais erros no uso dos IPrs e IP foram não expirar antes da inalação (66% e 47%, respectivamente), não fazer uma pausa inspiratória após a inalação (29% e 25%) e não agitar o IPr antes do uso (21%). Os indivíduos com idade ≥ 60 anos mais frequentemente cometeram erros. Das demonstrações de uso do IPr e IP, respectivamente, 72% e 51% apresentaram ao menos um erro, enquanto 13% das demonstrações foram plenamente corretas e 11% apresentaram erros em todas as fases. A proporção de indivíduos com menor nível de escolaridade que cometeram ao menos um erro foi significativamente maior do que a daqueles com maior nível de escolaridade tanto no uso de IPrs (85% vs. 60%; p = 0,018) quanto no de IPs (81% vs. 35%; p = 0,010). CONCLUSÕES: Nesta amostra, os principais erros cometidos no uso dos inaladores foram não realizar a expiração antes da inalação, não fazer a pausa inspiratória após a inalação e não agitar o IPr. Pacientes com menor nível socioeconômico e educacional, assim como aqueles com idade avançada, merecem especial atenção na educação sobre a realização da técnica inalatória, pois apresentam um maior risco de cometer erros durante o uso dos inaladores. .

Formulation and evaluation of CFC free inhalers for beclomethasone dipropionate

Beclomethasone dipropionate CFC free inhalation formulations were developed with a view to treat asthma prophylactically. Dry powder inhalers (DPI) for beclomethasone dipropionate were prepared with different grades of lactose monohydrate. The influence of carrier and overages on performance of DPI was studied. Metered dose inhalers (MDI) with HFA based propellants were formulated with various doses, overages and different concentrations of alcohol. Formulated DPI and MDI were evaluated for various official and unofficial quality control tests. The influence of over doses on valve delivery, effect of overages on emitted dose and influence of alcohol on spray pattern from MDI were studied. The better fine particle fraction and emitted dose were obtained from the DPI formulated with 10:90 ratio of fine lactose: coarse lactose and with 20% w/w overages. The studies on MDI revealed that the 15% of overdoses are required for effective valve delivery and 20% overages are required for 100% drug delivery. 5-10%v/v alcohol was found to be preferable to get optimum emitted dose and fine particle fraction.

Desenvolveram-se formulações por inalação de dipropionato de beclometasona, livres de CFC, com o objetivo de tratar a asma profilaticamente. Prepararam-se inaladores de pó seco (DPI) para o dipropionato de beclometasona com diferentes gradações de lactose monoidratada. Estudou-se a influência do transportador e dos excessos de fármaco em relação ao rotulado no desempenho do DPI. Inaladores de dose calibrada (MDI) com propelentes à base de hidrofluoralcanos (HFA) foram formulados com várias doses, excessos de fármaco em relação ao rotulado e diferentes concentrações de álcool. Avaliaram-se as DPI e MDI formuladas por vários métodos oficiais e não oficiais de controle de qualidade. Estudaram-se a influência da superdosagem na liberação da válvula, o efeito dos excessos na dose emitida e a influência do álcool no padrão do spray do MDI. Obtiveram-se a melhor partícula fina e a dose emitida do DPI formulado com proporção de 10:90 de lactose fina:lactose grossa e 20% p/p de excesso. Os estudos em MDI revelaram que 15% de sobredose são requeridos para a liberação efetiva da válvula e 20% de excessos, para a liberação de 100% dos fármacos. Álcool a 5-10% v/v permitiu alcançar ótima dose emitida e fração de partícula fina.

Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó / Pharmaceutical equivalence of the combination formulation of budesonide and formoterol in a single capsule with a dry powder inhaler

OBJETIVO: Avaliar a equivalência farmacêutica da formulação teste (associação fixa de budesonida e fumarato de formoterol em cápsula única dispensada com o dispositivo Aerocaps®) em relação a uma formulação referência (budesonida e fumarato de formoterol em duas cápsulas distintas dispensadas com o dispositivo Aerolizer®). MÉTODOS: Estudo in vitro no qual foram realizadas identificação/quantificação dos ingredientes ativos por HPCL e determinação da uniformidade da dose liberada e da distribuição aerodinâmica das partículas das formulações teste e referência. RESULTADOS: Na formulação teste, o teor de budesonida e de formoterol foi de 111,0% e 103,8%, respectivamente, enquanto esse foi de 110,5% e 104,5% na formulação referência. Na formulação teste, a uniformidade das doses de budesonida e de formoterol foi de 293,2 µg e 10,2 µg, respectivamente, enquanto essa foi de 353,0 µg e 11,1 µg na formulação referência. Esses resultados estão dentro da faixa recomendada para esse tipo de formulação (75-125% da dose rotulada). A fração de partículas finas (< 5 µm) para budesonida e formoterol foi de, respectivamente, 45% e 56% na formulação teste e de 54% e 52% na formulação referência. CONCLUSÕES: As formulações teste e referência apresentaram níveis de ingredientes ativos, uniformidade de doses e diâmetros aerodinâmicos apropriados ao uso com seus respectivos dispositivos inalatórios de pó.

