Formulations for COVID-19 Early Stage Treatment via Silver Nanoparticles Inhalation Delivery at Home and Hospital

Objectives : For suppressing both viral and bacterial respiratory infections, we investigate the possibility of obtaining real effective minimal inhibitory concentration (MIC) of silver nanoparticles in various respiratory system target locations. Applications include (i) control local outbreaks of COVID-19 via early stage home treatment, and (ii) lower the risk of ventilator associated pneumonia (VAP) in hospital ICU. Our prime objective is to propose a first line intervention measure with the potential to suppress proliferation of the viral infection across the respiratory system, thereby giving more time for proper immune system response and lowering the risk for aggravation and spread of the infection. We further discuss the available credible evidence for human safety consideration, by inhalation delivery, for facilitating immediate clinical trials. In addition, we discuss possible manufacturing and commercial availability of the method elements for near term wide public usage. Method : Based on previously published experimental data, on the antiviral effectiveness of colloidal silver, we propose a model method and computation for achieving antiviral MIC of silver particles in various respiratory system locations, by: (a) analysing the nanoparticle size dependent required concentration. (b) computing the required aerosol delivery characteristics. In order to compute the require delivery dosage, we take into account deposition fraction losses and also inhalation time fraction of the normal breathing cycle. We evaluate independent targeting of: (i) the trachea-bronchial tree (mucus volume of about 1cc), and (ii) the alveoli (total mucus volume of about 10cc). Results : The dosage is highly sensitive to the silver nanoparticle size, with 3nm - 7nm being the optimal size. Effective antibacterial MIC 10 μg/ml is estimated, but for more certainty 25 μg/ml is a reasonable target concentration to achieve in the mucus fluid of the respiratory system. In particular, using colloidal silver of 5nm particles, delivering inhalation of standard 5μ diameter droplets aerosol (e.g., using off-the-shelf ultrasonic mesh nebulizers), we assert that sufficient MIC can be achieved with: (i) depositing a total of just 0.25cc of a 100ppm (μg/ml) source concentration in the bronchial tree, and (ii) depositing a total of 1cc of a 250ppm (μg/ml) source concentration in the lungs alveoli. Yet, after accounting for deposition losses and due to the fact that active inhalation time is just about 1/3 of the breathing cycle, we find that that practical effective MIC can be achieved by these aerosolising dosages: (a) for the upper airways and bronchial tree use 2cc of a 100 μg/ml colloidal silver source, while (b) for lungs alveoli delivery use 6cc of a 200 μg/ml colloidal silver source. This would be reduced by a factor 3 if a breath actuated ultrasonic nebulizer is used. Conclusions : We conclude that effective MIC is achievable, both in the bronchial tree and in the alveoli (though the specific aerosol prescription may differ). Since respiratory infections start most commonly in the upper airways, it would be best to use the presented method early on as a first line treatment to suppress the progression of the infection. The required formulations are presently not available on the market but are easy to mass produce OTC in principle. Using off-the-shelf ultrasonic nebulizers and providable OTC colloidal silver formulations, we posit that our suggested method can be used precautionarily at home by anyone feeling the early signs of a potential infection. In addition, due to the anti-bacterial properties of colloidal silver, our method can serve in hospital intensive care units (ICU) as a new standard of care prophylactic treatment for ventilator acquired pneumonia (VAP).

Content

Author and article information

Journal

Title: ScienceOpen Preprints

Publisher: ScienceOpen

Publication date (Electronic preprint): 28 March 2020

Affiliations

[1 ] Yamor Technologies Ltd.

Author information

Oron Zachar https://orcid.org/0000-0003-0700-498X

Article

DOI: 10.14293/S2199-1006.1.SOR-.PPHBJEO.v1

SO-VID: e26cd100-4b89-4624-b4b0-d2e544e8923b

License:

This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

History

Date received : 28 March 2020

Data availability: Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

ScienceOpen disciplines: Respiratory medicine,Pharmacology & Pharmaceutical medicine,Infectious disease & Microbiology

Keywords: Nanoparticles,ICU,Treatment,VAP,covid-19,Inhalation,Silver,SARS-CoV-2,Pneumonia

Comments

Raphael Levy wrote:

A peer review should focus on the content but here it is necessary to comment on the single author of this preprint. This is his first article or preprint that has anything to do with biology or chemistry. The last article he published dates from more than 15 years ago and deals with theoretical physics. He has no academic affiliation but he is CEO of two companies. The one he uses to sign the article does not seem to have any existence beyond his profile (according to a Google search). The other one, Biovo technologies, develops/sells “groundbreaking medical devices […]” and its “premier product line – Airway Medix – presents a line of disposable respiratory devices used for mechanically ventilated patients.” In spite of this, there is no conflict of interest declaration in the preprint.

