Developing Dry Powder Inhaler Formulations.

This section aims to provide a concise and contemporary technical perspective and reference resource covering dry powder inhaler (DPI) formulations. While DPI products are currently the leading inhaled products in terms of sales value, a number of confounding perspectives are presented to illustrate why they are considered surprisingly, and often frustratingly, poorly understood on a fundamental scientific level, and most challenging to design from first principles. At the core of this issue is the immense complexity of fine cohesive powder systems. This review emphasizes that the difficulty of successful DPI product development should not be underestimated and is best achieved with a well-coordinated team who respect the challenges and who work in parallel on device and formulation and with an appreciation of the handling environment faced by the patient. The general different DPI formulation types, which have evolved to address the challenges of aerosolizing fine cohesive drug-containing particles to create consistent and effective DPI products, are described. This section reviews the range of particle engineering processes that may produce micron-sized drug-containing particles and their subsequent assembly as either carrier-based or carrier-free compositions. The creation of such formulations is then discussed in the context of the material, bulk, interfacial and ultimately drug-delivery properties that are considered to affect formulation performance. A brief conclusion then considers the future DPI product choices, notably the issue of technology versus affordability in the evolving inhaler market.

Effect on Physical Position of Peak Inspiratory Flow in Stable COPD: An Observational Study.

Background: We examined the effect of physical position on peak inspiratory flow (PIF) in patients with chronic obstructive pulmonary disease (COPD) using dry-powder inhalers (DPIs) with low­medium internal resistance (R2) and/or high internal resistance (R5). Methods: This prospective study in stable, ambulatory patients with spirometry-confirmed COPD evaluated the effect of 3 physical positions on maximal PIF achieved. Participants had PIFs of 30-90L/min (R5) or 60-90L/min (R2 DPIs) using the In-Check™ DIAL. PIF was measured in triplicate randomly in 3 positions that patients might be in while using their inhaler (standing, sitting, and semi-upright [supine position with the head of the bed at 45°, neck flexed forward]) against prescribed DPI resistance (R2/R5/both). Correlations between PIF and percentage decline in PIF between positions and differences in participant characteristics with >10% versus ≤10% PIF decline standing to semi-upright were calculated. Results: A total of 76 participants (mean age, 65.2 years) had positional measurements; 59% reported seated DPI use at home. The mean (standard deviation) PIF standing, sitting, and semi-upright was 80.7 (13.4), 77.8 (14.3), and 74.0 (14.5) L/min, respectively, for R2 and 51.1 (9.52), 48.6 (9.84), and 45.8 (7.69) L/min, respectively, for R5 DPIs. PIF semi-upright was significantly lower than sitting and standing (R2; P < 0.0001) and standing (R5; P= 0.002). Approximately half of the participants had >10% decline in PIF from standing to semi-upright. Patient characteristics exceeding the 0.10 absolute standardized difference threshold with the decline in PIF for both the R2 and R5 DPIs were waist-to-hip ratio, modified Medical Research Council dyspnea score, and postbronchodilator percentage predicted forced vital capacity and PIF by spirometry. Conclusions: PIF was significantly affected by physical position regardless of DPI resistance. PIF was highest when standing and lowest when semi-upright. We recommend that patients with COPD stand while using an R2 or R5 DPI. Where unfeasible, the position should be sitting rather than semi-upright. ClinicalTrials.gov identifier NCT04168775.

γ-Cyclodextrin metal-organic frameworks as the promising carrier for pulmonary delivery of cyclosporine A.

γ-Cyclodextrin metal-organic frameworks (CD-MOFs) are considered as a green and biocompatible material with great potential in drug delivery systems. Original CD-MOFs show the poor aerosol properties, which limit the application in pulmonary drug delivery. To improve the in vitro deposition properties, herein, we synthesized CD-MOFs by the vapor diffusion method using a series of modulators to achieve better pulmonary delivery of cyclosporine A (CsA). The results showed that blank CD-MOFs and drug loaded CD-MOFs prepared with different modulators all preserved the cubical shape, and exhibited the similar crystal form, structural characteristics, thermal behaviors and release properties. In addition, drug loaded CD-MOFs prepared with polyethylene glycol 10000 (PEG 10000) as a modulator exhibited better in vitro aerosol performance than those of synthesized using other modulators, and the in vivo pharmacokinetics data demonstrated that the bioavailability of CsA could be significantly enhanced by inhalation administration of drug loaded CD-MOFs compared with oral administration of Neoral®. The repeated dose inhalation toxicity also confirmed the fine biocompatibility of CD-MOFs as the carrier for pulmonary drug delivery. Therefore, the results demonstrated CD-MOFs as the promising carrier could be used for pulmonary drug delivery.

