Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine

Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine w/w. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops® dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses

The pharmacokinetics of antibiotics in cystic fibrosis

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity

Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted

Colistin dry powder inhalation with the Twincer (TM):An effective and more patient friendly alternative to nebulization

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates

Observed and predicted bed forms and their effect on suspended sand concentrations

In this paper, we study the effect of bed forms on suspended sand concentrations and we compare three existing bed form predictors to field and laboratory measurements over a wide range of conditions and propose a new predictor that better collapses the measured bed form dimensions. We apply the different bed form predictors to estimate the suspended sediment concentration distributions based on the 1D advection diffusion equation and the bed-form-enhanced shear stress, which includes the flow contraction effect according to Nielsen [Coast. Eng. 10 (1986) 23]. Predictions of suspended sand concentration improve when including a bed form predictor. Interestingly, it does not make much difference which bed form predictor is implemented but more whether a bed form predictor is implemented. However, the choice of a particular bed form predictor is more important when the bed form effect in the sand transport model is based a roughness length scale ks and thus on η2/λ instead of η/λ, where ks is Nikuradse's equivalent roughness length scale, η is the bed form height and λ is the bed form length. This is the case in the Van Rijn [Van Rijn, L.C., 2000. General view on sand transport by currents and waves: data analysis and engineering modelling for uniform and graded sand (TRANSPOR 2000 and CROSMOR 2000 models). Z2899.20 Z2099.30 Z 2824.30, WL Delft Hydraulics, Delft, The Netherlands] sand transport model, for example. We discuss the effect of so-called long wave ripples on the suspended sand concentrations. © 2004 Elsevier B.V. All rights reserved

Observed and predicted bed forms and their effect on suspended sand concentrations

In this paper, we study the effect of bed forms on suspended sand concentrations and we compare three existing bed form predictors to field and laboratory measurements over a wide range of conditions and propose a new predictor that better collapses the measured bed form dimensions. We apply the different bed form predictors to estimate the suspended sediment concentration distributions based on the 1D advection diffusion equation and the bed-form-enhanced shear stress, which includes the flow contraction effect according to Nielsen [Coast. Eng. 10 (1986) 23]. Predictions of suspended sand concentration improve when including a bed form predictor. Interestingly, it does not make much difference which bed form predictor is implemented but more whether a bed form predictor is implemented. However, the choice of a particular bed form predictor is more important when the bed form effect in the sand transport model is based a roughness length scale ks and thus on η2/λ instead of η/λ, where ks is Nikuradse's equivalent roughness length scale, η is the bed form height and λ is the bed form length. This is the case in the Van Rijn [Van Rijn, L.C., 2000. General view on sand transport by currents and waves: data analysis and engineering modelling for uniform and graded sand (TRANSPOR 2000 and CROSMOR 2000 models). Z2899.20 Z2099.30 Z 2824.30, WL Delft Hydraulics, Delft, The Netherlands] sand transport model, for example. We discuss the effect of so-called long wave ripples on the suspended sand concentrations. © 2004 Elsevier B.V. All rights reserved