Tan Suwandecha

Computer-aided design of dry powder inhalers using computational fluid dynamics to assess performance

Abstract Dry powder inhalers (DPIs) are gaining popularity for the delivery of drugs. A cost effective and efficient delivery device is necessary. Developing new DPIs by modifying an existing device may be the simplest way to improve the performance of the devices. The aim of this research was to produce a new DPIs using computational fluid dynamics (CFD). The new DPIs took advantages of the Cyclohaler® and the Rotahaler®. We chose a combination of the capsule chamber of the Cyclohaler® and the mouthpiece and grid of the Rotahaler®. Computer-aided design models of the devices were created and evaluated using CFD. Prototype models were created and tested with the DPI dispersion experiments. The proposed model 3 device had a high turbulence with a good degree of deagglomeration in the CFD and the experiment data. The %fine particle fraction (FPF) was around 50% at 60 L/min. The mass median aerodynamic diameter was around 2.8–4 μm. The FPF were strongly correlated to the CFD-predicted turbulence and the mechanical impaction parameters. The drug retention in the capsule was only 5–7%. In summary, a simple modification of the Cyclohaler® and Rotahaler® could produce a better performing inhaler using the CFD-assisted design.

Original article. Pharmacodynamics of dry powder formulations of salbutamol for delivery by inhalation

Abstract Background: Salbutamol is a β2-selective adrenoceptor agonist used as a bronchodilator. Delivery by inhalation has many advantages over oral dosage for the treatment of asthma. It offers rapid onset of action with low systemic side effects. Objective: Evaluate the relationship of in vitro particle size characteristics and pharmacodynamics of formulations of inhaled salbutamol dry powder. Methods: Three formulations contained micronized salbutamol and a lactose carrier with different size ranges (40- 80, 20-40, and 10-20 μm for formulations 1, 2, and 3, respectively). Following formulation of the drug, resultant powders were characterized using scanning electron microscopy and the aerosolization performance determined using an Andersen Cascade Impactor analysis. A high-performance liquid chromatography method was used for measuring the salbutamol drug content. The in vivo pharmacodynamics of the formulations was monitored in 12 healthy and 12 asthmatic volunteers. Results: The percentage of the fine particle fractions (FPF) for formulations 1, 2, and 3 were 24.87±0.52%, 33.82±3.80%, and 41.50±2.86%, respectively. The mass median aerodynamic diameters (MMAD) were around 3 μm for all formulations. The pharmacodynamic parameters, forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and mid expiratory flow (FEF25-75), were indices for evaluation of the bioavailability of the bronchodilatory drug. All formulations improved the FEF25-75 value in asthmatics, while FVC and FEV1 were not altered. Conclusion: The formulations of salbutamol dry powder aerosols with a fine lactose carrier produced a high deposition in the lower regions of the respiratory tract. Although the FEF25-75 value in asthmatics was improved, the value did not correlate well with the FPF of the salbutamol dry powder.

Host-guest interactions between sildenafil and cyclodextrins: Spectrofluorometric study and molecular dynamic modeling

Sildenafil (SF) was included in cyclodextrins (CD) to enhance its solubility. Spectrofluorometry was used to confirm the complexation constant (stability constant). The orientations of SF inside the β-CDs and γ-CDs were fully illustrated. Molecular dynamics simulations were performed on two inclusion complexes (β-CD/SF and γ-CD/SF) in the aqueous system. The polar methylpiperazine group was found to locate inside the β-CD cavity, both in the wide and narrow side and was positioned 2°A from the center. In contrast, the methylpiperazine group did not fit well within the γ-CD cavity. Moreover, these results also confirmed hydrogen bonding that the highest number of bonding formed between the polar methylpiperazine sulfonyl structure and the hydroxyl group of β-CD. The simulated binding free energy of the methylpiperazine-β-CD inclusion complex (-6.01kcal/mol), featured a large contribution from electrostatic and van der Waals forces, which was the most stable complex. The association constant of β-CD/SF (12.3) was higher than γ-CD/SF (3.3) and confirmed with in silico measurements of binding free energy. In summary, SF forms a stable complex with β-CD.

Evidences for salbutamol metabolism by respiratory and liver cell lines

This study aimed to investigate the enantiomeric biotransformation of salbutamol in the human respiratory and liver cells. The cells from the different cell growth cycles were treated with various concentrations of salbutamol sulfate. Salbutamol and its metabolites were analyzed using chiral liquid chromatography and mass spectrometry. There were no metabolites of salbutamol found in the extracellular medium, intracellular, and cell lysate of respiratory cell lines. The S/R ratios of salbutamol were found to be 0.99-1.10 in all cell lines, cell cycles, and salbutamol concentrations in this study. Salbutamol metabolites were found only in intracellular HepG2 cells. The S/R ratios of the salbutamol inside the liver cells were 10 times greater than the S/R ratios of the salbutamol in the liver extracellular medium (0.99-1.10). It is important to note that the S/R ratios of salbutamol in liver cell lysate enzyme were 0.99-1.10 whereas the S/R salbutamol metabolites inside the liver cell were around 1.91-2.14. Both salbutamol and sulfate conjugation metabolites were detected in MS chromatograms with an m/z of 239.2 and 317.6, respectively. Hence, the delivery of salbutamol directly to the respiratory system is a right target that can avoid first-pass metabolism.