Inhalation Dosage Forms: A Focus on Dry Powder Inhalers and Their Advancements.

In this review, an extensive analysis of dry powder inhalers (DPIs) is offered, focusing on their characteristics, formulation, stability, and manufacturing. The advantages of pulmonary delivery were investigated, as well as the significance of the particle size in drug deposition. The preparation of DPI formulations was also comprehensively explored, including physico-chemical characterization of powders, powder processing techniques, and formulation considerations. In addition to manufacturing procedures, testing methods were also discussed, providing insights into the development and evaluation of DPI formulations. This review also explores the design basics and critical attributes specific to DPIs, highlighting the significance of their optimization to achieve an effective inhalation therapy. Additionally, the morphology and stability of 3 DPI capsules (Spiriva, Braltus, and Onbrez) were investigated, offering valuable insights into the properties of these formulations. Altogether, these findings contribute to a deeper understanding of DPIs and their development, performance, and optimization of inhalation dosage forms.

Uso de inhaladores para la enfermedad pulmonar obstructiva crónica en un grupo de pacientes colombianos

Introducción: En Colombia son escasos los datos sobre el uso de los inhaladores en pacientes con EPOC. Objetivo: Describir la técnica de uso de inhaladores de dosis medida y polvo seco en pacientes de un hospital colombiano. Materiales y métodos: Estudio descriptivo en pacientes mayores de 40 años con EPOC atendidos en un hospital en La Virginia, Risaralda, Colombia, entre el 1 de septiembre de 2019 al 31 de enero de 2020. La unidad de análisis fueron los pacientes. Se incluyeron variables sociodemográficas, clínicas y lista de chequeo para uso de inhaladores. Se aplicaron frecuencias y proporciones para variables discretas, estadísticas de tendencia central y dispersión para variables continuas. Resultados: Se incluyeron 104 pacientes con edad media de 73,6 ± 10,1 años; 57 eran mujeres (54,8 %). Además, 48 pacientes estaban clasificados como GOLD-D (46,2 %). Igualmente, 89 pacientes manifestaron haber recibido educación sobre el uso de broncodilatadores (85,6 %). Los más frecuentes fueron los inhaladores de dosis medida (DM) en 95 casos (91,3 %), seguido de los de polvo seco unidosis (7,7 %). Así mismo, 37 pacientes que usaron DM sin inhalocámara (35,6 %) no cumplieron los pasos de la lista de chequeo. En el sistema multidosis, el más realizado fue cerrar de manera adecuada el inhalador y el menos ejecutado, expulsar el aire lentamente evitando hacerlo cerca del inhalador (n = 6; 5,7 %). Discusión: Se lograron describir las características de la técnica de uso de los inhaladores en pacientes con EPOC. A pesar de que ningún paciente logró utilizar el inhalador de forma "perfecta", la mayoría han recibido educación por parte de los profesionales de la salud. Conclusión: Un alto porcentaje de pacientes usa inadecuadamente los dispositivos para suministrar los broncodilatadores. Esto puede impactar negativamente en el control de la enfermedad.

