Improved Aerosol Deposition Profiles from Dry Powder Inhalers

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are major health burdens on the global population. To treat diseases of the lung, topical therapies using dry powder inhalers (DPIs) have been employed. However, a relatively small amount of dose (5.5 – 28 %) reaches the lung during DPI therapy leading to high inter-patient variability in therapy response and oropharyngeal deposition. Strategies were assessed to take patient variability in inhalation performance into account when developing devices to reduce throat deposition and to mitigate flow rate dependency of the emitted aerosol. A cyclone-spacer was manufactured and evaluated with marketed and in-house manufactured formulations. An in vivo study showed that a high resistance inhaler would produce longer inhalation times in lung disease patients and that a spacer with high resistance may prove a suitable approach to address inter-patient variability. Two spacer prototypes were evaluated with cohesively- and adhesively-balanced particle blends. The data suggested that the throat deposition dramatically decreased for the emitted particles when the spacers were used with the inhalers (e.g. 18.44 ± 2.79% for salbutamol sulphate, SS 4 kPa) due to high retention of the formulation within the spacer (87.61 ± 2.96%). Moreover, variation in fine particle fraction and dose was mitigated when increasing the flow rate (82.75 ± 7.34 %, 92.2 ± 7.7 % % and 77.0 ± 10.1 % at 30, 45 and 60 Lmin-1, respectively). The latter was an improvement over previous proposed DPI spacers, where variability in emitted dose due to airflow rate was a major issue. Due to the different physicochemical properties of the active pharmaceutical ingredients used in the formulation, throat deposition and respirable fraction for adhesively-balanced particles (e.g. SS) were double that of the cohesively- balanced particles (salmeterol xinafoate, SX) (e.g. 65.83 ± 8.99 % vs. 45.83 ± 5.04 % for SS:Coarse Lactose (CL) and SX:CL, respectively). Scanning electron microscopy revealed that surface-bound agglomerates were more freely removed from the carrier, but subject to decreased impaction-type deagglomeration forces in the spacer than for carrier-bound drug. An ex vivo study using breath profiles from healthy volunteers identified the minimization of differences between adhesively- and cohesively-balanced blends when full breath profiles were studied compared to square-wave airflow. Therefore the use of constant flow for in vitro testing should not be the sole flow regime to study aerosolization when developing new inhalation devices and formulations

Potential of a cyclone prototype spacer to improve in vitro dry powder delivery

Copyright The Author(s) 2013. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPurpose: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrierbased DPIs was investigated. Methods: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30-60 Lmin-1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. Results: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51 % at 30 Lmin-1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 μm vs. 3.00 ± 0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates. Conclusion: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.Peer reviewe

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk

Bio-compatibility of Nano-Composites on Airway Epithelial Cells

Nanoparticles are an emerging class of functional materials defined by size-dependant properties. Due to expanding use of NPs the risk of human exposure increases so it is important the study of their interactions to the cells. 2% v/v FBS in cell cellar medium was used as suspension for cell based toxicity assays. Size, zeta potential, oxidative potential wave measured and MTT and LDK assays were performed

Mathematical approach for understanding deagglomeration behaviour of drug powder in formulations with coarse carrier

AbstractDeagglomeration of cohesive particles in combination with coarse carrier is a key requirement for inhaled formulations. The aim of the project was to propose a mathematical approach to understand aerosolization behaviour of micronized particles alone and in formulation with carriers. Salbutamol sulphate and salmeterol xinafoate were blended separately with fine lactose (ratio 1:4) and fine and coarse lactose (1:4:63.5). Laser diffraction was employed to characterize the powder median particle size. The deagglomeration of micronized materials followed an asymptotic monoexponential relationship. When the coarse lactose was added, the relationship fitted a bi-exponential equation showing an easily and a poorly dispersed fraction. Using model hydrophobic and hydrophilic APIs, this study has demonstrated the utility of an analytical approach that can parameterize deagglomeration behaviour of carrier-free and carrier-based inhalation formulations. The analytical approach provides the ability to systematically study the effect of material, formulation and processing factors on deagglomeration behaviour

Interaction of Formulation and Device Factors Determine the In Vitro Performance of Salbutamol Sulphate Dry Powders for Inhalation

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device

Interaction of Formulation and Device Factors Determine the In Vitro Performance of Salbutamol Sulphate Dry Powders for Inhalation

Joanna Muddle, Darragh Murnane, Irene Parisini, Marc Brown, Clive Page, and Ben Forbes, 'Interaction of Formulation and Device Factors Determine In Vitro Performance of Salbutamol Sulphate Dry Powders for Ihnalation', Journal of Pharmaceutical Sciences, Vol. 104 (11): 3861-3869, November 2015, doi: https://doi.org/10.1002/jps.24599. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.Peer reviewe

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

AbstractClinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.</jats:p

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19

Introduction. The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions. Materials and Methods. In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( F 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded. Results. At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( χ 2 10.4; p &lt; 0.001 ), neutrophil-to-lymphocyte (NL) ratio ( χ 2 7.6; p = 0.006 ), and platelet count ( χ 2 5.39; p = 0.02 ), along with age ( χ 2 87.6; p &lt; 0.001 ) and gender ( χ 2 17.3; p &lt; 0.001 ), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL   ratio &gt; 4.68 was characterized by an odds ratio for in-hospital mortality   OR = 3.40 (2.40-4.82), while the OR for a RDW &gt; 13.7 % was 4.09 (2.87-5.83); a platelet   count &gt; 166,000 /μL was, conversely, protective (OR: 0.45 (0.32-0.63)). Conclusion. Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.</jats:p