The article itself makes the case for starting clinical trials consisting in injecting large amounts of silver nanoparticles by inhalation in Covid-19 patients. There is no preclinical work to support this. The in vitro work, from the literature, is on other viruses, and is of poor quality, often in completely artificial and unrealistic models. There is simply no reliable evidence or efficacy model to support exploring this route. The model – if I can use this word - shown in figure 5 is completely naïve.

In general, and particularly in a time of pandemic, sharing articles that make unsupported recommendations for therapeutic interventions is highly problematic. Whilst preprint servers have a role to play in accelerating the circulation of information, there is also a risk that they contribute to amplify bad science noise (at best) or even cause harm (at worst).

2020-04-22 11:31 UTC

2 people recommend this

Oron Zachar wrote:

Under the request of the journal editor, the detailed response below is coupled with an updated version of the article (dated 2020/May/28).

The field of colloidal silver (potential) therapy is indeed unfortunately plagued by commercial unscientific claims. The review itself does not provide any substantial technical claims. But we will still treat it seriously and take this opportunity to (i) improve some aspect of the article, (ii) prevent similar superficial reviewing in the future, and (iii) address the noted issues constructively.

1. The reviewer presents my position as CEO of a medical device company as a negative or irrelevant. For removal of any doubt, I will clarify: In the past 10 years I have been the founder and CEO of a medical device company developing hospital intensive care products for prevention of ventilator associated pneumonia (VAP) infection. In this context, I have initiated and designed animal trials, clinical trials, bacterial biofilm analysis, FDA/CE registration of medical products, and exhibited repeatedly at the annual meetings of the American Association for Respiratory Care (AARC). My personal research output in this context was expressed not in journal articles but in published, examined and approved medical device patents (some of which can be viewed on my ResearchGate profile).

2. The reviewer`s statement “There is simply no reliable evidence or efficacy model to support exploring this route [for starting clinical trials]….” is based on just his personal opinion that “The invitro work, from the literature, is on other viruses, and is of poor quality”. i.e., he criticizes my quoted references as of “poor quality” science. In response, (i) I added new references of work on Corona type viruses which were not in the original version. (ii) My most key references are by (a) H.H Lara & M.J. Yacaman, from University of Texas San Antonio [ref#5,9] ; (b) Dongxi Xiang, from Harvard Medical School [ref#27] ; (c) Chunying Chen, from the National Center for Nanoscience and Technology Beijing [ref#24]. The reviewer throws unsubstantiated dismissive adjectives. If the reviewer has some scientifically based negative statements to make about these references – We will be thankful to receive them and be appreciative of his insights.

3. The reviewer states his expert opinion that “The model …. is completely naïve”. The reviewer`s academic record does not show knowledge or experience about inhalation drug delivery. Yet, we don`t blame him for being unknowledgeable of the subject. We recognize that antimicrobial inhalation delivery is a very specialized domain which even most pharmacologists are not familiar with (if one is not involved with intensive care pneumonia research or CF treatment). Our model is in line with the cutting edge of inhalation drug delivery modelling, as elaborated particularly in reference [21] of our article. Indeed, in retrospect, we realized the need to explain in more approachable manner the core knowledge and assumptions that go into the model calculations. Hence, in the updated posting of the article, we expanded both the beginning of the “Formulation Calculation” section and the “Achieving IC at Target Airway Surface Liquid” section. We also added a new Figure-1 and two new references [38,39].

4. The reviewer comment that “there is no conflict of interest declaration in the preprint”. In response, in our updated article posting, we added a conflict of interest statement.

5. To end, the reviewer worries about “… in a time of pandemic, ….. make unsupported recommendations for therapeutic interventions is highly problematic… etc…”. To clarify, our article states clearly that its purpose is the planning of clinical trials.

Altogether, we thank the reviewer for stimulating our improved exposition in the updated post of the article.

2020-05-28 14:28 UTC