Introduction: In Colombia, there is limited data on the use of inhalers in patients with COPD. Objective: The objective was to describe the technique of using metered-dose inhalers and dry powder in patients in a Colombian hospital. Methods: Observational, descriptive study of patients over 40 years of age with COPD, treated in a hospital in La Virginia, Risaralda, Colombia, between September 1st, 2019 and January 31st, 2020. The unit of analysis were patients in consultation. Sociodemographic and clinical variables, and a checklist for use of inhalers were included. Frequencies and proportions were applied for discrete variables, statistics of central tendency and dispersion for continuous variables. Results: A total of 104 patients with an average age of 73.6 ± 10.1 years were included; 57 were women (54.8%). In addition, 48 patients were classified as GOLD-D (46.2%). Similarly, 89 patients reported having received education on the use of bronchodilators (85.6%). The most common were metered-dose (MD) inhalers in 95 cases (91.3%), followed by single-dose dry powder inhalers in eight patients (7.7%). Likewise, 37 patients who used DM without inhalochamber (35.6%) did not comply with the steps of the checklist. In the multidose system, the most performed was to properly close the inhaler and the least performed was to expel the air slowly, avoiding doing so near the inhaler (n=6; 5.7%). Discussion: The characteristics of the technique of using inhalers in patients with COPD were described. Although no patient was able to use the inhaler "perfectly", most have received education from health professionals. Conclusion: A high percentage of patients misuse the devices to deliver bronchodilators. This can negatively impact the control of the disease.

Understanding the effects of inhaler resistance on particle deposition behaviour - A computational modelling study.

BACKGROUND AND OBJECTIVE: Understanding the impact of inhaler resistance on particle transport and deposition in the human upper airway is essential for optimizing inhaler designs, thereby contributing to the enhancement of the therapeutic efficacy of inhaled drug delivery. This study demonstrates the potential effects of inhaler resistance on particle deposition characteristics in an anatomically realistic human oropharynx and the United States Pharmacopeia (USP) throat using computational fluid dynamics (CFD). METHOD: Magnetic resonance (MR) imaging was performed on a healthy volunteer biting on a small mockup inhaler mouthpiece. Three-dimensional geometry of the oropharynx and mouthpiece were reconstructed from the MR images. CFD simulations coupled with discrete phase modelling were conducted. Inhaled polydisperse particles under two different transient flow profiles with peak inspiratory flow rates (PIFR) of 30 L/min and 60 L/min were investigated. The effect of inhaler mouthpiece resistance was modelled as a porous medium by varying the initial resistance (Ri) and viscous resistance (Rv). Three resistance values, 0.02 kPa0.5minL-1, 0.035 kPa0.5minL-1 and 0.05 kPa0.5 minL-1, were simulated. The inhaler outlet velocity was set to be consistent across all models for both flow rate conditions to enable a meaningful comparison of models with different inhaler resistances. RESULT: The results from this study demonstrate that investigating the effect of inhaler resistance by solely relying on the USP throat model may yield misleading results. For the geometrically realistic oropharyngeal model, both the pressure and kinetic energy profiles at the mid-sagittal plane of the airway change dramatically when connected to a higher-resistance inhaler. In addition, the geometrically realistic oropharyngeal model appears to have a resistance threshold. When this threshold is surpassed, significant changes in flow dynamics become evident, which is not observed in the USP throat model. Furthermore, this study also reveals that the impact of inhaler resistance in a geometrically realistic throat model extends beyond the oral cavity and affects particle deposition downstream of the oral cavity, including the oropharynx region. CONCLUSION: Results from this study suggest that key mechanisms underpinning the working principles of inhaler resistance are intricately connected to their complex interaction with the pharynx geometry, which affects the local pressure, local variation in velocity and kinetic energy profile in the airway.

Cyclodextrin MOFs modified dry powder inhalers quadruple bioavailability of luteolin to ameliorate fibrosing interstitial lung disease.

Fibrosing interstitial lung disease (ILD) is a pathological condition that is highly heterogeneous and lethal, and has few effective treatment choices. Other than pirfenidone and nintedanib for the therapy of idiopathic pulmonary fibrosis, no medications are currently licensed for the treatment of ILD. Luteolin is a common flavonoid with multiple biological effects such as anti-inflammation but with poor solubility and absorption. In this study, we loaded luteolin into γ-cyclodextrin metal-organic frameworks (CD-MOFs) to deliver the medicine to the lungs using dry powder inhalers; in vitro pulmonary deposition results showed LUT@CDMOF had a high fine particle fraction (FPF) (59.77 ± 3.48%). LUT@CDMOF effectively inhibited ILD progression in the BLM-induced fibrosing ILD model rats. When compared to oral administration, the inhalation of LUT@CDMOF dry powder in rats showed considerable improvements in absorption and bioavailability, with a tmax of 0.08 h and a high absolute bioavailability (82%) of LUT (The AUC(0-t) and Cmax of inhal. LUT@CDMOF respectively increased about 4.03 times and 9.11 times, when compared with the i.g. LUT group). These studies demonstrate the potent anti-inflammatory activities of LUT@CDMOF. The inhaled LUT@CDMOF might be considered as a promising new strategy in the treatment of fibrosing ILD.

