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Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder

Saha et al., Pharmaceutics, doi:10.3390/pharmaceutics14071432
Jul 2022  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
 
*, now known with p < 0.00000000001 from 103 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,100+ studies for 60+ treatments. c19ivm.org
Development and analysis of an inhalable dry powder formulation of ivermectin. Authors optimized the formulation to have good aerosolization properties for lung delivery. The powder maintained ivermectin's ability to inhibit SARS-CoV-2 replication in cells, demonstrating its potential as an inhaled antiviral therapeutic.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, shows dose-dependent inhibition of wildtype and omicron variants Shahin, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, inhibits SARS-CoV-2 3CLpro Mody, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages Gao, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
7 studies investigate novel formulations of ivermectin for improved efficacy Albariqi, Albariqi (B), Chaccour, Errecalde, Mansour, Mohammed, Saha (B)
Saha et al., 8 Jul 2022, peer-reviewed, 5 authors. Contact: shyamal.das@otago.ac.nz (corresponding author), tushar.saha@postgrad.otago.ac.nz, shubhra.sinha@otago.ac.nz, rhodri.harfoot@otago.ac.nz, miguel.quinones-mateu@otago.ac.nz.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder
Tushar Saha, Shubhra Sinha, Rhodri Harfoot, Miguel E Quiñones-Mateu, Shyamal C Das
Pharmaceutics, doi:10.3390/pharmaceutics14071432
SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 2 3 factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 • C and 100 • C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1-5 µm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 • C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 • C/<15% RH and 25 ± 2 • C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC 50 values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract.
Conflicts of Interest: The authors declare no conflict of interest.
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{ 'DOI': '10.3390/pharmaceutics14071432', 'ISSN': ['1999-4923'], 'URL': 'http://dx.doi.org/10.3390/pharmaceutics14071432', 'abstract': '<jats:p>SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory ' 'tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting ' 'the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved ' 'anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit ' 'at relatively high concentrations, which is difficult to achieve in the lung. In this study, ' 'we tested the spray-drying conditions to develop an inhalable dry powder formulation that ' 'could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the ' 'lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a ' 'proof-of-concept, we evaluated spray-drying conditions that could lead to the development of ' 'antivirals in an inhalable dry powder formulation, which could then be used to ensure ' 'sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle ' 'experiments to evaluate our system, including physical characterization and in vitro ' 'aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini ' 'spray-dryer (Buchi B-290), using a 23 factorial design and manipulating spray-drying ' 'conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and ' '100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the ' 'size range of 1–5 μm and amorphous in nature with wrinkle morphology. We observed a higher ' 'fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet ' 'temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted ' 'for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/&lt;15% RH and 25 ± ' '2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 ' 'replication in vitro with a potency similar to ivermectin solution (EC50 values of 15.8 µM ' 'and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In ' 'summary, we were able to manipulate the spray-drying conditions to develop an effective ' 'ivermectin inhalable dry powder. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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