OBJECTIVE: To evaluate the pharmaceutical equivalence of a test formulation (fixed-dose combination of budesonide and formoterol fumarate in a single capsule dispensed in an Aerocaps® inhaler) in relation to a reference formulation (budesonide and formoterol fumarate in two separate capsules dispensed in an Aerolizer® inhaler). METHODS: This was an in vitro study in which we performed the identification/quantification of the active ingredients by HPLC and determined dose uniformity and aerodynamic particle size distribution in the test and reference formulations. RESULTS: In the test formulation, the content of budesonide and formoterol was 111.0% and 103.8%, respectively, compared with 110.5% and 104.5%, respectively, in the reference formulation. In the test formulation, dose uniformity regarding budesonide and formoterol was 293.2 µg and 10.2 µg, respectively, whereas it was 353.0 µg and 11.1 µg in the reference formulation. These values are within the recommended range for this type of formulation (75-125% of the labeled dose). The fine particle fraction (< 5 µm) for budesonide and formoterol was 45% and 56%, respectively, in the test formulation and 54% and 52%, respectively, in the reference formulation. CONCLUSIONS: For both of the formulations tested, the levels of active ingredients, dose uniformity, and aerodynamic diameters were suitable for use with the respective dry powder inhalers.

Eficácia e segurança de dois inaladores de pó seco usados para a aplicação de furoato de mometasona em pacientes com asma / Efficacy and safety of two dry-powder inhalers for the administration of mometasone furoate in asthma patients

OBJETIVO: O furoato de mometasona (FM) é um novo corticosteroide inalatório sintético potente. Internacionalmente, o FM é fornecido em um inalador de pó seco que permite sua administração em múltiplas doses. Para se obter uma preparação com melhor relação custo-eficácia, foram desenvolvidas no Brasil formulações de FM em cápsulas de pó seco para serem administradas em dose única. O presente estudo teve como objetivo avaliar a eficácia e a segurança dos dois inaladores usados para a administração de FM em pacientes asmáticos. MÉTODOS: Estudo clínico, aberto, comparativo, paralelo e multicêntrico com 74 adultos portadores de asma persistente e moderada, randomizados em dois grupos para receber FM em uma dose de aproximadamente 400 µg, fornecida por um inalador de dose múltipla ou pelo novo inalador de dose única, uma vez ao dia durante 60 dias. RESULTADOS: Não foram observadas diferenças significantes entre os dois grupos estudados nos desfechos primários (VEF1 e frequência do uso de medicação de resgate) ou nos desfechos secundários (PFE matinal, tolerabilidade e segurança, essa última avaliada pelo estudo do eixo hipotálamo-hipófise-adrenal). CONCLUSÕES: A administração de FM com o novo inalador de dose única desenvolvido no Brasil tem eficácia e segurança comparáveis à administração com o inalador de dose múltipla no tratamento de pacientes asmáticos.

OBJECTIVE: Mometasone furoate (MF) is a new, potent synthetic inhaled corticosteroid. Worldwide, MF is administered via a dry-powder inhaler that contains multiple doses. As a preparation that would be more cost-effective, single-dose MF capsules were developed in Brazil. The objective of the present study was to evaluate the efficacy and safety of the two inhalers for MF administration in patients with asthma. METHODS: A randomized, multicenter, open-label, parallel-group clinical trial involving 74 adult patients with moderate, persistent asthma who were randomized into two groups to receive approximately 400 µg of MF once a day for 60 days, either via the multiple-dose inhaler or via the newly developed single-dose inhaler. RESULTS: No significant differences were observed between the two groups regarding the primary endpoints (FEV1 and rescue medication use) or the secondary endpoints (morning PEF, tolerability, and safety, the last as assessed on the basis of hypothalamic-pituitary-adrenal axis function). CONCLUSIONS: The use of the single-dose inhaler developed in Brazil for MF administration is as effective and safe as is that of a standard inhaler in the treatment of patients with asthma.