Effect of Chronic Obstructive Pulmonary Disease Severity on Inspiratory Flow Rates via Inhaler Devices.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder that affects millions of people worldwide and inhalation therapy is central to the symptomatic management of the disease. Therefore, knowledge of the minimum Peak inspiratory flow (PIF) requirements for specific inhalers especially dry powder inhalers (DPI's) is necessary when prescribing inhalation therapy. The purpose of this study is to assess the effect of COPD severity on PIF in patients with COPD. METHODOLOGY: A total of 150 subjects (75 patients with stable COPD, and 75 apparently healthy subjects) participated in the study. PIF was assessed using the In-check Inhaler Assessment Kit (manufactured by Clement Clarke International Ltd, Harlow, UK). Lung function was assessed by spirometry with subjects divided into four groups based on the severity of their airway obstruction using the GOLD criteria. The Modified Medical Research Council (MMRC) dyspnea scale was used to assess dyspnea severity. Exercise capacity was assessed using the 6-minute walk test. Statistical analysis was performed with SPSS 23.0 software. In all the statistical tests, a p value of <0.05 was considered significant. RESULTS: The mean age for the COPD patient and control population are 72.48 ± 8.01 and 70.69 ± 5.82 respectively. The control group had higher PIF than COPD group; however, only the clickhler and pMDI had statistically significant difference between the mean PIF of the patients compared with the control group. Generally, there was an observed trend of a decrease in mean PIF as the COPD stage progresses with a statistically significant difference observed for Easibreathe (F= 3.52, p= 0.019) and pressurized Metered dose inhaler (pMDI) (F= 4.26, p= 0.008). There was a significant positive correlation between FEV1%, FVC, Exercise capacity (6-minute walk distance) and PIF for Clickhaler, Autohaler, Easybreathe and pMDI. For pMDI, there was a statistically significant difference between means of PIF across the MMRC dyspnea scale with PIF decreasing with increasing severity of dyspnea (F= 2.85, p= 0.033). CONCLUSION: COPD patients have slightly lower PIF than controls. Poor exercise tolerance and lower spirometric pulmonary function parameters may contribute to low PIF.

INTRODUCTION: La bronchopneumopathie chronique obstructive (BPCO) est un trouble respiratoire chronique qui touche des millions de personnes dans le monde et la thérapie par inhalation est essentielle à la gestion symptomatique de la maladie. Par conséquent, il est nécessaire de connaître les exigences minimales en matière de débit inspiratoire de pointe (DIP) pour certains inhalateurs, en particulier les inhalateurs de poudre sèche (IPS), lors de la prescription d'un traitement par inhalation. L'objectif de cette étude est d'évaluer l'effet de la gravité de la BPCO sur le débit de pointe inspiratoire chez les patients atteints de BPCO. MÉTHODOLOGIES: Un total de 150 sujets (75 patients atteints de BPCO stable et 75 sujets apparemment sains) ont participé à l'étude. Le PIF a été évalué à l'aide du kit d'évaluation In-check Inhaler (fabriqué par Clement Clarke International Ltd, Harlow, UK). La fonction pulmonaire a été évaluée par spirométrie, les sujets étant répartis en quatre groupes en fonction de la gravité de l'obstruction des voies respiratoires selon les critères GOLD. L'échelle de dyspnée modifiée du Medical Research Council (MMRC) a été utilisée pour évaluer la sévérité de la dyspnée. La capacité d'exercice a été évaluée à l'aide du test de marche de 6 minutes. L'analyse statistique a été réalisée avec le logiciel SPSS 23.0. Dans tous les tests statistiques, une valeur p de <0,05 a été considérée comme significative. RÉSULTATS: L'âge moyen des patients atteints de BPCO et de la population de contrôle est respectivement de 72,48 ± 8,01 et 70,69 ± 5,82. Le groupe de contrôle avait un PIF plus élevé que le groupe BPCO; cependant, seuls le clickhler et le pMDI présentaient une différence statistiquement significative entre le PIF moyen des patients et celui du groupe de contrôle. D'une manière générale, on a observé une tendance à la diminution du FRP moyen au fur et à mesure de l'évolution de la BPCO, avec une différence statistiquement significative pour l'Easibreathe (F= 3,52, p= 0,019) et l'aérosol-doseur pressurisé (pMDI) (F= 4,26, p= 0,008). Il existe une corrélation positive significative entre le VEMS, la CVF, la capacité d'exercice (distance de marche de 6 minutes) et le PIF pour Clickhaler, Autohaler, Easybreathe et pMDI. Pour le pMDI, il y avait une différence statistiquement significative entre les moyennes de PIF sur l'échelle de dyspnée du MMRC, le PIF diminuant avec l'augmentation de la sévérité de la dyspnée (F= 2,85, p= 0,033). CONCLUSION: Les patients atteints de BPCO ont un PIF légèrement inférieur à celui des témoins. Une mauvaise tolérance à l'exercice et des paramètres spirométriques de la fonction pulmonaire plus faibles peuvent contribuer à la faiblesse du PIF. Mots clés: Maladie pulmonaire obstructive chronique, Inhalateurs de poudre sèche, Débit inspiratoire de pointe, Aérosol-doseur pressurisé.

