Development of an inhalable antiviral powder formulation against respiratory syncytial virus

Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respi...

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Veröffentlicht in:Journal of controlled release 2023-05, Vol.357, p.264-273
Hauptverfasser: Heida, Rick, Akkerman, Renate, Jacob Silva, Paulo H., Lakerveld, Anke J., Ortiz, Daniel, Bigogno, Chiara, Gasbarri, Matteo, van Kasteren, Puck B., Stellacci, Francesco, Frijlink, Henderik W., Huckriede, Anke L.W., Hinrichs, Wouter L.J.
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container_end_page 273
container_issue
container_start_page 264
container_title Journal of controlled release
container_volume 357
creator Heida, Rick
Akkerman, Renate
Jacob Silva, Paulo H.
Lakerveld, Anke J.
Ortiz, Daniel
Bigogno, Chiara
Gasbarri, Matteo
van Kasteren, Puck B.
Stellacci, Francesco
Frijlink, Henderik W.
Huckriede, Anke L.W.
Hinrichs, Wouter L.J.
description Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflicted morbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection. [Display omitted] •The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler.
doi_str_mv 10.1016/j.jconrel.2023.03.059
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Entry inhibitors are a promising class of antiviral drugs for combating these viruses, as they can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrum entry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate (CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans (HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteins through a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated when administered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powder formulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops dry powder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activity against RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring the efficacy of pulmonary administered CD-MUS in animal models of RSV infection. [Display omitted] •The novel antiviral entry inhibitor CD-MUS is well-tolerated in vivo.•CD-MUS shows suitable pharmacokinetic behavior after pulmonary administration.•CD-MUS can successfully be formulated into an inhalable dry powder formulation.•CD-MUS retains its activity against respiratory syncytial virus after spray drying.•CD-MUS is well dispersed from the Cyclops dry powder inhaler.</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2023.03.059</identifier><identifier>PMID: 37015293</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Administration, Inhalation ; Animals ; Antiviral Agents - pharmacology ; Antiviral Agents - therapeutic use ; Broad-spectrum ; class ; dose response ; Dry powder inhalation ; Dry Powder Inhalers ; Entry inhibitor ; heparan sulfate ; lungs ; mortality ; Powders - therapeutic use ; proteoglycans ; Pulmonary drug delivery ; Respiratory syncytial virus ; Respiratory Syncytial Virus Infections - drug therapy ; Respiratory Syncytial Viruses - metabolism ; Spray drying ; Viral Proteins - metabolism</subject><ispartof>Journal of controlled release, 2023-05, Vol.357, p.264-273</ispartof><rights>2023 The Authors</rights><rights>Copyright © 2023 The Authors. 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subjects Administration, Inhalation
Animals
Antiviral Agents - pharmacology
Antiviral Agents - therapeutic use
Broad-spectrum
class
dose response
Dry powder inhalation
Dry Powder Inhalers
Entry inhibitor
heparan sulfate
lungs
mortality
Powders - therapeutic use
proteoglycans
Pulmonary drug delivery
Respiratory syncytial virus
Respiratory Syncytial Virus Infections - drug therapy
Respiratory Syncytial Viruses - metabolism
Spray drying
Viral Proteins - metabolism
title Development of an inhalable antiviral powder formulation against respiratory syncytial virus
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