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

Characterisation of jet-milled and spray dried isoniazid for pulmonary administration

The aim of this study was to develop a dry powder isoniazid formulation with no or a limited amount of excipients for pulmonary administration. Milled isoniazid showed an excellent particle size distribution for inhalation, however dispersion was poor. In 78% of the dispersion measurements the inhaler blocked, retaining most of its dose. Pure spray dried isoniazid yielded particles too large for pulmonary delivery, but the addition of 5% of L-leucine resulted in spray dried particles of inhalable size. DSC data showed complete crystallinity for all samples, while TGA analysis showed that isoniazid sublimates around 100°C. SEM imaging showed that pure jet milled and spray dried isoniazid particles fused together. Isoniazid spray dried with L-leucine resulted in spherical particles with no fusion visible. The most likely explanation for particle fusion is that isoniazid crystalizes, resulting in solid bridge formation. L-leucine however, forms a coating around isoniazid particles, thereby preventing this phenomenon. Further experiments are needed to show why isoniazid fuses together in the jet mill. A possible explanation is that some isoniazid sublimates due to heat generation during particle collisions, and causes solid bridge formation between particles when it ripens. Further experiments have to show whether isoniazid co-spray dried with L-leucine disperses efficiently and is stable over time