Cyclosporine A-loaded chitosan extra-fine particles for deep pulmonary drug delivery: In vitro and in vivo evaluation.

In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 µm and 1.94 ± 0.02 µm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 µm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.

The forgotten material: Highly dispersible and swellable gelatin-based microspheres for pulmonary drug delivery of cromolyn sodium and ipratropium bromide.

Controlled-release formulations for pulmonary delivery are highly desirable for treating chronic diseases such as COPD. However, a limited number of polymers are currently approved for inhalation. The study presents a promising strategy using gelatin as a matrix for inhalable dry powders, allowing the controlled release of ionic drugs. Ionized cromoglicate sodium (CS) and ipratropium bromide (IBr) interacted in solution with charged gelatin before spray drying (SD). Calcium carbonate was used as a crosslinker. The microspheres showed remarkable aerosol performance after optimizing the SD parameters and did not cause cytotoxicity in A549 cells. The microspheres were highly dispersible with âˆ¼ 50-60% of respirable fraction and fine particle fraction 55-70%. Uncrosslinked microspheres increased their size from four to ten times by swelling after 5 min showing potential as a strategy to avoid macrophage clearance and prolong the therapeutic effect of the drug. Crosslinkers prevented particle swelling. Ionic interaction generated a moderate reduction of the drug release. Overall, this study provides a novel approach for developing DPI formulations for treating chronic respiratory diseases using a biopolymer approved by the FDA, potentially enhancing drug activity through controlled release and avoiding macrophage clearance.

The effect of lung emptying before the inhalation of aerosol drugs on drug deposition in the respiratory system.

The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

Cepharanthine Dry Powder Inhaler for the Treatment of Acute Lung Injury.

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) induces a severe cytokine storm that may cause acute lung injury/acute respiratory distress syndrome (ALI/ARDS) with high clinical morbidity and mortality in infected individuals. Cepharanthine (CEP) is a bisbenzylisoquinoline alkaloid isolated and extracted from Stephania cepharantha Hayata. It exhibits various pharmacological effects, including antioxidant, anti-inflammatory, immunomodulatory, anti-tumor, and antiviral activities. The low oral bioavailability of CEP can be attributed to its poor water solubility. In this study, we utilized the freeze-drying method to prepare dry powder inhalers (DPI) for the treatment of acute lung injury (ALI) in rats via pulmonary administration. According to the powder properties study, the aerodynamic median diameter (Da) of the DPIs was 3.2 µm, and the in vitro lung deposition rate was 30.26; thus, meeting the Chinese Pharmacopoeia standard for pulmonary inhalation administration. We established an ALI rat model by intratracheal injection of hydrochloric acid (1.2 mL/kg, pH = 1.25). At 1 h after the model's establishment, CEP dry powder inhalers (CEP DPIs) (30 mg/kg) were sprayed into the lungs of rats with ALI via the trachea. Compared with the model group, the treatment group exhibited a reduced pulmonary edema and hemorrhage, and significantly reduced content of inflammatory factors (TNF-α, IL-6 and total protein) in their lungs (p < 0.01), indicating that the main mechanism of CEP underlying the treatment of ALI is anti-inflammation. Overall, the dry powder inhaler can deliver the drug directly to the site of the disease, increasing the intrapulmonary utilization of CEP and improving its efficacy, making it a promising inhalable formulation for the treatment of ALI.

