Inhaled hydroxychloroquine to improve efficacy and reduce harm in the treatment of COVID-19.

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.

Nanoscale Probing of Liposome Encapsulating Drug Nanocrystal Using Atomic Force Microscopy-Infrared Spectroscopy.

Use of liposomes encapsulating drug nanocrystals for the treatment of diseases like cancer and pulmonary infections is gaining attention. The potential therapeutic benefit of these engineered formulations relies on maintaining the physical integrity of the liposomes and the stability of the encapsulated drug. With the significant advancement in the microscopic and analytical techniques, analysis of the size and size distribution of these nanosized vesicles is possible. However, due to the limited spatial resolution of conventional vibrational spectroscopy techniques, the chemical composition of individual nanosized liposome cannot be resolved. To address this limitation, we applied atomic force microscopy infrared spectroscopy (AFM-IR) to assess the chemical composition of individual liposomes encapsulating ciprofloxacin in dissolved and nanocrystalline form. Spatially resolved AFM-IR spectra acquired from individual liposomes confirmed the presence of peaks related to N-H bending vibration, C-N stretching and symmetric, and asymmetric vibration of the carboxyl group present in the ciprofloxacin. Our results further demonstrated the effectiveness of AFM-IR in differentiating the liposome containing ciprofloxacin in dissolved or nanocrystalline form. Spectra acquired from dissolved ciprofloxacin had peaks related to the ionised carboxyl group, i.e., at 1576 and 1392 cm-1, which were either absent or far weaker in intensity in the spectra of liposomal sample containing ciprofloxacin nanocrystals. These findings are highly significant for pharmaceutical scientists to ascertain the stability and physicochemical composition of individual liposomes and will facilitate the design and development of liposomes with greater therapeutic benefits.

Formation of ciprofloxacin nanocrystals within liposomes by spray drying for controlled release via inhalation.

The present study was conducted to harness spray drying technology as a novel method of producing Ciprofloxacin nanocrystals inside liposomes (CNL) for inhalation delivery. Liposomal ciprofloxacin dispersions were spray dried with sucrose as a lyoprotectant in different mass ratios (0.5:1, 1:1 and 2:1 sucrose to lipids), along with 2% w/w magnesium stearate and 5% w/w isoleucine as aerosolization enhancers. Spray drying conditions were: inlet air temperature 50 °C, outlet air temperature 33-35 °C, atomizer rate 742 L/h and aspirator 35 m3/h. After spray drying, the formation of ciprofloxacin nanocrystals inside the liposomes was confirmed by cryo- transmission electron microscopy. The physiochemical characteristics of the spray dried powder (particle size, morphology, crystallinity, moisture content, drug encapsulation efficiency (EE), in vitro aerosolization performance and drug release) were determined. The EE of the liposomes was found to vary between 44 and 87% w/w as the sucrose content was increased from 25 to 57% w/w. The powders contained partially crystalline particles with a volume median diameter of ~1 µm. The powders had low water content (~2% wt.) and were stable at high relative humidity. Aerosol delivery using the Osmohaler® inhaler at a flow rate of 100 L/min produced an aerosol fine particle fraction (% wt. <5 µm) of 58-64%. The formulation with the highest sucrose content (2:1 w/w sucrose to lipid) demonstrated extended ciprofloxacin release from liposomes (80% released within 7 h) in comparison to the original liquid formulation (80% released within 2 h). In conclusion, a stable and inhalable CNL powder with controlled drug release was successfully prepared by spray drying.

Ciprofloxacin nanocrystals liposomal powders for controlled drug release via inhalation.

This study was conducted to evaluate the feasibility of developing inhalable dry powders of liposomal encapsulated ciprofloxacin nanocrystals (LECN) for controlled drug release. Dry powders of LECN were produced by freeze-thaw followed by spray drying. The formulations contained sucrose as a lyoprotectant in different weight ratios (0.75:1, 1:1 and 2:1 sucrose to lipids), along with 2% magnesium stearate and 5% isoleucine as aerosolization enhancers. The powder physical properties (particle size, morphology, crystallinity, moisture content), in vitro aerosolization performance, drug encapsulation efficiency and in vitro drug release were investigated. The spray dried powders were comprised of spherical particles with a median diameter of ∼1 µm, partially crystalline, with a low water content (∼2% mass) and did not undergo recrystallization at high relative humidity. When dispersed by an Osmohaler® inhaler at 100 L/min, the powders showed a high aerosol performance with a fine particle fraction (% wt. <5 µm) of 66-70%. After reconstitution of the powders in saline, ciprofloxacin nanocrystals were confirmed by cryo-electron microscopy. The drug encapsulation efficiency of the reconstituted liposomes was 71-79% compared with the stock liquid formulation. Of the three formulations, the one containing a sucrose to lipids wt. ratio of 2:1 demonstrated a prolonged release of ciprofloxacin from the liposomes. In conclusion, ciprofloxacin nanocrystal liposomal powders were prepared that were suitable for inhalation aerosol delivery and controlled drug release.