Inhaled budesonide in the treatment of early COVID-19

The Lancet published on an open-label, parallel-group, phase 2, randomised controlled trial, on inhaled budesonide (Ramakrishnan et al. 2021). Participants who met the inclusion criteria were randomly assigned to usual care or intervention with budesonide dry powder inhaler (Pulmicort Turbuhaler, AstraZeneca, Gothenburg, Sweden) at a dose of 400 μg per actuation (two puffs to be taken twice per day; total dose 1600 μg). 

When given to adults with early COVID-19, inhaled budesonide reduced the likelihood of requiring urgent care, emergency department consultation, or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19, and self-reported and questionnaire-reported symptom resolution was faster. There were fewer participants with persistent COVID-19 symptoms at days 14 and 28 after budesonide therapy compared with usual care. Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.

Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007). The mean proportion of days with a fever in the first 14 days was lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18; Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of fever was lower in the budesonide group when compared with the usual care group. As-needed antipyretic medication was required for fewer proportion of days in the budesonide group compared with the usual care group (27% [IQR 0–50] vs 50% [15–71]; p=0·025) Fewer participants randomly assigned to budesonide had persistent symptoms at days 14 and 28 compared with participants receiving usual care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). 

Although we don’t know much about the budesonide formulation applied in this clinical trial, it is well-known for the readers of the Cyclodextrin news blog that budesonide forms inclusion complexes with both beta- and gamma-cyclodextrin. Recent studies on A549 and A-THP-1 cells proved that budesonide-HPBCD complex attenuates ROS generation, IL-8 release and cell death induced by oxidant and inflammatory stress (Bayiha et al. 2020).

Some advantages of cyclodextrin complexation for pulmonary formulation of budesonide:

Spray-dried HPBCD/budesonide complex was found to improve lung targeting while decreasing systemic side effects associated with high doses (Dufour et al. 2015).

CDs may be used in inhalation powders to improve pharmaceutical and biopharmaceutical properties of drugs, e.g. budesonide without lowering their pulmonary deposition (Kinnarinen et al. 2003).

Spray freeze dried powder containing both leucine and HPBCD as excipients has good aerosolization performance and high fraction of fine particle fraction (Parsian et al. 2014)

GCD-metal-organic framework modified by cholesterol and optimized for delivery of budesonide by dry powder inhaler ensured even distribution of the drug within the lung (Hu et al. 2019).

Bayiha, J.C. et al. (2020) The Budesonide-Hydroxypropyl-β-Cyclodextrin Complex Attenuates ROS Generation, IL-8 Release and Cell Death Induced by Oxidant and Inflammatory Stress. Study on A549 and A-THP-1 Cells. Molecules (Basel, Switzerland) 25(21) https://doi.org/10.3390/molecules25214882

Dufour, G. et al. (2015) Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide. International Journal of Pharmaceutics 495(2), 869-878. https://doi.org/10.1016/j.ijpharm.2015.09.052

Hu, X. et al. (2019) Nanoporous CD-MOF particles with uniform and inhalable size for pulmonary delivery of budesonide. International Journal of Pharmaceutics 564, 153-161. https://doi.org/10.1016/j.ijpharm.2019.04.030

Kinnarenen, T. et al. (2003) Pulmonary deposition of a budesonide/γ-cyclodextrin complex in vitro. Journal of Controlled Release 90(2), 197-205. https://doi.org/10.1016/S0168-3659(03)00176-7

Parsian, A.R. et al. (2014) Inhalable budesonide porous microparticles tailored by spray freeze drying technique. Powder Technology 260, 36-41. https://doi.org/10.1016/j.powtec.2014.03.043

Ramakrishnan, S. et al. (2021) Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021 Apr 9
doi: 10.1016/S2213-2600(21)00160-0 [Epub ahead of print]