[Assessment of inhalation technique in patients with bronchial asthma and chronic obstructive pulmonary disease].

AIM: Investigate inhalation techniques using different inhalers types and their effect on the course of disease. MATERIALS AND METHODS: This cross-sectional study included 110 patients with asthma, chronic obstructive pulmonary disease using the inhaler at least one month. Inhaler errors performed during demonstration were evaluated for each patient and entered in the check-lists. We also collected information about co-morbidities, education, mMRC dyspnea score, rate of exacerbations, and performed spirometry. RESULTS: 80.9% of patients used metered-dose inhaler, 20.9% - single-dose and 21.8% - multiple-dose dry powder inhaler, 22.7% - soft-mist inhaler. Inhaler errors were made by 80.9% patients. The mean number of mistakes in metered-dose inhaler use was 2±1.6, single-dose powder inhaler -1.5±1.3, multiple-dose dry powder inhaler - 1.25±1.4, soft-mist inhaler - 0.68±0.7 (р=0.003). Age, diagnosis, duration of disease, education level, inhalers usage by relatives have no influence on the inhalation technique. A number of errors was related to female gender (р=0.007) and usage of more than 2 inhalers (r=0.3, p=0.002), previous instruction about inhalation technique (r=0.3, p=0.001). On the other hand, there were correlations between the number of errors and degree of bronchial obstruction, asthma control, severity of dyspnea by mMRC score, exacerbation rate. CONCLUSION: Patients with bronchoobstructive diseases perform many inhaler errors, that substantially influences the severity and course of asthma and chronic obstructive pulmonary disease.

Evaluating dry powder inhalers: From in vitro studies to mobile health technologies.

Dry powder inhalers (DPIs) are essential in treating patients with pulmonary diseases. Since DPIs were introduced in the 1960s, a remarkable improvement has been made in their technology, dose delivery, efficiency, reproducibility, stability, and performance based on safety and efficacy. While there are many DPIs on the market and several more under development, it is vital to evaluate the performance of DPIs for effective aerosol drug delivery to patients with respiratory disorders. Their performance evaluation includes the physicochemical properties of the drug powder formulation, metering system, device design, dose preparation, inhalation technique, and patient-device integration. The purpose of this paper is to review current literature evaluating DPIs through in vitro studies, computational fluid models, and in vivo/clinical studies. We will also explain how mobile health applications are used to monitor and evaluate patients' adherence to prescribed medications.

[Development of an Inhalation Dry Powder Preparation Method without Heat-drying Process].

Biopharmaceuticals, including therapeutic genes and proteins, are characterized by highly-targeted, specific action and flexible pharmacological design and have a rapidly growing market share; however, because of high molecular weight and low stability, injection is the most common delivery route of biopharmaceuticals. Thus, pharmaceutical innovations are required to provide alternative delivery routes for biopharmaceuticals. Pulmonary drug delivery via inhalation is a promising approach, particularly for targeting local diseases of the lung, because it can exert therapeutic effects in small doses and can noninvasively and directly deliver drugs to airway surfaces. However, biopharmaceutical inhalers must ensure that the biopharmaceuticals maintain their integrity as they are subjected to several types of physicochemical stress, such as hydrolysis, ultrasound, and heating, at various stages during the process from manufacturing to administration. In this symposium, I present a novel dry powder inhaler (DPI) preparation method without heat-drying, with the goal of developing biopharmaceutical DPIs. Spray-freeze-drying is a nonthermal drying technique that produces a powder with porous shapes; this powder has suitable inhalation characteristics for DPI. A model drug, plasmid DNA (pDNA), was stably prepared as a DPI using the spray-freeze-drying process. Under dry conditions, the powders maintained high inhalation characteristics and maintained pDNA integrity for 12 months. The powder induced pDNA expression in mouse lungs that exceeded at higher levels than the solution did. This novel preparation method is suitable for DPI preparation for various drugs and may help expand the clinical application of DPIs.

