Evaluation of patients' real-world post-dispensing use and storage environments of tiotropium bromide Respimat® soft mist inhaler on its in vitro dose delivery and lung deposition.

BACKGROUND: Oral inhalation is the main drug delivery route for treating obstructive lung conditions. Thus, many inhaler devices with various design and pharmaceutical formulation have been introduced. The fine particle dose (FPD) and mass median aerodynamic diameter (MMAD ≤ 5 µm) of the aerosol delivered dose (DD) dictate the therapeutically effective peripheral lung deposition. This study evaluated the in vitro aerosol emission performance of tiotropium bromide emitted from Spiriva® Respimat® soft mist inhalers (R) after living under patients' real-world, post-dispensing handling environments. METHODS: This was a two-stage investigation. In the first clinical stage, research ethical approval was obtained to enrol patients already been using R for at least 3 months. Those who signed consent were given both new R to use and temperature and relative humidity (RH) handheld, portable data loggers to keep in the vicinity of the given R. The participants returned the given R and data loggers after 2 weeks. Patient recruitment took place in Amman, Jordan, during the summer (RS) and winter (RW). Subsequently, in the second laboratory stage, other R were strictly stored at an average of 21.0 °C and 46.9% RH as control (RC). The Next Generation Impactor (NGI) was used to evaluate the RS, RW and RC. The NGI was operated at a flow rate of 30 L/min. RESULTS: The RS were exposed to an average (range) 23.6 °C (18.2-37.5 °C) and 43.8% RH (21.4-60.0% RH) that were statistically comparable (p > 0.05) to that of the RW; 17.3 °C (13.2-26.7 °C) and 52.8% RH (26.3-69.1% RH). The RW and RC retention environments were statistically different (p < 0.05), whilst the RS and RC had comparable (p > 0.05) conditions. No significant differences (p > 0.05) were found in the tiotropium bromide DD (2.39 vs 2.43 µg), FPD (0.88 vs 0.90 µg) and MMAD (5.1 vs 4.98 µm) between the RS and RW, respectively. Compared to the RC inhalers, both the RS and RW devices had significantly higher FPD and relatively smaller tiotropium bromide particles. CONCLUSIONS: Using the R under the fluctuating summer and winter environments of our patients would not affect its overall tiotropium bromide emission performance. The significant increase in the respirable mass of the RS and RW might be offset by the increase in particles <1 µm particularly in patients with poor inhaler technique.

Delivered Lung Dose and Aerodynamic Particle Size Distribution of Salbutamol Pressurized Metered Dose Inhaler After Living Under Patients' Realistic Retention Environments.

Background: The impact of inhalers' postdispensing, real-life temperature and relative humidity (RH) environments on their delivered dose (DD) and aerodynamic particle size distribution (APSD) is usually overlooked. This work evaluated the salbutamol DD and APSD of Ventolin® Evohaler® (V) inhalers already been used and stored by respiratory patients. Methods: Adult patients, prescribed V for ≥3 months before study enrollment, were dispensed both new V to use and portable, handheld electronic temperature and RH data loggers to keep close to the given V before returning them both after 2-3 weeks. Patients' enrollment took place during summer (VS) and winter (VW) seasons. The returned V was then in vitro evaluated using the Next Generation Impactor, and compared with control V (VC) counterparts stored under 21°C and 46% RH. Results: The VS survived in fluctuating habitats of 21.2°C-40.4°C and 16.2%-63.2% RH, which significantly (p < 0.05) decreased the salbutamol DD from 80.4 to 70.5 µg compared with VC. This 12.3% DD reduction was accompanied with a decrease in the fine particle dose from 26.2 to 20.4 µg (p < 0.05), and an increase in the mass median aerodynamic diameter from 2.3 to 2.5 µm (p < 0.05). The VW and VC had equivalent DD and APSD. Conclusion: Patients using V are expected to receive smaller lung doses during the hot summer season compared with intentionally well-kept VC. To have equivalent lung deposition, V users should be advised to retain their inhalers around 20°C with minimal daily environmental fluctuations during summer times.

The impact of patients' real-life environmental temperature and humidity use conditions of tiotropium dry powder inhaler on its aerosol emission characteristics.

INTRODUCTION: Many factors can affect dry powder inhalers' (DPIs) aerosol emission and lung deposition. The fluctuation of environmental temperature and relative humidity (RH) that inhalers experience in realistic daily use has not been extensively evaluated. This work aimed to evaluate the delivered dose (DD) and aerodynamic particle size distribution (APSD) of tiotropium Handihaler DPI (H) after exposure to patients' real-life use environments. METHODS: Ethical approval was obtained to enrol adult patients already using H. Patients who gave written consent were given new H to use and HygroLog temperature and RH data loggers to keep in the vicinity of the given inhaler. The H and HygroLog were returned after 2 weeks. Patient recruitment was done during the summer (HS) and winter (HW). As control, other HC were stored as per the leaflet storage instructions. The Next Generation Impactor was used to evaluate the inhalers. RESULTS: The HC were stored under an average of 21.0 °C and 46.9% RH. The patients' HS and HW lived in an average (range) temperature (°C) 23.2 (18.3-38.2) and 17.8 (13.5-24.6), respectively, and RH 50.8% (24.3-65.3%) and 50.4% (30.6-72.4%), respectively. All H groups had comparable environments (p > 0.05). The HC, HS and HW gave similar tiotropium DD (µg) 7.60, 8.01 and 7.61, respectively (p > 0.05). Moreover, the fine particle dose µg (median diameter (µm)) were HC 2.41 (3.84), HS 2.55 (3.81) and HW 2.37 (3.83) (p > 0.05). CONCLUSIONS: The aerosol emission behaviour of tiotropium Handihaler was tolerant to real-life retention environments of patients in Amman, Jordan.

Ligand-based designing, in silico screening, and biological evaluation of new potent fructose-1,6-bisphosphatase (FBPase) inhibitors.

Fructose-1,6-bisphosphatase - hereafter abbreviated as FBPase has been recently implicated in diabetes prompting several attempts to discover and optimize new FBPase inhibitors. Toward this end we explored the pharmacophoric space of 136 FBPase inhibitors using three diverse sets of inhibitors. This identified 520 pharmacophores that were subsequently clustered into 104 groups. Cluster centers were evaluated by receiver operating characteristic (ROC) curves analysis and correlation with bioactivities of collected compounds. Pharmacophore model Hypo1/7 illustrated the best combination of classification power (ROC-AUC) and correlation with bioactivity. Two other pharmacophores (Hypo2/1 and Hypo2/6) were found to be mergeable and their combined model (Hypo2-1/2-6) illustrated excellent ROC performance. We employed Hypo1/7 and Hypo2-1/2-6 models to screen the National Cancer Institute (NCI) list of compounds. In silico mining identified 18 FBPase inhibitors out of which six were of sub-micromolar IC(50) values.