Nanoformulated Remdesivir with Extremely Low Content of Poly(2‐oxazoline)‐Based Stabilizer for Aerosol Treatment of COVID‐19
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Abstract
The rise of the novel virus SARS‐CoV2 which causes the disease known as COVID‐19 has led to a global pandemic claiming millions of lives. With no clinically approved treatment for COVID‐19, physicians initially struggled to treat the disease, and a need remains for improved antiviral therapies in this area. It is conceived early in the pandemic that an inhalable formulation of the drug remdesivir which directly targets the virus at the site of infection could improve therapeutic outcomes in COVID‐19. A set of requirements are developed that would be conducive to rapid drug approval: 1) try to use GRAS reagents 2) minimize excipient concentration and 3) achieve a working concentration of 5 mg/mL remdesivir to obtain a deliverable dose which is 5–10% of the IV dose. In this work, it is discovered that Poly(2‐oxazoline) block copolymers can stabilize drug nanocrystal suspensions and provide suitable formulation characteristics for aerosol delivery while maintaining antiviral efficacy. The authors believe POx block copolymers can be used as a semi‐ubiquitous stabilizer for the rapid development of nanocrystal formulations for new and existing diseases.
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SciScore for 10.1101/2022.01.21.477258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources The A549 cells expressing Ace2 (A549-Ace2) were seeded at 1 × 104 cells/well in black walled clear bottom 96 well plates the day prior to treatment and infection. A549suggested: NoneSoftware and Algorithms Sentences Resources Equation 2: GSD = [% mass of distribution at D84/% mass of distribution at D16]0.5 1H-NMR of Polymers: 1H-NMR spectra were recorded on an INOVA 400 at room temperature. Polymerssuggested: NoneResults from OddPub: We did not detect open data. We …
SciScore for 10.1101/2022.01.21.477258: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources The A549 cells expressing Ace2 (A549-Ace2) were seeded at 1 × 104 cells/well in black walled clear bottom 96 well plates the day prior to treatment and infection. A549suggested: NoneSoftware and Algorithms Sentences Resources Equation 2: GSD = [% mass of distribution at D84/% mass of distribution at D16]0.5 1H-NMR of Polymers: 1H-NMR spectra were recorded on an INOVA 400 at room temperature. Polymerssuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:However, the bottom-up approach has its limitations. Namely, it can be more difficult to control crystal growth and produce small, monodisperse nanocrystals27,35. If successful, an inhalable formulation of Remdesivir could produce higher Remdesivir concentrations at the site of disease without increasing systemic toxicity, which could potentially improve therapeutic outcomes in COVID-19. Indeed, there are several recent examples of nebulized treatments for COVID-19, some of which have entered clinical trials ([NCT05116865],[NCT04578236],[NCT04381364]). For example, Gilead has attempted to bring an inhaled formulation of Remdesivir to market [NCT04480333]. Their inhalable formulation is identical to their formulation designed for IV administration, utilizing SBECD at a 30:1 weight ratio to solubilize Remdesivir. The MMAD of the formulation was 2.7 um, and in a non-human primate model, they utilized a delivered dose (deposited in the lungs) of 0.35 mg/kg (over 60 minutes) to achieve lung concentrations of Remdesivir comparable to the 10 mg/K IV dose24. Thus, our initial assumption that dosing at 5-10% of the IV dose would be adequate was correct. Additionally, they utilized a Pari LC Plus nebulizer, which is of comparable design to our Nebutech 8960. Our approach delivers 7-9% of the formulation suspension concentration in “respirable particles” (<5 μm). In 10 kg non-human primates, we would require a dose of roughly 3.5 mg. We estimate that this dose could be delivered from ou...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT05116865 Not yet recruiting A Study to Assess the Safety, Tolerability and Pharmacokinet… NCT04578236 Not yet recruiting Efficacy of Aerosol Combination Therapy of 13 Cis Retinoic A… NCT04381364 Recruiting Inhalation of Ciclesonide for Patients With COVID-19: A Rand… NCT04480333 Recruiting Safety, Tolerability and Pharmacokinetics of Inhaled Nanopar… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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