Feedback systems in multi-dose dry powder inhalers.

Dry powder inhalers (DPIs) are a large, highly diverse group of inhalation devices. DPIs differentiate the process of measuring the dose of the drug and preparing the inhaler for use, but also the way of transmitting and the scope of feedback on the inhalation process that the user receives. The functioning of simple and technologically advanced systems of feedback on the inhalation process in the most commonly used multi-dose DPIs is discussed. All these DPIs have a dose counter. Only three DPIs - Novolizer®, Genuair® and NEXThaler® provide feedback to the patient in the form of auditory and visual signals confirming the correctness of the inhalation performed. This is important for the correct use of the inhaler, and thus for obtaining the expected therapeutic effects.

Thinking "Green" When Treating "Pink Puffers" and "Blue Bloaters"-Reducing Carbon Footprint When Prescribing Inhalers.

The impact of man-made climate change is already affecting millions of people worldwide. The health care sector in the US is a relevant contributor, accounting for about 8 to 10% of national greenhouse gas emissions. This special communication describes the harmful impact of propellant gases in metered dose inhalers (MDI) on the climate and summarizes and discusses current knowledge and recommendations from European countries. Dry powder inhalers (DPI) are a good alternative to MDIs and are available for all inhaler drug classes recommended in current asthma and COPD guidelines. Changing an MDI to PDI can significantly reduce carbon footprints. The majority of the US population is willing to do more to protect the climate. Primary care providers can engage in this by addressing the impacts of drug therapy on climate change in medical decision making.

On the Physical Stability of Leucine-Containing Spray-Dried Powders for Respiratory Drug Delivery.

Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be approved for inhalation soon and has been studied exhaustively. However, during stability, small fibers protruding from the particles of leucine-containing powders have occasionally been observed. To clarify the origin of these fibers and assess their potential influence on the performance of the powders, three different classes of spray-dried leucine-containing formulation systems were studied over an 8-month accelerated stability program. These systems consisted of a large molecule biologic (bevacizumab) in conjunction with a glass former (trehalose), an amorphous small-molecular mass active (moxidectin), and a crystallizing active (mannitol). It was determined that the appearance of the fibers was due to the presence of small quantities of leucine in higher energy states, either because these were amorphous or present as a less stable crystalline polymorph. It was further shown that the growth of these leucine fibers caused no significant physicochemical instability in the powders. Nor, more importantly, did it decrease their aerosol performance in a dry powder inhaler or reduce the concentration of their active pharmaceutical ingredients.

An evaluation of the use of inhalers in asthma and chronic obstructive pulmonary disease.

Objectives: Inhaled therapy is the treatment of choice for obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, the maximum benefit from such therapy depends on the correct use of inhaler devices. In this study, our primary aim was to evaluate inhaler techniques in patients with asthma and COPD in order to identify common errors. In addition, we investigated the effect of various parameters on the rate of inhaler misuse. Methods: We enrolled a total of 300 asthma/COPD patients, who presented at the Chest Diseases and Family Medicine Outpatient Clinics of a tertiary hospital located in Ankara, Turkey. We used a face-to-face survey that included questions about sociodemographic features and inhaler therapy. Subsequently, we requested patients to demonstrate how they use their inhalers and assessed their inhalation technique according to checklists. Results: Of the 300 patients, 70.2% used their inhaler drugs incorrectly. The rate of misuse among metered dose inhaler (MDI) users was significantly higher than those using dry powder inhalers (DPIs) (77.6% vs 64%; p = 0.002). When DPI devices were analyzed, the rates of misuse were significantly higher in Handihaler users (p = 0.012) and Diskus inhaler users (p = 0.009) when compared to Sanohaler users. Gender, type of disease (asthma/COPD), duration of inhaler use, and duration of illness had no impact on the rate of misuse. However, an advanced age (>60 years old), a level of education lower than high school, and the use of MDI were all identified as factors associated with misuse. The most common mistake was 'failing to breath out before inhalation' for all types of devices (for MDI: 66.7%, and for DPI: 71.1-82.8%). Conclusions: The rate of inhaler drug misuse was high. The identification of factors associated with misuse could provide information to implement appropriate actions to reduce the rates of misuse.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions.

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.